How can autoimmunity be selective?

How can autoimmunity be selective?

We are searching data for your request:

Forums and discussions:
Manuals and reference books:
Data from registers:
Wait the end of the search in all databases.
Upon completion, a link will appear to access the found materials.

Vitiligo is a skin disorder where the pigment disappears. More on Wikipedia. This is believed to be caused by autoimmunity and has made me interested in autoimmunity in general. I am still very much a layman, however.

One of the characteristics of vitiligo is that it is uneven. Some patches of skin look normal, others are completely albino-like.

If the immune system has decided that skin pigment is an enemy, why doesn't it destroy all the skin pigment?

I understand that little is known about vitiligo, so I will accept answers describing similar effects in other autoimmune disorders.

How can autoimmunity be selective? - Biology

Immunodeficiency occurs when the immune system cannot appropriately respond to infections.

Learning Objectives

Explain the problems associated with immunodeficiency

Key Takeaways

Key Points

  • If a pathogen is allowed to proliferate to certain levels, the immune system can become overwhelmed immunodeficiency occurs when the immune system fails to respond sufficiently to a pathogen.
  • Immunodeficiency can be caused by many factors, including certain pathogens, malnutrition, chemical exposure, radiation exposure, or even extreme stress.
  • HIV is a virus that causes immunodeficiency by infecting helper T cells, causing cytotoxic T cells to destroy them.

Key Terms

  • phagocyte: a cell of the immune system, such as a neutrophil, macrophage or dendritic cell, that engulfs and destroys viruses, bacteria, and waste materials
  • lysis: the disintegration or destruction of cells
  • immunodeficiency: a depletion in the body’s natural immune system, or in some component of it


Failures, insufficiencies, or delays at any level of the immune response can allow pathogens or tumor cells to gain a foothold to replicate or proliferate to high enough levels that the immune system becomes overwhelmed, leading to immunodeficiency it may be acquired or inherited. Immunodeficiency can be acquired as a result of infection with certain pathogens (such as HIV), chemical exposure (including certain medical treatments), malnutrition, or, possibly, by extreme stress. For instance, radiation exposure can destroy populations of lymphocytes, elevating an individual’s susceptibility to infections and cancer. Dozens of genetic disorders result in immunodeficiencies, including Severe Combined Immunodeficiency (SCID), bare lymphocyte syndrome, and MHC II deficiencies. Rarely, primary immunodeficiencies that are present from birth may occur. Neutropenia is one form in which the immune system produces a below-average number of neutrophils, the body’s most abundant phagocytes. As a result, bacterial infections may go unrestricted in the blood, causing serious complications.


Human immunodeficiency virus infection / acquired immunodeficiency syndrome (HIV/AIDS), is a disease of the human immune system caused by infection with human immunodeficiency virus (HIV). During the initial infection, a person may experience a brief period of influenza-like illness. This is typically followed by a prolonged period without symptoms. As the illness progresses, it interferes more and more with the immune system. The person has a high probability of becoming infected, including from opportunistic infections and tumors that do not usually affect people who have working immune systems.

Image of HIV: scanning electron micrograph of HIV-1 budding (in green, color added) from cultured lymphocyte: Multiple round bumps on cell surface represent sites of assembly and budding of HIV. During primary infection, the level of HIV may reach several million virus particles per milliliter of blood.

After the virus enters the body, there is a period of rapid viral replication, leading to an abundance of virus in the peripheral blood. During primary infection, the level of HIV may reach several million virus particles per milliliter of blood. This response is accompanied by a marked drop in the number of circulating CD4+ T cells, cells that are or will become helper T cells. The acute viremia, or spreading of the virus, is almost invariably associated with activation of CD8+ T cells (which kill HIV-infected cells) and, subsequently, with antibody production. The CD8+ T cell response is thought to be important in controlling virus levels, which peak and then decline, as the CD4+ T cell counts recover.

Ultimately, HIV causes AIDS by depleting CD4+ T cells (helper T cells). This weakens the immune system, allowing opportunistic infections. T cells are essential to the immune response without them, the body cannot fight infections or kill cancerous cells. The mechanism of CD4+ T cell depletion differs in the acute and chronic phases. During the acute phase, HIV-induced cell lysis and killing of infected cells by cytotoxic T cells accounts for CD4+ T cell depletion, although apoptosis (programmed cell death) may also be a factor. During the chronic phase, the consequences of generalized immune activation coupled with the gradual loss of the ability of the immune system to generate new T cells appear to account for the slow decline in CD4+ T cell numbers.


The immune system is a complex set of organs, cells, proteins and other substances that function to prevent infection. Primary immunodeficiency diseases are characterized by abnormalities in specific components of the immune system that lead to an increased susceptibility to infection. Many times, abnormalities in the immune system that lead to primary immunodeficiency diseases also result in immune dysregulation, which is an immune response that is not properly controlled or restrained. This can lead to autoimmunity, one form of immune dysregulation in which the immune response is directed against normal parts of the body such as cells, tissues or organs (called auto-antigens). Put another way, it is when the immune system attacks the body in which it resides.

Definition of Autoimmunity in Primary Immunodeficiency

A normal immune system makes proteins known as antibodies that recognize and prevent foreign organisms (bacteria, viruses) from causing infection. One common type of autoimmunity is when the immune system makes antibodies against normal cells and/or tissues of the body which are known as “autoantibodies.” Sometimes people with primary immunodeficiency diseases cannot make “good” antibodies to protect against infection but only make “bad” autoantibodies, which then cause autoimmune disease. Sometimes these antibodies themselves are harmless but suggest the presence of an autoimmune disease. In other autoimmune diseases, the cellular immune system may also react against a body’s auto-antigens.

One of the ironies of this situation is that the treatment for autoimmune conditions is the use of immune suppression to shut down the inappropriate immune response that is causing the problem. Obviously, using immunosuppressive treatment in a patient already afflicted with immunodeficiency involves a complex balancing act to avoid unwanted infections and other serious side effects while still using sufficient immunosuppressive treatment to control the autoimmune process. It is recommended to use a team approach when using immunosuppressive treatment, joining the skills of the immunologist with those of a specialist in treating the organ system involved, be it gastroenterology, rheumatology, pulmonology, endocrinology, nephrology, dermatology or hematology.

Autoimmune complications have been reported in a wide range of primary immunodeficiency diseases. However, certain primary immunodeficiency diseases have autoimmune disease as their primary problem. These include Autoimmune Polyendocrinopathy Candidiasis Ectodermal Dysplasia (APECED or APS-1) Autoimmune Lymphoproliferative Syndrome (ALPS) and Immune dysregulation Polyendocrinopathy, Enteropathy, and X-linked (IPEX) syndrome.

Certain other immune disorders are frequently associated with autoimmune complications. These include Common Variable Immune Deficiency (CVID), Wiskott-Aldrich Syndrome (WAS), IgA deficiency, Good Syndrome, Hyper IgM Syndrome, Idiopathic T-cell Lymphopenia (ICL) and Complement disorders. Most of these diseases are discussed in greater detail in other chapters. The focus of this chapter is to provide an overview of the types of immune dysregulation and autoimmunity that can occur in various primary immunodeficiency diseases.

Autoimmune Cytopenias

The development of autoantibodies that bind to and destroy blood cells is the most common autoimmune disease seen in primary immunodeficiency diseases. The blood cells affected are the red blood cells (RBCs), platelets and white blood cells (WBCs).

Red Blood Cells

The RBCs carry oxygen to the body’s tissues. Oxygen is necessary for the body’s tissues to perform their function. Anemia is the term used to describe a low number of RBCs. Autoantibodies against the RBCs can cause destruction of these cells and is called autoimmune hemolytic anemia (AIHA).

Symptoms associated with AIHA include fatigue, headache, dizziness, fainting and poor exercise tolerance. The person sometimes looks pale. In severe cases the individual can develop a yellow discoloration to the skin and eyes known as jaundice. The spleen may become enlarged as it traps the damaged red blood cells. The body tries to compensate for the decreased capacity to carry oxygen by working the lungs and heart harder.


Injuries to the tissues can cause bleeding. Platelets help create blood clots to stop bleeding. A low number of platelets is called thrombocytopenia. When autoantibodies are formed against the platelets and cause thrombocytopenia, it is known as idiopathic thrombocytopenic purpura (ITP). ITP can cause abnormal bleeding. Patients frequently notice increased bruising, sometimes in unusual areas or without known trauma to the area. They may develop a pinpoint red rash caused by small hemorrhages called petechiae. They may notice nosebleeds that are more frequent and difficult to resolve. The gums may bleed easily. The urine may have an orange, pink or red color. Stools may appear black and tarry, which can indicate bleeding in the intestinal tract. Rarely, bleeding in the brain can cause altered mental status or death.

White Blood Cells

There are many different types of WBCs. Neutrophils are WBCs that have a major role in responding to infections. A low number of neutrophils is called neutropenia. Autoimmune neutropenia (AIN) occurs when antibodies are produced against neutrophils.

The most significant symptom associated with AIN is fever, as this may indicate a serious infection. Other signs of infection such as cough, vomiting, diarrhea and rash may also be present. Serious infections can progress rapidly in people with AIN, and they may require evaluation in the emergency room or admission to the hospital. Antibiotic therapy is urgently needed in these cases. Patients with AIN may also have ulcers or sores develop in the mouth, esophagus or intestine. The gums may also become inflamed and red.

Diagnosis of Autoimmune Cytopenias

Autoimmune cytopenias are diagnosed with blood tests. Typically, a simple blood count is the blood test performed to establish the presence of a cytopenia. Additional blood tests can determine whether an autoantibody is present. A specialist such as a clinical immunologist, hematologist or oncologist typically evaluates patients for these disorders. Sometimes a bone marrow sample needs to be obtained to determine whether there is a problem with production of blood cells.

Treatment of Autoimmune Cytopenias

Autoimmune cytopenias may be temporary and require little to no treatment. If treated, the goal of therapy is to remove the autoantibodies and let the body replenish the blood cells. Several treatments have been used including intravenous immunoglobulin (IVIG), steroids, chemotherapy drugs and drugs such as anti-CD20, which is used to specifically deplete B-cells that produce antibodies. The therapy that is best for a particular patient is based on many factors. Autoimmune cytopenias often respond well to therapy. At times however, symptoms may recur or may require long-term treatment. Patients rarely require blood transfusions except in extreme circumstances. In all cases, patients with cytopenias require close follow-up by their specialist.

Most patients can be treated successfully and have no major restrictions on their daily activities. However patients with chronically low platelet counts may have to refrain from activities with a higher risk of injury such as contact sports.

Autoimmune Lung Disease

There are multiple causes of lung disease in patients with primary immunodeficiency diseases, including infection, malignancy and autoimmunity. Differentiating between these can be difficult. In most cases of lung disease, the autoimmunity is not due to formation of an antibody, but an abnormal accumulation of white blood cells in the lung tissues, causing inflammation and damage. Sometimes white blood cells accumulate in a specific part of the lung known as the interstitium. This is called interstitial lung disease and interferes with the ability of oxygen to be absorbed into the bloodstream.

Some patients with certain types of primary immunodeficiency diseases develop aggregates of immune cells called granulomas in the lung. Granulomas are sometimes formed in an attempt to contain an infection that cannot be resolved or because the immune cells are not being regulated properly, a situation that sometimes occurs in primary immunodeficiency diseases. Two primary immunodeficiency diseases that often have granulomas in the lung are Chronic Granulomatous Disease (CGD) and CVID. Patients with CVID sometimes develop both interstitial lung disease and granulomas in the lung. This disease is called Granulomatous Lymphocytic Interstitial Lung Disease (GLILD). Occasionally, patients with Ataxia-Telangiectasia and APECED also develop interstitial lung disease. At times, the inflammation caused by granulomas and/or the accumulation of white blood cells in the interstitium of the lung can be so severe and persistent that fibrosis, or scarring, develops in the lung.


In most cases, the symptoms of interstitial lung disease develop slowly over time. Patients with CGD will usually have a more acute onset as they have a persistent infection causing the lung inflammation. Patients may notice a decrease in their endurance with everyday activities. They may find themselves having to cut back on exercise such as biking or running. These changes are often attributed to other causes, which may delay the diagnosis of the lung disease itself. Patients often complain of a cough, which is usually non-productive. Enlargement and rounding of the toenails and fingernails can be seen and is termed clubbing. Clubbing is not specific to primary immunodeficiency diseases or to lung damage but is a clue that the lungs should be evaluated. In some cases, the lung damage can lead to a severe lowering of blood oxygen causing patients to have a bluish tint to their skin or mucous membranes known as cyanosis. Fever is not a typical finding, unless infection is also present. On the lung exam, a practitioner may hear abnormal breath sounds such as crackles, wheezes or a decrease in the amount of air moving in and out of the lung with breathing. Often these symptoms lead to the incorrect diagnosis of asthma or a lung infection by physicians not familiar with autoimmune lung diseases in primary immunodeficiency diseases.

Diagnosis of Pulmonary Complications

Radiology tests can be helpful in identifying lung problems. Chest X-rays are useful for diagnosing infections (pneumonia). However, a chest X-ray can sometimes be normal, even when there is still significant lung disease present. A chest CT scan can frequently pick up abnormalities not seen on a routine chest X-ray. In patients with CVID and GLILD, changes on the chest CT scan will often appear before the patient exhibits symptoms.

Breathing tests, called pulmonary function tests (PFTs), can indicate the degree of lung impairment. There are changes in PFTs that can be found in interstitial lung disease and other types of lung disease. However, patients often must lose a significant amount of lung function to demonstrate symptoms that prompt ordering of the PFTs.

In some cases, a lung biopsy is needed to make the correct diagnosis and define the correct treatment course. A lung biopsy is a surgical procedure usually done by making a small incision in the chest and inserting a small scope and instruments to obtain a piece of lung tissue. The biopsy is evaluated by a pathologist, a doctor who performs a variety of tests on the lung tissue including a microscopic examination. The tests performed by the pathologist can determine the specific type of lung disease that is present (for example, cancer, infection, interstitial lung disease, granuloma).


Patients with malignancies are referred to an oncologist (cancer doctor) for continuing care. Patients with infections are treated with antibiotics. Inflammatory changes in the lung are usually treated with immunosuppressant drugs that suppress or alter the immune system. The most common medicine used is corticosteroids (like prednisone), which can be given by inhalation, orally or intravenously (IV). Steroids can be effective, but sometimes may not provide long-term improvement. Prolonged oral or IV steroid use is associated with significant side effects such as high blood pressure, high blood sugar, osteopenia (weak bones), hyperlipidemia (high cholesterol), and stress on the kidney and eyes. Other immune suppressive medicines such as cyclosporine and Sirolimus are sometimes helpful. Some types of lung disease respond to one type of immunosuppressant medication but not another. IVIG can sometimes improve the inflammation in the lungs in addition to other drugs.

Without treatment, interstitial lung disease can progress and cause permanent lung damage. Fibrosis (scarring), which is the end result of chronic untreated inflammation, cannot be reversed. It is very important that your doctor has the correct diagnosis of your specific lung disease and expertise in treating the specific disorder in order to insure the best outcome.

Autoimmune Skin Disease

Skin conditions due to autoimmunity or immune dysregulation are not unique to people with primary immunodeficiency diseases. Common skin conditions like eczema or psoriasis are seen in people with normal immune systems as well. Sometimes, skin disease is one of the earliest symptoms of a primary immunodeficiency disease and can lead to further clinical or laboratory evaluation to identify immune deficiency. In addition to skin disorders that are autoimmune or inflammatory in nature, other abnormal skin manifestations, such as dry, sparse hair, abnormally formed teeth and fingernails, and absent sweat glands, can be seen in certain primary immunodeficiency diseases but are not due to autoimmunity, and these will not be covered in detail here.


Eczema, also known as atopic dermatitis, is generally a mild skin disease and is the most common skin disease in primary immunodeficiency diseases. Often referred to as “the itch that rashes,” eczema typically begins as patches of dry, itchy skin which worsen and erupt into rash as they are scratched. It is not unusual for patients with primary immunodeficiency diseases who have other autoimmune manifestations to also have eczema. Some primary immunodeficiency diseases are, however, associated with more severe eczema. These include WAS, Hyper-IgE Syndrome (HIES), IPEX syndrome, and certain forms of Severe Combined Immune Deficiency (SCID). In these disorders, the eczema may be quite resistant to typical therapies.


Psoriasis is another type of autoimmune skin disease that is more severe than eczema. Psoriasis plaques are typically red, raised, itchy and painful. They are characterized by the presence of a silvery scale on the surface of the plaques that often bleeds if it is removed. Plaques of psoriasis occur most frequently on the scalp or on the elbows or knees. It occurs most frequently in patients with CVID but can also be seen in IPEX and occasionally in other primary immunodeficiency diseases.

Hair and Skin Pigmentation Changes

Multiple primary immunodeficiency diseases can have autoimmunity that affects the hair and skin pigment. Some patients develop alopecia, or patches of baldness as a result of autoantibodies against hair producing cells. Alopecia areata refers to round circular areas of hair loss. Some patients also develop vitiligo, or loss of the pigment in the skin. The affected area of skin will appear white in color. The contrast of the surrounding skin will determine how apparent the change is. The affected areas often change somewhat over time. Vitiligo and alopecia are most commonly associated with APECED, CVID, IPEX and T-cell disorders such as 22q11 deletion (Di George) syndrome although they can develop in a wide range of primary immunodeficiency diseases.

Diagnosis of Skin Diseases

Most of the time, a knowledgeable healthcare provider can diagnose skin disorders just by physical exam. If a rash is unusual, however, a skin biopsy is sometimes needed to determine what type of rash it is. Biopsies are typically taken from the area where the rash is most evident using a sharp “punch” that cuts and removes a small circular core of skin tissue that can be evaluated microscopically by a pathologist to determine what type of rash it is. This is typically a very minor procedure that can be done in the office with local numbing of the skin.


While not typically life threatening, autoimmune and inflammatory disorders of the skin can lead to significant emotional consequences and in rare situations can lead to permanent disfigurement. Because the skin plays an important role as a barrier to bacteria and other organisms from the environment, severe rashes like eczema may serve as an entry point to the bloodstream for bacteria from the skin.

Mild skin conditions can be diagnosed and treated by a primary care provider or an Immunologist but more severe skin conditions often require diagnosis and treatment by a dermatologist. Treatment for most conditions typically begins with local application of moisturizing lotions and steroid ointments directly to the rash. If this is not sufficient to control the symptoms, ointments containing more potent steroids or other immunosuppressant medications can be applied. In rare cases, oral or IV immunosuppressant medications may be needed to treat severe disease.

Autoimmune Gastrointestinal Disease

Autoimmune gastrointestinal diseases are common among patients with primary immunodeficiency diseases, particularly patients with CVID, CGD, IPEX, X-linked Agammaglobulinemia (XLA), APECED, WAS, Omenn syndrome, NEMO deficiency and others. This is likely due to the fact that the intestines are constantly bathed in bacteria, bacterial products and food, which all have the potential to cause irritation of the intestinal lining (the mucosa). As a result, the immune system plays a particularly important role in maintaining the barrier function of the intestines and in protecting the body from invasion by the bacteria present in the bowel.

Mucosal Changes

Autoimmune or inflammatory diseases of the gastrointestinal tract can disrupt the mucous membranes that line the mouth, esophagus, stomach, and intestines. This can cause a variety of symptoms including: geographic tongue, an abnormal appearance of the tongue that can be mistaken for an oral yeast infection (thrush) gingivitis or inflammation of the gums oral ulcers or canker sores abdominal pain diarrhea that may be watery or bloody an urgency to stool after eating and weight loss despite a reasonable diet. Similar symptoms can also be present in patients with primary immunodeficiency diseases who have bowel infections with organisms such as Giardia, Cryptosporidium or Clostridium difficile. Because both autoimmune and infectious complications can lead to serious problems in patients with primary immunodeficiency diseases, it is important that new gastrointestinal symptoms be evaluated (see next page) when they arise. In rare cases, ongoing gastrointestinal symptoms can be a sign of cancer in the bowel, which is more common in some types of primary immunodeficiency diseases than in the general population. 

Liver Inflammation

The liver is part of the gastrointestinal system and plays many important roles in the normal function of the body. Among the most important are: the metabolism of nutrients absorbed from the intestines, the production of important blood proteins such as clotting factors, the metabolism of drugs and other toxic molecules present in the blood, and the removal of waste products from the blood and excretion of these into the bile. Autoimmune or inflammatory disease of the liver, which can occur in primary immunodeficiency diseases, can cause temporary or permanent damage that can disrupt one or more of the liver’s important functions. This may lead to accumulation of fluid in the abdomen (ascites), elevated bilirubin in the blood leading to jaundice, blood clotting abnormalities, etc.

CVID and CGD are among the primary immunodeficiency diseases most commonly associated with autoimmune or inflammatory liver disease but this has also been observed in APECED, IPEX, X-linked Hyper IgM syndrome, and others. Since infections by certain viruses, including Hepatitis (A, B, or C), Cytomegalovirus (CMV), Epstein Barr virus (EBV), and others, can also cause severe liver inflammation and damage, these are typically excluded as the cause of disease before autoimmunity can be confirmed.

Diagnosis of Gastrointestinal Disease

The diagnosis of gastrointestinal disorders in primary immunodeficiency diseases often requires a combination of approaches that include a physical exam, laboratory tests on blood and stool, radiology tests, and endoscopy with biopsies of the intestinal mucosa. Common physical exam findings include oral or anal ulcers, abdominal tenderness, fluid in the abdomen (ascites), enlargement or tenderness of the liver, cracks or fissures around the anus, etc.

Laboratory tests that are often recommended on the blood include a complete blood count to determine whether the patient may be losing blood in the inflamed bowel, measures of inflammation including C reactive protein (CRP) and erythrocyte sedimentation rate (ESR), albumin and pre-albumin levels as a rough measure of nutritional status, and AST, ALT, and Bilirubin levels as a measure of liver irritation. To exclude the possibility of a bowel infection, stool is often collected and cultured to identify bacteria or viruses. Samples of stool are also stained and evaluated under the microscope for the presence of specific bacteria or parasitic organisms.

Radiologic tests that may be helpful include an abdominal X-ray, abdominal and liver ultrasounds, and a CT scan of the abdomen after contrast material has been swallowed. Sometimes the only way to make a definitive diagnosis of either bowel or liver inflammation is to obtain a fragment of tissue that can be evaluated under the microscope by a pathologist. In the bowel, this is done by passing an endoscope into the bowel to both look at the mucosa and to obtain small pinch biopsies of mucosal tissue from the inside surface of the intestine. In the liver, this is done by obtaining a small piece of liver tissue with a biopsy needle inserted into the liver through the skin. Both of these procedures are typically done by a gastroenterologist, a doctor who specializes in the treatment of intestinal disorders.


In general, immunosuppressant medications are used to treat autoimmune or inflammatory disorders of the bowel in most patients with primary immunodeficiency diseases. This process is very individualized requiring flexible treatment plans to balance the severity and risks of the autoimmune process with the severity and risks of the immune deficiency and immunosuppressive therapy. In some cases, including the bowel disease associated with CVID or CGD, steroids are often the first line of therapy, and in many cases, may be sufficient to control symptoms. In contrast, the severe bowel disease associated with IPEX syndrome or Omenn syndrome typically requires more aggressive immunosuppression with stronger medications. For patients with primary immunodeficiency diseases who have significant gastrointestinal symptoms, it is essential to have a gastroenterologist involved to assist with diagnostic testing and with directing treatment.

Autoimmune Kidney Disease

The kidney is made up of a large number of tiny filtration units. Each unit is called a glomerulus. The most common form of autoimmune kidney disease in primary immunodeficiency diseases is called glomerulonephritis inflammation and destruction of the glomeruli caused either by direct attack or by deposition of immune complexes (aggregates containing autoantibodies and the proteins they are bound to). Destruction of the glomeruli leads to progressive loss of filtering capacity and decreased kidney function.

Glomerulonephritis is a common feature of patients with complement deficiencies, particularly those affecting complement components C1, C2, C3, or C4. Autoimmune kidney disease can also be seen less commonly in other primary immunodeficiency diseases including CVID and APECED.


In many cases, the first sign of autoimmune kidney disease is elevated blood pressure. This is often accompanied by the appearance of blood or protein in the urine. In the setting of active glomerulonephritis, blood in the urine may not appear pink, but instead is more likely to cause the urine to have a color closer to that of tea or cola. Blood and protein are easily detected in the urine using readily available test strips that are frequently called urine “dipsticks.” If there is substantial protein loss in the urine, it can lead to fluid retention and swelling (edema) of the legs and feet.

Diagnosis of Kidney Complications

When kidney disease is suspected, common blood tests are helpful to determine just how dysfunctional the kidneys may have become. Evaluation of the urine for the presence of blood, protein, inflammatory cells and electrolytes is also typically very informative. In many cases, a kidney biopsy is needed to make the correct diagnosis and define the correct treatment course. A kidney biopsy is usually done by inserting a biopsy needle through the skin and into the kidney to obtain a small core of tissue, which is usually sufficient to make the diagnosis. The biopsy is evaluated by a pathologist, who performs a variety of tests on the kidney tissue including a microscopic examination.


Patients with autoimmune kidney disease are often referred to a nephrologist (kidney doctor) for evaluation and management of the kidney problems. Blood pressure medications are typically prescribed to manage the elevated blood pressure, and immunosuppressants are used to control the autoimmune process. 

Autoimmune Endocrine Disease

The major endocrine organs include the pituitary gland in the brain, the thyroid and parathyroid glands, the pancreas, the adrenal glands and the gonads (testicles or ovaries). The endocrine organs secrete important hormones that play essential roles in maintaining basic bodily functions. Autoimmunity directed against endocrine organs can therefore cause significant health problems. Patients who have endocrine autoimmunity are often referred to an endocrine specialist (endocrinologist) for evaluation and management.


The thyroid gland secretes thyroid hormone, which plays an important role in maintaining the metabolic rate of the body. Patients with hypothyroidism (abnormally low thyroid hormone levels) typically gain weight, have a slow heart rate, feel cold and fatigued, are constipated and have coarse hair and stiffening in the skin. In contrast, patients with hyperthyroidism (abnormally high thyroid hormone levels) typically lose weight, have a rapid heart rate, feel hot and energetic, and have thin hair. Autoantibodies directed against the thyroid can cause either hypothyroidism or hyperthyroidism. Autoimmune thyroid disease is the most common autoimmune disease among the general population with an incidence of approximately 1 in 200. In certain primary immunodeficiency diseases, including CVID and IPEX syndrome, the incidence is even higher.

Diagnosis of thyroid autoimmunity is typically made by a series of blood tests. Hypothyroidism is treated by taking supplements of thyroid hormone. Hyperthyroidism often has to be treated by decreasing the thyroid’s ability to make thyroid hormone. This may require surgical removal of part of the thyroid or radiation or other drugs. This is always done under the direction of an endocrinologist.


Diabetes (abnormally elevated blood sugar levels) results from either not being able to produce enough insulin (Type I diabetes) or as a result of the cells of the body becoming resistant to the effects of insulin (Type II diabetes). Type I diabetes (T1D) is the form caused by autoimmune attack on the islet cells in the pancreas that produce insulin. Once islet cells are destroyed, they do not recover. When the number of Islet cells producing insulin drops below a particular threshold, patients develop diabetes. T1D is very common in some primary immunodeficiency diseases, such as IPEX syndrome where it occurs in approximately 70% of patients. Incidence is also higher in other primary immunodeficiency diseases, including CVID, APECED syndrome and others.

T1D is typically diagnosed by screening for the presence of glucose (sugar) in the urine and by measuring blood glucose levels. If these do not decrease as expected after eating or if they are high even when a patient is fasting, then diabetes may have developed. Identification of autoantibodies directed toward proteins in the pancreas (anti-islet cell antibodies) can help confirm that the process is autoimmune.

Treatment of T1D typically involves the administration of insulin either via shots or via an insulin pump. Even though T1D is autoimmune mediated, it is not yet clear whether the use of potent immunosuppressive drugs early in the course of disease will change the need for insulin treatment or not, but there are a number of therapeutic trials have been designed to address this question.

Other Autoimmune Endocrine Disorders

Insufficient parathyroid function leading to problems with regulation of calcium levels is a feature of DiGeorge syndrome and CHARGE syndrome, but in these cases the defect is caused by abnormal development of the glands, not by autoimmunity. Parathyroid autoimmunity does, however, occur as one of the main features of APECED syndrome, often in association with autoimmunity to adrenal glands and gonads.

Diagnosis of Endocrine Complications

As discussed above, diagnosis of endocrine complications revolves around identifying abnormal levels of specific hormones in the blood or in measuring abnormal electrolyte or glucose levels in the blood. The identification of specific autoantibodies in the blood is helpful in confirming that the process is autoimmune in nature.


In general, most autoimmune endocrine disease leads to a deficiency of critically important hormones that are supposed to be made by the targeted endocrine organs. Treatment typically involves administering replacement hormone to try and achieve normal levels. In the case of the thyroid, autoimmunity can also cause increased function, which requires removal or destruction of at least part of the gland to correct the problem.

Autoimmune Musculoskeletal Disease

Arthritis (inflammation of the joints) is a common malady in the general population. Arthritis can either occur as a result of wear-and-tear on the joints (osteoarthritis) or as a result of autoimmune attack of the joints (as in rheumatoid arthritis). There is no evidence that the incidence of osteoarthritis is higher in patients with primary immunodeficiency diseases but some primary immunodeficiency diseases are associated with a higher incidence of certain autoimmune arthritis syndromes.

For example, both DiGeorge syndrome and Selective IgA Deficiency have been associated with an increased risk for developing Juvenile Idiopathic Arthritis (JIA), a type of arthritis that affects children. Approximately 20% of patients with XLA develop arthritis at some point, although it is often not terribly inflammatory and frequently resolves when immunoglobulin replacement therapy (IVIG or SCIG) is optimized. In contrast, patients with CVID can develop severe rheumatoid arthritis or psoriatic arthritis (a type of arthritis that often accompanies psoriasis – see previous Autoimmune Skin Disease section). These can cause significant pain and limitation of daily activities and can lead to permanent damage to the joint.

Unlike arthritis, myositis (inflammation of the muscles) is relatively uncommon in primary immunodeficiency diseases with one exception, which is a dermatomyositis syndrome that occurs in patients with XLA who become infected with a particular type of bacteria called Helicobacter. In these cases, the inflammation is not treated with immunosuppressant medications but instead with antibiotics to treat the bacterial infection.


Typical signs and symptoms of arthritis include pain and stiffness of the joints, joint swelling, and sometimes warmth or redness over the joints that have arthritis. The stiffness is often worst after not moving the joint, like in the morning after sleep or after resting, and often improves somewhat with activity. When the arthritis is active and flaring, patients may also have fevers, feel fatigued, and may have decreased appetite.

Diagnosis of Musculoskeletal Complications

A physical exam by an experienced healthcare provider is extremely helpful in diagnosing arthritis. Patients are often referred to an arthritis specialist (rheumatologist) for evaluation.

Blood tests can help to determine whether there is ongoing inflammation. Measurement of specific autoantibodies in the blood can also be helpful for making a diagnosis. Radiology tests including X-rays, CT scans and MRI scans of inflamed joints can be helpful in determining if there is ongoing inflammation and whether the joint has signs of damage from the arthritis. Sometimes, obtaining a sample of the fluid from inside the joint for testing can be extremely informative in making a firm diagnosis and ruling out infection in the joint. This is typically done by withdrawing the fluid from the joint with a needle and syringe.


Treatment of arthritis typically requires the use of immunosuppressants. Steroids like prednisone are among the most commonly used. These can be given by mouth, injected into the blood through an IV or injected directly into the inflamed joints. They are often very effective for a time but may not provide a long-term effect. To improve the chances for control of the arthritis, other non-steroid drugs are often added. Since giving immunosuppressant medicines to a patient with primary immunodeficiency diseases may suppress their immune system even more, making them more susceptible to certain types of infections, these treatments often need to be coordinated between an immunologist and a rheumatologist.


Significant autoimmune or inflammatory disease is common among patients with primary immunodeficiency diseases. Early recognition and treatment of these symptoms is critical for optimizing quality of life and decreasing complications associated with primary immunodeficiency diseases. This requires that patients and their care providers be aware of signs and symptoms that may suggest an autoimmune disease and that appropriate diagnostic testing and treatment be initiated in a timely fashion. Maintaining a balance between the immunosuppression used to control the autoimmune process while avoiding compounding the defects of the underlying primary immunodeficiency requires close cooperation between the patient and the various specialists involved in their care. Treatment may require frequent dosage adjustments or changes in overall approach to reach the desired balance.

Excerpted from the IDF Patient & Family Handbook for Primary Immunodeficiency Diseases FIFTH EDITION Copyright 2013 by Immune Deficiency Foundation, USA. This page contains general medical information which cannot be applied safely to any individual case. Medical knowledge and practice can change rapidly. Therefore, this page should not be used as a substitute for professional medical advice.

It’s Time for an Autoimmune Revolution

This informational summit is taking place January 30 – February 6, 2017 and will be jam-packed with life-changing information.

Why Attend the Autoimmune Revolution?

Dr. Osborne created The Autoimmune Revolution to help you prevent and reverse autoimmune pain. It’s time to achieve greater health and improved happiness so you can break the cycle of pain and start living again!

During The Autoimmune Revolution, you’ll learn about:

  • Conquering chronic pain and autoimmune conditions
  • The connection between autoimmune diseases, diet and lifestyle choices
  • 6 diet and behavior changes you need to make to radically improve health
  • Breaking the cycle of medications and dependency on allopathic treatments
  • And so, so, so much more…

The Autoimmune Revolution is online and free from January 30 – February 6, 2017! The Autoimmune Revolution Summit with Dr. Peter Osborne is primed to help tens of thousands will learn from the expert wisdom so important to breaking the cycle of pain to achieve greater health and improved happiness!

I am really looking forward to the new info and I hope you are too! Don’t forget to save your spot so that you receive the daily summit emails with info on how to watch each day’s presentations.

Here’s a Sneak Peek at the Topics:

  • Autoimmune Recovery: Putting the Puzzle Pieces Together
  • CIRS: Mold Toxicity, Hormone Disruption, and Autoimmunity
  • Lyme Disease: Infections and Autoimmune Diseases
  • Inexpensive Ways to Reduce Autoimmune Pain and Inflammation
  • Emotional Trauma and Autoimmune Pain
  • Mind-Body Medicine: Surrender to Win the Autoimmune Battle
  • The Microbiome and Autoimmune Diseases
  • Parasites and Autoimmune Disease
  • Hidden Danger in Your Food: Mycotoxins and Autoimmune Diseases
  • Overcoming the “Chemical Soup” of Autoimmune Diseases
  • Physical Activity: A Necessity for Autoimmune Recovery
  • Exercise, Diet and Chronic Autoimmune Pain
  • And more…

Here’s a sneak peek at just a few of the presenters:

  • Alan Christianson, ND
  • Peter Osborne, DC, DACBN, PScD
  • Izabella Wentz, PharmD
  • David Perlmutter, MD
  • Donna Gates MEd, ABAAHP
  • Tom O’Bryan, DC, CCN
  • Mark Hyman, MD
  • Mark Sisson
  • Andrea Gruszecki, ND
  • Dave Asprey
  • Mike Mutzel, MS
  • Amy Myers, MD
  • Sayer Ji
  • Jill Carnahan, MD
  • And SO many more!

Together, let’s make 2017 an empowering and health-filled year! See you at the summit!

Autoimmune Disease: Meaning, Causes and Treatment

Autoimmunity is a condition characterized by the presence of serum autoantibodies and self-reactive lymphocytes (T-cells).

It manifests sometimes when the body loses immune tolerance (body’s condition to distinguish its own self-antigens from foreign non-self-antigens and not mounting on immunogenic attack against the former) and mounts an abnormal immune attack, either with antibodies or T-cells, against a person’s own self-antigens.

In other words, the immune system of the body, like any complex multi-component system, is subject to failure of some or all of its parts. When the system loses its sense of “self” and begins to attack cells and tissues of the body, the result is autoimmunity. Autoimmune reactions can cause serious damage to cells/tissues and organs and may result in diseases called autoimmune diseases.

Human beings suffer from several autoimmune diseases, some of which are listed in Table 43.2. Some of these diseases are caused by autoantibodies, while others are due to T- cells that cause tissue destruction. Autoimmune diseases arc cither organ-specific or systemic.

In case of organ-specific diseases, the immune response is directed to a target antigen unique to a single gland or organ. As a result, the manifestations are largely limited to that organ the manifestation may be tissue damage or blockage/overstimulation of the normal function of the organ.

Direct cellular damage occurs when lymphocytes or antibodies bind to cell-membrane antigens causing cellular lysis and/or an inflammatory response in the affected organ. Gradually, the damaged cellular structure is replaced by connective tissue leading to a decrease in function of that organ.

Examples of such diseases are autoimmune anaemias insulin- dependent diabetes mellitus, etc. In some diseases, e.g., Grave’s disease, the antibodies bind to hormone receptors and activate them, while in some others, e.g., myasthenia gravis, antibody binding blocks the activation of the receptors.

In case of systemic autoimmune diseases, the immune response is directed towards a broad range of target antigens and, as a result, involves a number of organs and tissues.

These diseases reflect a general defect in immune regulation that results in hyperactive T-cells and B-cells. Tissue damage is widespread, is caused by both T-cells, e.g.. multiple sclerosis and autoantibodies, e.g., systemic lupus erythematous, or by accumulation of immune complexes, e.g., rheumatoid arthritis.

Causes of Autoimmune Disease:

Autoimmune diseases could arise in many possible ways, some of which are as follows:

(1) A tissue antigen that is sequestered from circulation will not be employed in the thymus for clonal deletion of T cells reactive to this antigen. When such an antigen is released into circulation due to trauma to tissues caused by an accident or a viral or bacterial infection, it may induce autoantibody formation.

(2) A number of bacteria and viruses have antigenic determinants that are identical or similar to, normal host cell components. Infection by such pathogens may initiate autoimmunity.

(3) A number of viruses and bacteria can induce nonspecific polyclonal B cells that produce IgM in the absence of TH cells. Such infections could activate B cells reactive to self-antigens and, thereby, cause autoimmunity.

(4) Expression of MHC II in cells that normally do not express them could lead to autoimmunity. Such an inappropriate expression of MHC II is induced by certain agents like IFN-γ.

Treatment of Autoimmune Diseases:

The current therapies provide relief by nonspecific suppression of the immune system. Some agents like cyclosporin A are somewhat selective in that they inhibit only antigen-activated T cells.

More directed approaches are still at experimental level some of these are briefly summarise below:

(i) T cells specific for the concerned antigen are injected into individuals to immunize them against these T cells (T cell vaccination).

(ii) A synthetic peptide differing by only one (or few) amino acid from the auto-antigenic peptide may be used as therapy. The synthetic peptide competes with the auto-antigenic peptide for MHC molecules (peptide blockade of MHC molecules).

(iii) Monoclonal antibodies may be directed against the following:

(a) CD4 (depletes all TH cells),

(b) The α subunit of IL-2 receptor, which is expressed only by antigen-activated TH cells (blocks antigen- activated TH cells),

(c) Specific T cell receptor, and

(d) The specific allelic variant of the MHC molecule that is associated with the autoimmune disease.

(iv) Oral administration of the concerned auto-antigen way induce tolerance to the antigen.

6.3C: Selective and Differential Media

  • Contributed by Boundless
  • General Microbiology at Boundless

There are many types of media used in the studies of microbes. Two types of media with similar implying names but very different functions, referred to as selective and differential media, are defined as follows.

Selective media are used for the growth of only selected microorganisms. For example, if a microorganism is resistant to a certain antibiotic, such as ampicillin or tetracycline, then that antibiotic can be added to the medium in order to prevent other cells, which do not possess the resistance, from growing. Media lacking an amino acid such as proline in conjunction with E. coli unable to synthesize it were commonly used by geneticists before the emergence of genomics to map bacterial chromosomes. Selective growth media are also used in cell culture to ensure the survival or proliferation of cells with certain properties, such as antibiotic resistance or the ability to synthesize a certain metabolite. Normally, the presence of a specific gene or an allele of a gene confers upon the cell the ability to grow in the selective medium. In such cases, the gene is termed a marker. Selective growth media for eukaryotic cells commonly contain neomycin to select cells that have been successfully transfected with a plasmid carrying the neomycin resistance gene as a marker. Gancyclovir is an exception to the rule as it is used to specifically kill cells that carry its respective marker, the Herpes simplex virus thymidine kinase (HSV TK). Some examples of selective media include:

  • Eosin methylene blue (EMB) that contains methylene blue &ndash toxic to Gram-positive bacteria, allowing only the growth of Gram negative bacteria.
  • YM (yeast and mold) which has a low pH, deterring bacterial growth.
  • MacConkey agar for Gram-negative bacteria.
  • Hektoen enteric agar (HE) which is selective for Gram-negative bacteria.
  • Mannitol salt agar (MSA) which is selective for Gram-positive bacteria and differential for mannitol.
  • Terrific Broth (TB) is used with glycerol in cultivating recombinant strains of Escherichia coli.
  • Xylose lysine desoxyscholate (XLD), which is selective for Gram-negative bacteria buffered charcoal yeast extract agar, which is selective for certain gram-negative bacteria, especially Legionella pneumophila.

Differential media or indicator media distinguish one microorganism type from another growing on the same media. This type of media uses the biochemical characteristics of a microorganism growing in the presence of specific nutrients or indicators (such as neutral red, phenol red, eosin y, or methylene blue) added to the medium to visibly indicate the defining characteristics of a microorganism. This type of media is used for the detection of microorganisms and by molecular biologists to detect recombinant strains of bacteria. Examples of differential media include:

Systemic Autoimmune Diseases

Whereas organ-specific autoimmune diseases target specific organs or tissues, systemic autoimmune diseases are more generalized, targeting multiple organs or tissues throughout the body. Examples of systemic autoimmune diseases include multiple sclerosis, myasthenia gravis, psoriasis, rheumatoid arthritis, and systemic lupus erythematosus.

Multiple Sclerosis

Multiple sclerosis (MS) is an autoimmune central nervous system disease that affects the brain and spinal cord. Lesions in multiple locations within the central nervous system are a hallmark of multiple sclerosis and are caused by infiltration of immune cells across the blood-brain barrier. The immune cells include T cells that promote inflammation, demyelination, and neuron degeneration, all of which disrupt neuronal signaling. Symptoms of MS include visual disturbances muscle weakness difficulty with coordination and balance sensations such as numbness, prickling, or &ldquopins and needles&rdquo and cognitive and memory problems.

Myasthenia Gravis

Autoantibodies directed against acetylcholine receptors (AChRs) in the synaptic cleft of neuromuscular junctions lead to myasthenia gravis (Figure (PageIndex<4>)). Anti-AChR antibodies are high-affinity IgGs and their synthesis requires activated CD4 T cells to interact with and stimulate B cells. Once produced, the anti-AChR antibodies affect neuromuscular transmission by at least three mechanisms:

  • Complement binding and activation at the neuromuscular junction
  • Accelerated AChR endocytosis of molecules cross-linked by antibodies
  • Functional AChR blocking, which prevents normal acetylcholine attachment to, and activation of, AChR

Regardless of the mechanism, the effect of anti-AChR is extreme muscle weakness and potentially death through respiratory arrest in severe cases.

Figure (PageIndex<4>): Myasthenia gravis and impaired muscle contraction. (a) Normal release of the neurotransmitter acetylcholine stimulates muscle contraction. (b) In myasthenia gravis, autoantibodies block the receptors for acetylcholine (AChr) on muscle cells, resulting in paralysis.


Psoriasis is a skin disease that causes itchy or sore patches of thick, red skin with silvery scales on elbows, knees, scalp, back, face, palms, feet, and sometimes other areas. Some individuals with psoriasis also get a form of arthritis called psoriatic arthritis, in which the joints can become inflamed. Psoriasis results from the complex interplay between keratinocytes, dendritic cells, and T cells, and the cytokines produced by these various cells. In a process called cell turnover, skin cells that grow deep in the skin rise to the surface. Normally, this process takes a month. In psoriasis, as a result of cytokine activation, cell turnover happens in just a few days. The thick inflamed patches of skin that are characteristic of psoriasis develop because the skin cells rise too fast.

Rheumatoid Arthritis

The most common chronic inflammatory joint disease is rheumatoid arthritis (RA) (Figure (PageIndex<5>)) and it is still a major medical challenge because of unsolved questions related to the environmental and genetic causes of the disease. RA involves type III hypersensitivity reactions and the activation of CD4 T cells, resulting in chronic release of the inflammatory cytokines IL-1, IL-6, and tumor necrosis factor-&alpha (TNF-&alpha). The activated CD4 T cells also stimulate the production of rheumatoid factor (RF) antibodies and anticyclic citrullinated peptide antibodies (anti-CCP) that form immune complexes. Increased levels of acute-phase proteins, such as C-reactive protein (CRP), are also produced as part of the inflammatory process and participate in complement fixation with the antibodies on the immune complexes. The formation of immune complexes and reaction to the immune factors cause an inflammatory process in joints, particularly in the hands, feet, and legs. Diagnosis of RA is based on elevated levels of RF, anti-CCP, quantitative CRP, and the erythrocyte sedimentation rate (ESR) (modified Westergren). In addition, radiographs, ultrasound, or magnetic resonance imaging scans can identify joint damage, such as erosions, a loss of bone within the joint, and narrowing of joint space.

Figure (PageIndex<5>): The radiograph (left) and photograph (right) show damage to the hands typical of rheumatoid arthritis. (credit right: modification of work by &ldquohandarmdoc&rdquo/Flickr)

Systemic Lupus Erythematosus

The damage and pathology of systemic lupus erythematosus (SLE) is caused by type III hypersensitivity reactions. Autoantibodies produced in SLE are directed against nuclear and cytoplasmic proteins. Anti-nuclear antibodies (ANAs) are present in more than 95% of patients with SLE, 4 with additional autoantibodies including anti-double&ndashstranded DNA (ds-DNA) and anti-Sm antibodies (antibodies to small nuclear ribonucleoprotein). Anti-ds-DNA and anti-Sm antibodies are unique to patients with SLE thus, their presence is included in the classification criteria of SLE. Cellular interaction with autoantibodies leads to nuclear and cellular destruction, with components released after cell death leading to the formation of immune complexes.

Because autoantibodies in SLE can target a wide variety of cells, symptoms of SLE can occur in many body locations. However, the most common symptoms include fatigue, fever with no other cause, hair loss, and a sunlight-sensitive "butterfly" or wolf-mask (lupus) rash that is found in about 50% of people with SLE (Figure (PageIndex<6>)). The rash is most often seen over the cheeks and bridge of the nose, but can be widespread. Other symptoms may appear depending on affected areas. The joints may be affected, leading to arthritis of the fingers, hands, wrists, and knees. Effects on the brain and nervous system can lead to headaches, numbness, tingling, seizures, vision problems, and personality changes. There may also be abdominal pain, nausea, vomiting, arrhythmias, shortness of breath, and blood in the sputum. Effects on the skin can lead to additional areas of skin lesions, and vasoconstriction can cause color changes in the fingers when they are cold (Raynaud phenomenon). Effects on the kidneys can lead to edema in the legs and weight gain. A diagnosis of SLE depends on identification of four of 11 of the most common symptoms and confirmed production of an array of autoantibodies unique to SLE. A positive test for ANAs alone is not diagnostic.

Figure (PageIndex<6>): (a) Systemic lupus erythematosus is characterized by autoimmunity to the individual&rsquos own DNA and/or proteins. (b) This patient is presenting with a butterfly rash, one of the characteristic signs of lupus. (credit a: modification of work by Mikael Häggström credit b: modification of work by Shrestha D, Dhakal AK, Shiva RK, Shakya A, Shah SC, Shakya H)

Role of MHC variants in human diseases

Insights into MHC susceptibility for autoimmune diseases: fine-mapping results, epistasis, and disease biology

Associations between the MHC and autoimmune diseases reported in the 1970s were some of the earliest described genetic associations [31, 32], and they remain the strongest risk factors for autoimmune diseases. After the development of wide-screen genotyping platforms and imputation pipelines, MHC imputation and fine-mapping were performed in European and Asian populations for most common autoimmune diseases, including RA [19, 25, 33, 34], CeD [35], psoriasis [36], ankylosing spondylitis (AS) [37], systemic lupus erythematosus (SLE) [33, 38,39,40,41], T1D [42, 43], multiple sclerosis (MS) [44, 45], Graves’ disease [24], inflammatory bowel disease (IBD) [46], and dermatomyositis (DM) [47]. Table 1 shows the main associated variants and independently associated loci for autoimmune diseases.

In 2012, a pioneering MHC fine-mapping study, performed in individuals of European ancestry with RA [19], confirmed the strongest association with the class II HLA-DRB1 gene, as well as other independent associations. Previously an increased risk of RA was reported for a set of consensus amino acid sequences at positions 70–74 in the HLA-DRB1 gene, known as the “shared epitope” locus [48]. The imputed data revealed the most significant associations were with two amino acids at position 11, located in a peptide-binding groove of the HLA-DR heterodimer. This suggested a functional role for this amino acid in binding the RA-triggering antigen. Similar fine-mapping studies followed for other autoimmune diseases (Table 1).

In general, in most autoimmune diseases, fine-mapping strategies have confirmed the main associated locus reported by serotype analysis within a certain MHC locus. Such strategies have also allowed identification of specific allelic variants or amino acids, as well as independent variants in different HLA classes. For instance, in CeD, the strongest association was with the known DQ-DR locus, and five other independent signals in classes I and II were also identified. CeD is the only autoimmune disease for which the antigen, gluten, is known and well studied. Gluten is a dietary product in wheat, barley, and rye. It is digested in the intestine and deamidated by tissue transglutaminase enzymes such that it perfectly fits the binding pockets of a particular CeD-risk DQ heterodimer (encoded by the DQ2.2, DQ2.5, and DQ8 haplotypes). This association was confirmed by MHC fine-mapping, which indicated roles for four amino acids in the DQ genes with the strongest independent associations to CeD risk [35]. Similarly, the main associations were determined for T1D, MS, and SLE within the MHC class II locus (the associations for these three diseases are to a particular HLA-DQ-DR haplotype), and there are also independent, but weaker associations with the class I and/or III regions. In DM, fine mapping in an Asian population identified MHC associations driven by variants located around the MHC class II region, with HLA-DP1*17 being the most significant [47]. In contrast, the primary and strongest associations in psoriasis and AS were to MHC class I molecules, while independent associations to the class I locus were also reported for IBD and Graves’ disease. Class III variants are weakly implicated in autoimmune diseases, but several associations in the MHC class III region were seen for MS for instance, the association to rs2516489 belonging to the long haplotype between MICB and LST1 genes. The association signal to rs419788-T in the class III region gene SKIV2L has also been implicated in SLE susceptibility, representing a novel locus identified by fine-mapping in UK parent–child trios [39]. An independent association signal to class III was also identified (rs8192591) by a large meta-analysis of European SLE cases and controls and, specifically, upstream of NOTCH4 [40]. However, further studies are needed to explain how these genetic variations contribute to predisposition to SLE.

In addition to identifying independent variants, MHC fine-mapping studies permit analysis of epistatic and non-additive effects in the locus. These phenomena occur when the effect of one allele on disease manifestation depends on the genotype of another allele in the locus (non-additive effect), or on the genotype of the “modifier” gene in another locus (epistasis). Non-additive MHC effects were established in CeD, in which knowing gluten was the causal antigen offered an advantage in investigating the antigen-specific structure of the DQ-heterodimer. CeD risk is mediated by the presence of several HLA-DQ haplotypes, including the DQ2.5, DQ2.2, and DQ8 haplotypes, which form the specific pocket that efficiently presents gluten to T cells. These haplotypes can be encoded either in cis, when both DQA1 and DQB1 are located on the same chromosome, or in trans, when they are located on different chromosomes. Some DQ allelic variants confer susceptibility to CeD only in combination with certain other haplotypes, forming a CeD-predisposing trans-combination. For example, HLA-DQA1*0505-DQB1*0301 (DQ7) confers risk to CeD only if it is combined with DQ2.2 or DQ2.5, contributing to the formation of susceptible haplotypes in trans. In particular, DQ7/DQ2.2 heterozygosity confers a higher risk for CeD than homozygosity for either of these alleles, and is an example of a non-additive effect for both alleles.

Unlike CeD, the exact haplotypes and their associated properties remain unknown for most other autoimmune diseases therefore, analyzing non-additive effects might yield new insights into potentially disease-causing antigens. Lenz et al. provided evidence of significant non-additive effects for autoimmune diseases, including CeD, RA, T1D, and psoriasis, which were explained by interactions between certain classic HLA alleles [29]. For instance, specific interactions that increase T1D disease risk were described between HLA-DRB1*03:01-DQB1*02:01/DRB1*04:01-DQB1*03:02 genotypes [49] and for several combinations of the common HLA-DRB1, HLA-DQA1, and HLA-DQB1 haplotypes [43]. In AS, epistatic interaction was observed for combinations of HLA-B60 and HLA-B27, indicating that individuals with the HLA-B27+/HLA-B60+ genotype have a high risk of developing AS [50]. Moreover, a recent study in MS found evidence for two interactions involving class II alleles: HLA-DQA1*01:01-HLA-DRB1*15:01 and HLA-DQB1*03:01-HLA-DQB1*03:02, although their contribution to the missing heritability in MS was minor [44].

Epistatic interactions between MHC and non-MHC alleles have also been reported in several autoimmune diseases, including SLE, MS, AS, and psoriasis. For instance, in a large European cohort of SLE patients, the most significant epistatic interaction was identified between the MHC region and cytotoxic T lymphocyte antigen 4 (CTLA4) [9], which is upregulated in T cells upon encountering APCs. This highlights that appropriate antigen presentation and T-cell activation are important in SLE pathogenesis [9]. Notably, interactions between MHC class I and specific killer immunoglobulin receptor (KIR) genes are important in predisposition to autoimmune diseases such as psoriatic arthritis, scleroderma, sarcoidosis, and T1D [51,52,53,54]. KIR genes are encoded by the leukocyte receptor complex on chromosome 19q13 and expressed on natural killer cells and subpopulations of T cells [55]. Finally, epistatic interactions between MHC class I and ERAP1 have been described for AS, psoriasis, and Behçet’s disease [10].

Association of novel MHC variants and identification of interaction effects within the MHC are increasing our understanding of the biology underlying autoimmune and inflammatory diseases. Fine-mapping the main associated locus within HLA-DQ-DR haplotypes has allowed determination of the key amino acid positions in the DQ or DR heterodimer. Pinpointing specific amino acids leads to a better understanding of the structure and nature of potential antigens for autoimmune or inflammatory diseases, and these can then be tested through binding assays and molecular modeling. The fact that these positions are located in peptide-binding grooves suggests they have a functional impact on antigenic peptide presentation to T cells, either during early thymic development or during peripheral immune responses [19]. In addition, analysis of non-additive effects in MHC-associated loci offers the possibility to identify antigen-specific binding pockets and key amino acid sequences. For example, identification of the protective, five-amino acid sequence DERAA as a key sequence in the RA-protective HLA-DRB1:13 allele, and its similarity to human and microbial peptides, led to identification of (citrullinated) vinculin and some pathogen sequences as novel RA antigens [56].

The identification of independent signals in MHC classes I and III for many autoimmune diseases implies that these diseases involve novel pathway mechanisms. For example, association of CeD to class I molecules suggests a role for innate-like intraepithelial leucocytes that are restricted to class I expression and that are important in epithelial integrity and pathogen recognition [57]. Class I associations to RA, T1D, and other autoimmune diseases suggest that CD8 + cytotoxic cells are involved in disease pathogenesis, as well as CD4 + helper T cells.

Discovering the epistatic effects of MHC and non-MHC loci can also shed light on disease mechanisms. For example, ERAP1 loss-of-function variants reduce the risk of AS in individuals who are HLA-B27-positive and HLAB-40:01-positive, but not in carriers of other risk haplotypes [37]. Similar epistatic effects were also observed for psoriasis, such that individuals who carry variants in ERAP1 showed an increased risk only when they also carried an HLA-C risk allele [58]. In line with these observations, mouse studies have shown that ERAP1 determines the cleavage of related epitopes in such a way that they can be presented by the HLA-B27 molecule [37]. Confirming that certain epitopes must be cleaved by ERAP1 to be efficiently presented by CD4 + and CD8 + cells will be a critical step in identifying specific triggers for autoimmune diseases.

The recent discoveries of genetic associations between MHC alleles and autoimmune diseases are remarkable and offer the potential to identify disease-causing antigens. This would be a major step towards developing new treatments and preventing disease. However, we still do not understand exactly how most associated alleles and haplotypes work, and extensive functional studies are needed to clarify their involvement in disease.

Explained heritability by independent MHC loci for autoimmune diseases

Heritability is an estimation of how much variation in a disease or phenotype can be explained by genetic variants. Estimating heritability is important for predicting diseases but, for common diseases, it is challenging and depends on methodological preferences, disease prevalence, and gene–environment interactions that differ for each phenotype [59]. It is therefore difficult to compare heritability estimates across diseases. Nevertheless, for many diseases, estimates have been made as to how much phenotypic variance can be explained by the main locus and by independent MHC loci [29].

For autoimmune diseases with a main association signal coming from a class II locus, the reported variance explained by MHC alleles varies from 2 − 30% [9]. The strongest effect is reported for T1D, in which the HLA-DR and HLA-DQ haplotypes explain 29.6% of phenotypic variance independently associated loci in HLA-A, HLA-B, and HLA-DPB1 together explain about 4% of the total phenotypic variance, while all other non-MHC loci are responsible for 9% [60]. Similarly, in CeD, which has the same main associated haplotype as T1D, the HLA-DQ-DR locus explains 23 − 29% of disease variance (depending on the estimated prevalence of disease, which is 1 − 3%), whereas other MHC alleles explain 2 − 3%, and non-MHC loci explain 6.5 − 9% [35]. In seropositive RA, 9.7% of phenotypic variance is explained by all the associated DR haplotypes, whereas a model including three amino acid positions in DRB1, together with independently associated amino acids in HLA-B and HLA-DP loci, explains 12.7% of the phenotypic variance [19]. This indicates that non-DR variants explain a proportion of heritability comparable to that in other non-MHC loci (4.7 − 5.5% in Asians and Europeans) [19]. The non-additive effects of DQ-DR haplotypes can also explain a substantial proportion of phenotypic variance: 1.4% (RA), 4.0% (T1D), and 4.1% (CeD) [29]. In MS, the major associated allele, DRB1*15:01, accounts for 10% of the phenotypic variance, whereas all the alleles in DRB1 explain 11.6%. A model including all of the independent variants (and those located in classes I, II, and III) explains 14.2% of the total variance in MS susceptibility [45].

In SLE, the proportion of variance explained by the MHC is notably lower, at only 2% [41], and is mostly due to class II variants. In IBD, the association with MHC is weaker than in classic autoimmune diseases, with a lower contribution seen in Crohn’s disease (CD) than in ulcerative colitis (UC) [61]. The main and secondary variants can now explain 3.1% of heritability in CD and 6.2% in UC, which is two to ten times greater than previously attributed by main effect analysis in either disease (0.3% in CD and 2.3% in UC for the main SNP effect) [46]. Among all the diseases discussed here, the main effect of the associated haplotype is far stronger than the independent effects from other loci (with the exception of IBD, in which the MHC association is weaker overall). However, independent MHC loci can now explain a comparable amount of the disease variance to that explained by the non-MHC associated genes known so far.

Insights into MHC susceptibility for infectious diseases: GWAS, fine-mapping results, and epistasis

In principle, an infectious disease is caused by interactions between a pathogen, the environment, and host genetics. Here, we discuss MHC genetic associations reported in infectious diseases from GWAS (Table 2) and how these findings can explain increased susceptibility or protection by affecting human immune responses. This is why certain MHC classes are important in infectious diseases. We note that fewer MHC associations have been found for infectious diseases than for autoimmune diseases, mainly because of the smaller cohort sizes for infectious diseases. Thus, extensive fine-mapping studies (and imputation) have yet to be performed, with the exception of a few studies on infections such as human immunodeficiency virus (HIV) [62], human hepatitis B virus (HBV) [63, 64], human hepatitis C virus (HCV) [65], human papilloma virus (HPV) seropositivity [66], and tuberculosis [67].

From a genetic viewpoint, one of the best-studied infectious diseases is HIV infection. MHC class I loci have strong effects on HIV control [62,69,70,, 68–71] and acquisition [72], viral load set point [69,70,71], and non-progression of disease [73] in Europeans [69, 70, 72, 73], and in multi-ethnic populations (Europeans, African-Americans, Hispanics, and Chinese) [62, 68, 71]. A GWAS of an African-American population indicated a similar HIV-1 mechanism in Europeans and African-Americans: about 9.6% of the observed variation in viral load set point can be explained by HLA-B*5701 in Europeans [69], while about 10% can be explained by HLA-B*5703 in African-Americans [68]. In contrast, the MHC associations and imputed amino acids identified in Europeans and African-Americans were not replicated in Chinese populations, possibly because of the varied or low minor allele frequencies of these SNPs in Chinese people [71]. A strong association to the MHC class I polypeptide-related sequence B (MICB) was also revealed by a recent GWAS for dengue shock syndrome (DSS) in Vietnamese children [74]. This result was replicated in Thai patients, indicating MICB can be a strong risk factor for DSS in Southeastern Asians [75].

HLA-DP and HLA-DQ loci, along with other MHC or non-MHC loci (TCF19, EHMT2, HLA-C, HLA-DOA, UBE2L3, CFB, CD40, and NOTCH4) are consistently associated with susceptibility to HBV infection in Asian populations [76,77,78,79,80,81,82,83]. Significant associations between the HLA-DPA1 locus and HBV clearance were also confirmed in independent East Asian populations [79, 81]. A fine-mapping study of existing GWAS data from Han Chinese patients with chronic HBV infection used SNP2HLA as the imputation tool and a pan-Asian reference panel. It revealed four independent associations at HLA-DPβ1 positions 84–87, HLA-C amino acid position 15, rs400488 at HCG9, and HLA-DRB1*13 together, these four associations could explain over 72.94% of the phenotypic variance caused by genetic variations [64]. Another recent study using imputed data from Japanese individuals indicated that class II alleles were more strongly associated with chronic HBV infection than class I alleles (Additional file 1) [63]. Similarly, the HLA-DQ locus influences the spontaneous clearance of HCV infection in cohorts of European and African ancestry, while DQB1*03:01, which was identified by HLA genotyping together with the non-MHC IL28B, can explain 15% of spontaneous HCV infection clearance cases [65]. HLA-DQB1*03 also confers susceptibility to chronic HCV in Japanese people [84]. A GWAS in a European population revealed that HPV8 seropositivity is influenced by the MHC class II region [85]. However, HPV type 8 showed a higher seropositivity prevalence than other HPV types at the population level [66] this led to a limited power to detect associations with other HPV types. Fine-mapping using the same European population as in the GWAS [66] revealed significant associations with HPV8 and HPV77 seropositivity, but only with MHC class II alleles, not with class I alleles. This indicates a pivotal role for class II molecules in antibody immune responses in HPV infection. Notably in this study, imputation was performed using HLA*IMP:02 and reference panels from the HapMap Project [86] and the 1958 British Birth Cohort, as well as using SNP2HLA with another reference panel from the T1DGC. Both imputation tools provided comparable results, thus highlighting the important role of MHC class II alleles in antibody response to HPV infection [66].

A GWAS on leprosy in Chinese populations pointed to significant associations with HLA-DR-DQ loci [87, 88] these results were replicated in an Indian population [89]. Fine-mapping the MHC showed that variants in HLA class II were extensively associated with susceptibility to leprosy in Chinese people, with HLA-DRB1*15 being the most significant variant [87]. HLA class II variants also influence the mycobacterial infection tuberculosis in European and African populations [67, 90]. Fine-mapping identified the DQA1*03 haplotype, which contains four missense variants and contributes to disease susceptibility [67]. A meta-analysis showed that five variants (HLA-DRB1*04, *09, *10, *15, and *16) increase the risk of tuberculosis, especially in East Asian populations, whereas HLA-DRB1*11 is protective [91].

Using a population from Brazil, the first GWAS on visceral leishmaniasis revealed that the class II HLA-DRB1-HLA-DQA1 locus had the strongest association signal this was replicated in an independent Indian population [92]. This common association suggests that Brazilians and Indians share determining genetic factors that are independent of the different parasite species in these geographically distinct regions.

Finally, epistatic interactions between MHC class I alleles and certain KIR alleles (between KIR3DS1 combined with HLA-B alleles) are associated with slower progression to acquired immunodeficiency syndrome (AIDS) [93] and better resolution of HCV infection (between KIR2DL3 and its human leukocyte antigen C group 1, HLA-C1) [94].

Insights into the biology of infectious diseases

Associations with the MHC class I locus suggest a critical role for CD8 + T-cell responses in major viral infections such as HIV, dengue, and HCV. This critical role of CD8 + T-cell responses in HIV infection is reflected by the slow disease progression seen in infected individuals because of their increasing CD8 + T-cell responses that are specific to conserved HIV proteins such as Gap p24 [95]. Interestingly, five out of six amino acid residues (Additional file 1) identified as associated with HIV control [62] lie in the MHC class I peptide-binding groove, implying that MHC variation affects peptide presentation to CD8 + T cells. In particular, the amino acid at position 97, which lies in the floor of the groove in HLA-B, was most significantly associated with HIV control (P = 4 × 10 −45 ) [62]. This amino acid is also implicated in MHC protein folding and cell surface expression [96]. An association found in severe dengue disease also underscores the role of CD8 + T cells in disease pathogenesis: class I alleles that were associated with an increased risk of severe dengue disease were also associated with weaker CD8 + T-cell responses in a Sri Lankan population from an area of hyper-endemic dengue disease [97]. In HCV, similar to the protective alleles against HIV infection [95], HLA-B*27 presents the most conserved epitopes of HCV to elicit strong cytotoxic T-cell responses, thereby reducing the ability of HCV to escape from host immune responses [98].

Associations between genetic variants in the MHC class II region and disease susceptibility imply that impaired antigen presentation or unstable MHC class II molecules contribute to insufficient CD4 + T-cell responses and, subsequently, to increased susceptibility to infections. For instance, the amino acid changes at positions of HLA-DPβ1 and HLA-DRβ1 in the antigen-binding groove that influence HBV infection may result in defective antigen presentation to CD4 + T cells or to impaired stability of MHC class II molecules, thereby increasing susceptibility to HBV infection [64]. CD4 + T-cell responses are also critical in mycobacterial infections, such as has been described for leprosy and tuberculosis [99, 100]. Notably, monocyte-derived macrophages treated with live Mycobacterium leprae showed three main responses that explain infection persistence: downregulation of certain pro-inflammatory cytokines and MHC class II molecules (HLA-DR and HLA-DQ), preferentially primed regulatory T-cell responses, and reduced Th1-type and cytotoxic T-cell function [99]. Macrophages isolated from the lesions of patients with the most severe disease form, lepromatous leprosy, also showed lower expression of MHC class II molecules, providing further evidence that defective antigen presentation by these molecules leads to more persistent and more severe M. leprae infection [99].

Recently, it has been shown that CD4 + T-cells are essential for the optimal production of IFNγ by CD8 + T-cells in the lungs of mice infected with M. tuberculosis, indicating that communication between these two distinct effector cell populations is critical for a protective immune response against this infection [101]. Impaired antigen processing and presentation from Leishmania-infected macrophages (which are the primary resident cells for this parasite) to CD4 + T cells could explain increased susceptibility to leishmaniasis [102]. The association between HPV seropositivity and the MHC class II region also suggests that class II molecules bind and present exogenous antigens more effectively to a subset of CD4 + T cells known as Th2. These Th2 cells help primed B lymphocytes to differentiate into plasma cells and to secrete antibodies against the HPV virus.

In support of the hypothesis that genetic effects on both CD8 + (class I) and CD4 + (class II) cells modify the predisposition to infections, it should be noted that some infectious diseases, such as HIV, HBV, HCV, and leprosy, show associations to more than one of the classic MHC classes and, in some cases, the associations differ between populations (Table 2). Moreover, consideration must be given to the differences between viral and bacterial genotypes in the same infection, which play a role in determining potentially protective effects. Overall, associations with multiple MHC loci reflect the complex and interactive nature of host immune responses when the host encounters a pathogen.

The immune reaction that results from immediate hypersensitivities in which an antibody-mediated immune response occurs within minutes of exposure to a usually harmless antigen is called an allergy. In the United States, 20 percent of the population exhibits symptoms of allergy or asthma, whereas 55 percent test positive against one or more allergens. On initial exposure to a potential allergen, an allergic individual synthesizes antibodies through the typical process of APCs presenting processed antigen to TH cells that stimulate B cells to produce the antibodies. The antibody molecules interact with mast cells embedded in connective tissues. This process primes, or sensitizes, the tissue. On subsequent exposure to the same allergen, antibody molecules on mast cells bind the antigen and stimulate the mast cell to release histamine and other inflammatory chemicals these chemical mediators then recruit eosinophils (a type of white blood cell), which also appear to be adapted to responding to parasitic worms (Figure 12.22). Eosinophils release factors that enhance the inflammatory response and the secretions of mast cells. The effects of an allergic reaction range from mild symptoms like sneezing and itchy, watery eyes to more severe or even life-threatening reactions involving intensely itchy welts or hives, airway constriction with severe respiratory distress, and plummeting blood pressure caused by dilating blood vessels and fluid loss from the circulatory system. This extreme reaction, typically in response to an allergen introduced to the circulatory system, is known as anaphylactic shock. Antihistamines are an insufficient counter to anaphylactic shock and if not treated with epinephrine to counter the blood pressure and breathing effects, this condition can be fatal.

Figure 12.22 On first exposure to an allergen, an antibody is synthesized by plasma cells in response to a harmless antigen. The antibodies bind to mast cells, and on secondary exposure, the mast cells release histamines and other modulators that cause the symptoms of allergy. (credit: modification of work by NIH)

Delayed hypersensitivity is a cell-mediated immune response that takes approximately one to two days after secondary exposure for a maximal reaction. This type of hypersensitivity involves the TH1 cytokine-mediated inflammatory response and may cause local tissue lesions or contact dermatitis (rash or skin irritation). Delayed hypersensitivity occurs in some individuals in response to contact with certain types of jewelry or cosmetics. Delayed hypersensitivity facilitates the immune response to poison ivy and is also the reason why the skin test for tuberculosis results in a small region of inflammation on individuals who were previously exposed to Mycobacterium tuberculosis, the organism that causes tuberculosis.

Abe, Y., Yoshikawa, T., Inoue, M., Nomura, T., Furuya, T., Yamashita, T., et al. (2011). Fine tuning of receptor-selectivity for tumor necrosis factor-α using a phage display system with one-step competitive panning. Biomaterials 32, 5498�. doi: 10.1016/j.biomaterials.2011.04.018

Ablamunits, V., Bisikirska, B., and Herold, K. C. (2010). Acquisition of regulatory function by human CD8(+) T cells treated with anti-CD3 antibody requires TNF. Eur. J. Immunol. 40, 2891�. doi: 10.1002/eji.201040485

Aggarwal, B. B. (2003). Signalling pathways of the TNF superfamily: a double-edged sword. Nat. Rev. Immunol. 3, 745�. doi: 10.1038/nri1184

Alessi, D. R. (2001). Discovery of PDK1, one of the missing links in insulin signal transduction. Colworth Medal Lecture. Biochem. Soc. Trans. 29, 1�. doi: 10.1042/0300-5127:0290001

Alexopoulou, L., Kranidioti, K., Xanthoulea, S., Denis, M., Kotanidou, A., Douni, E., et al. (2006). Transmembrane TNF protects mutant mice against intracellular bacterial infections, chronic inflammation and autoimmunity. Eur. J. Immunol. 36, 2768�. doi: 10.1002/eji.200635921

Ando, D., Inoue, M., Kamada, H., Taki, S., Furuya, T., Abe, Y., et al. (2016). Creation of mouse TNFR2-selective agonistic TNF mutants using a phage display technique. Biochem. Biophys. Rep. 7, 309�. doi: 10.1016/j.bbrep.2016.06.008

Armour, K. L., Clark, M. R., Hadley, A. G., and Williamson, L. M. (1999). Recombinant human IgG molecules lacking Fcgamma receptor I binding and monocyte triggering activities. Eur. J. Immunol. 29, 2613�. doi: 10.1002/(SICI)1521-4141(199908)29:08�::AID-IMMU2613ϣ.0.CO2-J

Arnett, H. A., Mason, J., Marino, M., Suzuki, K., Matsushima, G. K., and Ting, J. P. (2001). TNF alpha promotes proliferation of oligodendrocyte progenitors and remyelination. Nat. Neurosci. 4, 1116�. doi: 10.1038/nn738

Atretkhany, K.-S. N., Mufazalov, I. A., Dunst, J., Kuchmiy, A., Gogoleva, V. S., Andruszewski, D., et al. (2018). Intrinsic TNFR2 signaling in T regulatory cells provides protection in CNS autoimmunity. Proc. Natl. Acad. Sci. U.S.A. 115, 13051�. doi: 10.1073/pnas.1807499115

Ban, L., Kuhtreiber, W., Butterworth, J., Okubo, Y., Vanamee, ÉS., and Faustman, D. L. (2015). Strategic internal covalent cross-linking of TNF produces a stable TNF trimer with improved TNFR2 signaling. Mol. Cell. Ther. 3:7. doi: 10.1186/s40591-015-0044-4

Ban, L., Zhang, J., Wang, L., Kuhtreiber, W., Burger, D., and Faustman, D. L. (2008). Selective death of autoreactive T cells in human diabetes by TNF or TNF receptor 2 agonism. Proc. Natl. Acad. Sci. U.S.A. 105, 13644�. doi: 10.1073/pnas.0803429105

Barnum, C. J., Chen, X., Chung, J., Chang, J., Williams, M., Grigoryan, N., et al. (2014). Peripheral administration of the selective inhibitor of soluble tumor necrosis factor (TNF) XPro ® 1595 attenuates nigral cell loss and glial activation in 6-OHDA hemiparkinsonian rats. J. Parkinsons Dis. 4, 349�. doi: 10.3233/JPD-140410

Black, R. A., Rauch, C. T., Kozlosky, C. J., Peschon, J. J., Slack, J. L., Wolfson, M. F., et al. (1997). A metalloproteinase disintegrin that releases tumour-necrosis factor-alpha from cells. Nature 385, 729�. doi: 10.1038/385729a0

Bodmer, J.-L., Schneider, P., and Tschopp, J. (2002). The molecular architecture of the TNF superfamily. Trends Biochem. Sci. 27, 19�. doi: 10.1016/s0968-0004(01)01995-8

Borghi, A., Haegman, M., Fischer, R., Carpentier, I., Bertrand, M. J. M., Libert, C., et al. (2018). The E3 ubiquitin ligases HOIP and cIAP1 are recruited to the TNFR2 signaling complex and mediate TNFR2-induced canonical NF-㮫 signaling. Biochem. Pharmacol. 153, 292�. doi: 10.1016/j.bcp.2018.01.039

Boschert, V., Krippner-Heidenreich, A., Branschl, M., Tepperink, J., Aird, A., and Scheurich, P. (2010). Single chain TNF derivatives with individually mutated receptor binding sites reveal differential stoichiometry of ligand receptor complex formation for TNFR1 and TNFR2. Cell. Signal. 22, 1088�. doi: 10.1016/j.cellsig.2010.02.011

Brambilla, R., Ashbaugh, J. J., Magliozzi, R., Dellarole, A., Karmally, S., Szymkowski, D. E., et al. (2011). Inhibition of soluble tumour necrosis factor is therapeutic in experimental autoimmune encephalomyelitis and promotes axon preservation and remyelination. Brain 134, 2736�. doi: 10.1093/brain/awr199

Brinkman, B. M., Telliez, J. B., Schievella, A. R., Lin, L. L., and Goldfeld, A. E. (1999). Engagement of tumor necrosis factor (TNF) receptor 1 leads to ATF-2- and p38 mitogen-activated protein kinase-dependent TNF-alpha gene expression. J. Biol. Chem. 274, 30882�. doi: 10.1074/jbc.274.43.30882

Brünker, P., Wartha, K., Friess, T., Grau-Richards, S., Waldhauer, I., Koller, C. F., et al. (2016). RG7386, a novel tetravalent FAP-DR5 antibody, effectively triggers FAP-dependent, avidity-driven DR5 hyperclustering and tumor cell apoptosis. Mol. Cancer Ther. 15, 946�. doi: 10.1158/1535-7163.MCT-15-0647

Cantley, L. C. (2002). The phosphoinositide 3-kinase pathway. Science 296, 1655�.

Chalasani, N., Younossi, Z., Lavine, J. E., Charlton, M., Cusi, K., Rinella, M., et al. (2018). The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of liver diseases. Hepatology 67, 328�. doi: 10.1002/cld.722

Chan, F. K., Chun, H. J., Zheng, L., Siegel, R. M., Bui, K. L., and Lenardo, M. J. (2000). A domain in TNF receptors that mediates ligand-independent receptor assembly and signaling. Science 288, 2351�. doi: 10.1126/science.288.5475.2351

Chen, X., Bäumel, M., Männel, D. N., Howard, O. M. Z., and Oppenheim, J. J. (2007). Interaction of TNF with TNF receptor type 2 promotes expansion and function of mouse CD4+CD25+ T regulatory cells. J. Immunol. 179, 154�. doi: 10.4049/jimmunol.179.1.154

Chen, X., Hamano, R., Subleski, J. J., Hurwitz, A. A., Howard, O. M. Z., and Oppenheim, J. J. (2010a). Expression of costimulatory TNFR2 induces resistance of CD4+FoxP3- conventional T cells to suppression by CD4+FoxP3+ regulatory T cells. J. Immunol. 185, 174�. doi: 10.4049/jimmunol.0903548

Chen, X., Nie, Y., Xiao, H., Bian, Z., Scarzello, A. J., Song, N.-Y., et al. (2016). TNFR2 expression by CD4 effector T cells is required to induce full-fledged experimental colitis. Sci. Rep. 6:32834. doi: 10.1038/srep32834

Chen, X., Subleski, J. J., Hamano, R., Howard, O. Z., Wiltrout, R. H., and Oppenheim, J. J. (2010b). Co-expression of TNFR2 and CD25 identifies more of the functional CD4+FoxP3+ regulatory T cells in human peripheral blood. Eur. J. Immunol. 40, 1099�. doi: 10.1002/eji.200940022

Chen, X., Subleski, J. J., Kopf, H., Howard, O. M. Z., Männel, D. N., and Oppenheim, J. J. (2008). Cutting edge: expression of TNFR2 defines a maximally suppressive subset of mouse CD4+CD25+FoxP3+ T regulatory cells: applicability to tumor-infiltrating T regulatory cells. J. Immunol. 180, 6467�. doi: 10.4049/jimmunol.180.10.6467

Chen, X., Wu, X., Zhou, Q., Howard, O. M. Z., Netea, M. G., and Oppenheim, J. J. (2013). TNFR2 is critical for the stabilization of the CD4+Foxp3+ regulatory T. cell phenotype in the inflammatory environment. J. Immunol. 190, 1076�. doi: 10.4049/jimmunol.1202659

Chopra, M., Biehl, M., Steinfatt, T., Brandl, A., Kums, J., Amich, J., et al. (2016). Exogenous TNFR2 activation protects from acute GvHD via host T reg cell expansion. J. Exp. Med. 213, 1881�. doi: 10.1084/jem.20151563

Clausen, B. H., Degn, M., Martin, N. A., Couch, Y., Karimi, L., Ormhøj, M., et al. (2014). Systemically administered anti-TNF therapy ameliorates functional outcomes after focal cerebral ischemia. J. Neuroinflammation 11:203. doi: 10.1186/s12974-014-0203-6

Constantin, C. E., Mair, N., Sailer, C. A., Andratsch, M., Xu, Z.-Z., Blumer, M. J. F., et al. (2008). Endogenous tumor necrosis factor alpha (TNFalpha) requires TNF receptor type 2 to generate heat hyperalgesia in a mouse cancer model. J. Neurosci. 28, 5072�. doi: 10.1523/JNEUROSCI.4476-07.2008

Cordy, J. C., Morley, P. J., Wright, T. J., Birchler, M. A., Lewis, A. P., Emmins, R., et al. (2015). Specificity of human anti-variable heavy (VH) chain autoantibodies and impact on the design and clinical testing of a VH domain antibody antagonist of tumour necrosis factor-α receptor 1. Clin. Exp. Immunol. 182, 139�. doi: 10.1111/cei.12680

Crespo, J., Cayón, A., Fernández-Gil, P., Hernández-Guerra, M., Mayorga, M., Domínguez-Dໞz, A., et al. (2001). Gene expression of tumor necrosis factor alpha and TNF-receptors, p55 and p75, in nonalcoholic steatohepatitis patients. Hepatology 34, 1158�. doi: 10.1053/jhep.2001.29628

del Rivero, T., Fischer, R., Yang, F., Swanson, K. A., and Bethea, J. R. (2019). Tumor necrosis factor receptor 1 inhibition is therapeutic for neuropathic pain in males but not in females. Pain 160, 922�. doi: 10.1097/j.pain.0000000000001470

Dellarole, A., Morton, P., Brambilla, R., Walters, W., Summers, S., Bernardes, D., et al. (2014). Neuropathic pain-induced depressive-like behavior and hippocampal neurogenesis and plasticity are dependent on TNFR1 signaling. Brain Behav. Immun. 41, 65�. doi: 10.1016/j.bbi.2014.04.003

Deng, G.-M., Zheng, L., Chan, F. K.-M., and Lenardo, M. (2005). Amelioration of inflammatory arthritis by targeting the pre-ligand assembly domain of tumor necrosis factor receptors. Nat. Med. 11, 1066�. doi: 10.1038/nm1304

Dolga, A. M., Granic, I., Blank, T., Knaus, H.-G., Spiess, J., Luiten, P. G. M., et al. (2008). TNF-alpha-mediates neuroprotection against glutamate-induced excitotoxicity via NF-kappaB-dependent up-regulation of K2.2 channels. J. Neurochem. 107, 1158�. doi: 10.1111/j.1471-4159.2008.05701.x

Dong, Y., Fischer, R., Naudé, P. J. W., Maier, O., Nyakas, C., Duffey, M., et al. (2016). Essential protective role of tumor necrosis factor receptor 2 in neurodegeneration. Proc. Natl. Acad. Sci. U.S.A. 113, 12304�. doi: 10.1073/pnas.1605195113

Ellman, D. G., Degn, M., Lund, M. C., Clausen, B. H., Novrup, H. G., Flæng, S. B., et al. (2016). Genetic ablation of soluble TNF does not affect lesion size and functional recovery after moderate spinal cord injury in mice. Mediators Inflamm. 2016:2684098. doi: 10.1155/2016/2684098

Eugster, H. P., Frei, K., Bachmann, R., Bluethmann, H., Lassmann, H., and Fontana, A. (1999). Severity of symptoms and demyelination in MOG-induced EAE depends on TNFR1. Eur. J. Immunol. 29, 626�. doi: 10.1002/(SICI)1521-4141(199902)29:02𼘦::AID-IMMU626ϣ.0.CO2-A

Farrell, K., and Houle, J. D. (2019). Systemic inhibition of soluble tumor necrosis factor with XPro1595 exacerbates a post-spinal cord injury depressive phenotype in female rats. J. Neurotrauma 36, 2964�. doi: 10.1089/neu.2019.6438

Fischer, R., Kontermann, R., and Maier, O. (2015). Targeting sTNF/TNFR1 signaling as a new therapeutic strategy. Antibodies 4, 48�.

Fischer, R., and Maier, O. (2015). Interrelation of oxidative stress and inflammation in neurodegenerative disease: role of TNF. Oxid. Med. Cell. Longev. 2015:610813. doi: 10.1155/2015/610813

Fischer, R., Maier, O., Naumer, M., Krippner-Heidenreich, A., Scheurich, P., and Pfizenmaier, K. (2011a). Ligand-induced internalization of TNF receptor 2 mediated by a di-leucin motif is dispensable for activation of the NF㮫 pathway. Cell. Signal. 23, 161�. doi: 10.1016/j.cellsig.2010.08.016

Fischer, R., Maier, O., Siegemund, M., Wajant, H., Scheurich, P., and Pfizenmaier, K. (2011b). A TNF receptor 2 selective agonist rescues human neurons from oxidative stress-induced cell death. PLoS One 6:e27621. doi: 10.1371/journal.pone.0027621

Fischer, R., Marsal, J., Guttà, C., Eisler, S. A., Peters, N., Bethea, J. R., et al. (2017). Novel strategies to mimic transmembrane tumor necrosis factor-dependent activation of tumor necrosis factor receptor 2. Sci. Rep. 7:6607. doi: 10.1038/s41598-017-06993-4

Fischer, R., Padutsch, T., Bracchi-Ricard, V., Murphy, K. L., Martinez, G. F., Delguercio, N., et al. (2019a). Exogenous activation of tumor necrosis factor receptor 2 promotes recovery from sensory and motor disease in a model of multiple sclerosis. Brain Behav. Immun. 81, 247�. doi: 10.1016/j.bbi.2019.06.021

Fischer, R., Proske, M., Duffey, M., Stangl, H., Martinez, G. F., Peters, N., et al. (2018). Selective activation of tumor necrosis factor receptor II induces antiinflammatory responses and alleviates experimental arthritis. Arthr. Rheumatol. 70, 722�. doi: 10.1002/art.40413

Fischer, R., Sendetski, M., del Rivero, T., Martinez, G. F., Bracchi-Ricard, V., Swanson, K. A., et al. (2019b). TNFR2 promotes Treg-mediated recovery from neuropathic pain across sexes. Proc. Natl. Acad. Sci. U.S.A. 116, 17045�. doi: 10.1073/pnas.1902091116

Fischer, R., Wajant, H., Kontermann, R., Pfizenmaier, K., and Maier, O. (2014). Astrocyte-specific activation of TNFR2 promotes oligodendrocyte maturation by secretion of leukemia inhibitory factor. Glia 62, 272�. doi: 10.1002/glia.22605

Fontaine, V., Mohand-Said, S., Hanoteau, N., Fuchs, C., Pfizenmaier, K., and Eisel, U. (2002). Neurodegenerative and neuroprotective effects of tumor Necrosis factor (TNF) in retinal ischemia: opposite roles of TNF receptor 1 and TNF receptor 2. J. Neurosci. 22:RC216. doi: 10.1523/JNEUROSCI.22-07-j0001.2002

Fromm, P. D., Kling, J. C., Remke, A., Bogdan, C., and Körner, H. (2015). Fatal leishmaniasis in the absence of TNF despite a strong Th1 response. Front. Microbiol. 6:1520. doi: 10.3389/fmicb.2015.01520

Gao, H., Danzi, M. C., Choi, C. S., Taherian, M., Dalby-Hansen, C., Ellman, D. G., et al. (2017). Opposing functions of microglial and macrophagic TNFR2 in the pathogenesis of experimental autoimmune encephalomyelitis. Cell Rep. 18, 198�. doi: 10.1016/j.celrep.2016.11.083

Geis, C., Graulich, M., Wissmann, A., Hagenacker, T., Thomale, J., Sommer, C., et al. (2010). Evoked pain behavior and spinal glia activation is dependent on tumor necrosis factor receptor 1 and 2 in a mouse model of bone cancer pain. Neuroscience 169, 463�. doi: 10.1016/j.neuroscience.2010.04.022

Gerald, M. J., Bracchi-Ricard, V., Ricard, J., Fischer, R., Nandakumar, B., Blumenthal, G. H., et al. (2019). Continuous infusion of an agonist of the tumor necrosis factor receptor 2 in the spinal cord improves recovery after traumatic contusive injury. CNS Neurosci. Ther. 25, 884�. doi: 10.1111/cns.13125

Gerken, M., Krippner-Heidenreich, A., Steinert, S., Willi, S., Neugart, F., Zappe, A., et al. (2010). Fluorescence correlation spectroscopy reveals topological segregation of the two tumor necrosis factor membrane receptors. Biochim. Biophys. Acta 1798, 1081�. doi: 10.1016/j.bbamem.2010.02.021

Goodall, L. J., Ovecka, M., Rycroft, D., Friel, S. L., Sanderson, A., Mistry, P., et al. (2015). Pharmacokinetic and pharmacodynamic characterisation of an anti-mouse TNF receptor 1 domain antibody formatted for in vivo half-life extension. PLoS One 10:e0137065. doi: 10.1371/journal.pone.0137065

Gray, P. W., Aggarwal, B. B., Benton, C. V., Bringman, T. S., Henzel, W. J., Jarrett, J. A., et al. (1984). Cloning and expression of cDNA for human lymphotoxin, a lymphokine with tumour necrosis activity. Nature 312, 721�. doi: 10.1038/312721a0

Gregory, A. P., Dendrou, C. A., Attfield, K. E., Haghikia, A., Xifara, D. K., Butter, F., et al. (2012). TNF receptor 1 genetic risk mirrors outcome of anti-TNF therapy in multiple sclerosis. Nature 488, 508�. doi: 10.1038/nature11307

Grell, M., Douni, E., Wajant, H., Löhden, M., Clauss, M., Maxeiner, B., et al. (1995). The transmembrane form of tumor necrosis factor is the prime activating ligand of the 80 kDa tumor necrosis factor receptor. Cell 83, 793�. doi: 10.1016/0092-8674(95)90192-2

Grell, M., Wajant, H., Zimmermann, G., and Scheurich, P. (1998). The type 1 receptor (CD120a) is the high-affinity receptor for soluble tumor necrosis factor. Proc. Natl. Acad. Sci. U.S.A. 95, 570�. doi: 10.1073/pnas.95.2.570

Grootjans, S., Vanden Berghe, T., and Vandenabeele, P. (2017). Initiation and execution mechanisms of necroptosis: an overview. Cell Death Differ. 24, 1184�. doi: 10.1038/cdd.2017.65

Guenzi, E., Stroissnig, H., Vierboom, M., and Herrmann, A. (2013). FRI0231 Atrosab, a humanized antibody directed against tnf-receptor 1, hold great promises for the treatment of rheumatoid arthritis. Ann. Rheum. Dis. 72, 2�.

Hamid, T., Gu, Y., Ortines, R. V., Bhattacharya, C., Wang, G., Xuan, Y.-T., et al. (2009). Divergent tumor necrosis factor receptor-related remodeling responses in heart failure: role of nuclear factor-kappaB and inflammatory activation. Circulation 119, 1386�. doi: 10.1161/CIRCULATIONAHA.108.802918

Harms, A. S., Barnum, C. J., Ruhn, K. A., Varghese, S., Treviño, I., Blesch, A., et al. (2011). Delayed dominant-negative TNF gene therapy halts progressive loss of nigral dopaminergic neurons in a rat model of Parkinson’s disease. Mol. Ther. 19, 46�. doi: 10.1038/mt.2010.217

He, T., Liu, S., Chen, S., Ye, J., Wu, X., Bian, Z., et al. (2018). The p38 MAPK inhibitor SB203580 abrogates tumor necrosis factor-induced proliferative expansion of mouse CD4+Foxp3+ regulatory T cells. Front. Immunol. 9:1556. doi: 10.3389/fimmu.2018.01556

Hirose, T., Fukuma, Y., Takeshita, A., and Nishida, K. (2018). The role of lymphotoxin-α in rheumatoid arthritis. Inflamm. Res. 67, 495�. doi: 10.1007/s00011-018-1139-6

Holland, M. C., Wurthner, J. U., Morley, P. J., Birchler, M. A., Lambert, J., Albayaty, M., et al. (2013). Autoantibodies to variable heavy (VH) chain Ig sequences in humans impact the safety and clinical pharmacology of a VH domain antibody antagonist of TNF-α receptor 1. J. Clin. Immunol. 33, 1192�. doi: 10.1007/s10875-013-9915-0

Horwitz, D. A., Pan, S., Ou, J.-N., Wang, J., Chen, M., Gray, J. D., et al. (2013). Therapeutic polyclonal human CD8+ CD25+ Fox3+ TNFR2+ PD-L1+ regulatory cells induced ex-vivo. Clin. Immunol. 149, 450�. doi: 10.1016/j.clim.2013.08.007

Hotamisligil, G. S., Shargill, N. S., and Spiegelman, B. M. (1993). Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science 259, 87�. doi: 10.1126/science.7678183

Hui, J. M., Hodge, A., Farrell, G. C., Kench, J. G., Kriketos, A., and George, J. (2004). Beyond insulin resistance in NASH: TNF-alpha or adiponectin? Hepatology 40, 46�. doi: 10.1002/hep.20280

Hutt, M., Fellermeier-Kopf, S., Seifert, O., Schmitt, L. C., Pfizenmaier, K., and Kontermann, R. E. (2018). Targeting scFv-Fc-scTRAIL fusion proteins to tumor cells. Oncotarget 9, 11322�. doi: 10.18632/oncotarget.24379

Inglis, J. J., Nissim, A., Lees, D. M., Hunt, S. P., Chernajovsky, Y., and Kidd, B. L. (2005). The differential contribution of tumour necrosis factor to thermal and mechanical hyperalgesia during chronic inflammation. Arthritis Res. Ther. 7, R807–R816. doi: 10.1186/ar1743

Inoue, M., Ando, D., Kamada, H., Taki, S., Niiyama, M., Mukai, Y., et al. (2017). A trimeric structural fusion of an antagonistic tumor necrosis factor-α mutant enhances molecular stability and enables facile modification. J. Biol. Chem. 292, 6438�. doi: 10.1074/jbc.M117.779686

Inoue, M., Kamada, H., Abe, Y., Higashisaka, K., Nagano, K., Mukai, Y., et al. (2015). Aminopeptidase P3, a new member of the TNF-TNFR2 signaling complex, induces phosphorylation of JNK1 and JNK2. J. Cell Sci. 128, 656�. doi: 10.1242/jcs.149385

Jupp, O. J., McFarlane, S. M., Anderson, H. M., Littlejohn, A. F., Mohamed, A. A., MacKay, R. H., et al. (2001). Type II tumour necrosis factor-alpha receptor (TNFR2) activates c-Jun N-terminal kinase (JNK) but not mitogen-activated protein kinase (MAPK) or p38 MAPK pathways. Biochem. J. 359, 525�. doi: 10.1042/0264-6021:3590525

Karamita, M., Barnum, C., Mཫius, W., Tansey, M. G., Szymkowski, D. E., Lassmann, H., et al. (2017). Therapeutic inhibition of soluble brain TNF promotes remyelination by increasing myelin phagocytosis by microglia. JCI Insight 2:e87455. doi: 10.1172/jci.insight.87455

Kassiotis, G., and Kollias, G. (2001). Uncoupling the proinflammatory from the immunosuppressive properties of tumor necrosis factor (TNF) at the p55 TNF receptor level: implications for pathogenesis and therapy of autoimmune demyelination. J. Exp. Med. 193, 427�. doi: 10.1084/jem.193.4.427

Kennedy, W. P., Simon, J. A., Offutt, C., Horn, P., Herman, A., Townsend, M. J., et al. (2014). Efficacy and safety of pateclizumab (anti-lymphotoxin-α) compared to adalimumab in rheumatoid arthritis: a head-to-head phase 2 randomized controlled study (The ALTαRA Study). Arthritis Res. Ther. 16:467. doi: 10.1186/s13075-014-0467-3

Khaksar, S., and Bigdeli, M. R. (2017a). Correlation between cannabidiol-induced reduction of infarct volume and inflammatory factors expression in ischemic stroke model. Basic Clin. Neurosci. 8, 139�. doi: 10.18869/

Khaksar, S., and Bigdeli, M. R. (2017b). Intra-cerebral cannabidiol infusion-induced neuroprotection is partly associated with the TNF-α/TNFR1/NF-㮫 pathway in transient focal cerebral ischaemia. Brain Inj. 31, 1932�. doi: 10.1080/02699052.2017.1358397

Kim, E. Y., Priatel, J. J., Teh, S.-J., and Teh, H.-S. (2006). TNF receptor type 2 (p75) functions as a costimulator for antigen-driven T cell responses in vivo. J. Immunol. 176, 1026�. doi: 10.4049/jimmunol.176.2.1026

Kitagaki, M., Isoda, K., Kamada, H., Kobayashi, T., Tsunoda, S., Tsutsumi, Y., et al. (2012). Novel TNF-α receptor 1 antagonist treatment attenuates arterial inflammation and intimal hyperplasia in mice. J. Atheroscler Thromb. 19, 36�. doi: 10.5551/jat.9746

Kodama, S., Davis, M., and Faustman, D. L. (2005). The therapeutic potential of tumor necrosis factor for autoimmune disease: a mechanistically based hypothesis. Cell. Mol. Life Sci. 62, 1850�. doi: 10.1007/s00018-005-5022-6

Kodama, S., Kühtreiber, W., Fujimura, S., Dale, E. A., and Faustman, D. L. (2003). Islet regeneration during the reversal of autoimmune diabetes in NOD mice. Science 302, 1223�. doi: 10.1126/science.1088949

Kontermann, R. E. (2011). Strategies for extended serum half-life of protein therapeutics. Curr. Opin. Biotechnol. 22, 868�. doi: 10.1016/j.copbio.2011.06.012

Kontermann, R. E., Münkel, S., Neumeyer, J., Müller, D., Branschl, M., Scheurich, P., et al. (2008). A humanized tumor necrosis factor receptor 1 (TNFR1)-specific antagonistic antibody for selective inhibition of tumor necrosis factor (TNF) action. J. Immunother. 31, 225�. doi: 10.1097/CJI.0b013e31816a88f9

Kontermann, R. E., Scheurich, P., and Pfizenmaier, K. (2009). Antagonists of TNF action: clinical experience and new developments. Expert Opin. Drug Discov. 4, 279�. doi: 10.1517/17460440902785167

Kriegler, M., Perez, C., DeFay, K., Albert, I., and Lu, S. D. (1988). A novel form of TNF/cachectin is a cell surface cytotoxic transmembrane protein: ramifications for the complex physiology of TNF. Cell 53, 45�. doi: 10.1016/0092-8674(88)90486-2

Krippner-Heidenreich, A., Grunwald, I., Zimmermann, G., Kühnle, M., Gerspach, J., Sterns, T., et al. (2008). Single-chain TNF, a TNF derivative with enhanced stability and antitumoral activity. J. Immunol. 180, 8176�. doi: 10.4049/jimmunol.180.12.8176

Krippner-Heidenreich, A., T࿋ing, F., Bryde, S., Willi, S., Zimmermann, G., and Scheurich, P. (2002). Control of receptor-induced signaling complex formation by the kinetics of ligand/receptor interaction. J. Biol. Chem. 277, 44155�. doi: 10.1074/jbc.M207399200

Lamontain, V., Schmid, T., Weber-Steffens, D., Zeller, D., Jenei-Lanzl, Z., Wajant, H., et al. (2019). Stimulation of TNF receptor type 2 expands regulatory T cells and ameliorates established collagen-induced arthritis in mice. Cell. Mol. Immunol. 16, 65�. doi: 10.1038/cmi.2017.138

Lawlor, M. A., and Alessi, D. R. (2001). PKB/Akt: a key mediator of cell proliferation, survival and insulin responses? J. Cell Sci. 114, 2903�.

Lenercept Study Group (1999). TNF neutralization in MS: results of a randomized, placebo-controlled multicenter study. The lenercept multiple sclerosis study group and the University of British Columbia MS/MRI analysis group. Neurology 53, 457�.

Lis, K., Grygorowicz, T., Cudna, A., Szymkowski, D. E., and Bałkowiec-Iskra, E. (2017). Inhibition of TNF reduces mechanical orofacial hyperalgesia induced by complete Freund’s adjuvant by a TRPV1-dependent mechanism in mice. Pharmacol. Rep. 69, 1380�. doi: 10.1016/j.pharep.2017.05.013

Lo, C. H., Schaaf, T. M., Grant, B. D., Lim, C. K.-W., Bawaskar, P., Aldrich, C. C., et al. (2019). Noncompetitive inhibitors of TNFR1 probe conformational activation states. Sci. Signal. 12:eaav5637. doi: 10.1126/scisignal.aav5637

Lo, C. H., Vunnam, N., Lewis, A. K., Chiu, T.-L., Brummel, B. E., Schaaf, T. M., et al. (2017). An innovative high-throughput screening approach for discovery of small molecules that inhibit TNF receptors. SLAS Discov. 22, 950�. doi: 10.1177/2472555217706478

Loetscher, H., Stueber, D., Banner, D., Mackay, F., and Lesslauer, W. (1993). Human tumor necrosis factor alpha (TNF alpha) mutants with exclusive specificity for the 55-kDa or 75-kDa TNF receptors. J. Biol. Chem. 268, 26350�.

MacPherson, K. P., Sompol, P., Kannarkat, G. T., Chang, J., Sniffen, L., Wildner, M. E., et al. (2017). Peripheral administration of the soluble TNF inhibitor XPro1595 modifies brain immune cell profiles, decreases beta-amyloid plaque load, and rescues impaired long-term potentiation in 5xFAD mice. Neurobiol. Dis. 102, 81�. doi: 10.1016/j.nbd.2017.02.010

Madsen, P. M., Desu, H. L., Pablo de Rivero Vaccari, J., Florimon, Y., Ellman, D. G., Keane, R. W., et al. (2019). Oligodendrocytes modulate the immune-inflammatory response in EAE via TNFR2 signaling. Brain Behav. Immun. 84, 132�. doi: 10.1016/j.bbi.2019.11.017

Madsen, P. M., Motti, D., Karmally, S., Szymkowski, D. E., Lambertsen, K. L., Bethea, J. R., et al. (2016). Oligodendroglial TNFR2 mediates membrane TNF-dependent repair in experimental autoimmune encephalomyelitis by promoting oligodendrocyte differentiation and remyelination. J. Neurosci. 36, 5128�. doi: 10.1523/JNEUROSCI.0211-16.2016

Maier, O., Fischer, R., Agresti, C., and Pfizenmaier, K. (2013). TNF receptor 2 protects oligodendrocyte progenitor cells against oxidative stress. Biochem. Biophys. Res. Commun. 440, 336�. doi: 10.1016/j.bbrc.2013.09.083

Mann, D. L. (2002). Inflammatory mediators and the failing heart: past, present, and the foreseeable future. Circ. Res. 91, 988�. doi: 10.1161/01.res.0000043825.01705.1b

Marchetti, L., Klein, M., Schlett, K., Pfizenmaier, K., and Eisel, U. L. M. (2004). Tumor necrosis factor (TNF)-mediated neuroprotection against glutamate-induced excitotoxicity is enhanced by N-methyl-D-aspartate receptor activation. Essential role of a TNF receptor 2-mediated phosphatidylinositol 3-kinase-dependent NF-kappa B pathway. J. Biol. Chem. 279, 32869�. doi: 10.1074/jbc.M311766200

McAlpine, F. E., Lee, J.-K., Harms, A. S., Ruhn, K. A., Blurton-Jones, M., Hong, J., et al. (2009). Inhibition of soluble TNF signaling in a mouse model of Alzheimer’s disease prevents pre-plaque amyloid-associated neuropathology. Neurobiol. Dis. 34, 163�. doi: 10.1016/j.nbd.2009.01.006

McCoy, M. K., Martinez, T. N., Ruhn, K. A., Szymkowski, D. E., Smith, C. G., Botterman, B. R., et al. (2006). Blocking soluble tumor necrosis factor signaling with dominant-negative tumor necrosis factor inhibitor attenuates loss of dopaminergic neurons in models of Parkinson’s disease. J. Neurosci. 26, 9365�. doi: 10.1523/JNEUROSCI.1504-06.2006

McCoy, M. K., Ruhn, K. A., Martinez, T. N., McAlpine, F. E., Blesch, A., and Tansey, M. G. (2008). Intranigral lentiviral delivery of dominant-negative TNF attenuates neurodegeneration and behavioral deficits in hemiparkinsonian rats. Mol. Ther. 16, 1572�. doi: 10.1038/mt.2008.146

Medler, J., Nelke, J., Weisenberger, D., Steinfatt, T., Rothaug, M., Berr, S., et al. (2019). TNFRSF receptor-specific antibody fusion proteins with targeting controlled FcγR-independent agonistic activity. Cell Death Dis. 10, 224. doi: 10.1038/s41419-019-1456-x

Mehta, A. K., Gracias, D. T., and Croft, M. (2018). TNF activity and T cells. Cytokine 101, 14�. doi: 10.1016/j.cyto.2016.08.003

Micheau, O., and Tschopp, J. (2003). Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes. Cell 114, 181�. doi: 10.1016/s0092-8674(03)00521-x

Miller, P. G., Bonn, M. B., and McKarns, S. C. (2015). Transmembrane TNF-TNFR2 Impairs Th17 Differentiation by Promoting Il2 Expression. J. Immunol. 195, 2633�. doi: 10.4049/jimmunol.1500286

Mironets, E., Fischer, R., Bracchi-Ricard, V., Saltos, T. M., Truglio, T. S., O’Reilly, M. L., et al. (2020). Attenuating neurogenic sympathetic hyperreflexia robustly improves antibacterial immunity after chronic spinal cord injury. J. Neurosci. 40, 478�. doi: 10.1523/JNEUROSCI.2417-19.2019

Mironets, E., Osei-Owusu, P., Bracchi-Ricard, V., Fischer, R., Owens, E. A., Ricard, J., et al. (2018). Soluble TNFα signaling within the spinal cord contributes to the development of autonomic dysreflexia and ensuing vascular and immune dysfunction after spinal cord injury. J. Neurosci. 38, 4146�. doi: 10.1523/JNEUROSCI.2376-17.2018

Monaco, C., Nanchahal, J., Taylor, P., and Feldmann, M. (2015). Anti-TNF therapy: past, present and future. Int. Immunol. 27, 55�. doi: 10.1093/intimm/dxu102

Monden, Y., Kubota, T., Inoue, T., Tsutsumi, T., Kawano, S., Ide, T., et al. (2007). Tumor necrosis factor-alpha is toxic via receptor 1 and protective via receptor 2 in a murine model of myocardial infarction. Am. J. Physiol. Heart Circ. Physiol. 293, H743–H753. doi: 10.1152/ajpheart.00166.2007

Mori, L., Iselin, S., De Libero, G., and Lesslauer, W. (1996). Attenuation of collagen-induced arthritis in 55-kDa TNF receptor type 1 (TNFR1)-IgG1-treated and TNFR1-deficient mice. J. Immunol. 157, 3178�.

Mukai, Y., Shibata, H., Nakamura, T., Yoshioka, Y., Abe, Y., Nomura, T., et al. (2009). Structure-function relationship of tumor necrosis factor (TNF) and its receptor interaction based on 3D structural analysis of a fully active TNFR1-selective TNF mutant. J. Mol. Biol. 385, 1221�. doi: 10.1016/j.jmb.2008.11.053

Murphy, K. L., Bethea, J. R., and Fischer, R. (2017). “Neuropathic pain in multiple sclerosis𠄼urrent therapeutic intervention and future treatment perspectives,” in Multiple Sclerosis: Perspectives in Treatment and Pathogenesis, eds I. S. Zagon and P. J. McLaughlin (Brisbane, QLD: Codon Publications). doi: 10.15586/codon.multiplesclerosis.2017.ch4

Musicki, K., Briscoe, H., Tran, S., Britton, W. J., and Saunders, B. M. (2006). Differential requirements for soluble and transmembrane tumor necrosis factor in the immunological control of primary and secondary Listeria monocytogenes infection. Infect. Immun. 74, 3180�. doi: 10.1128/IAI.02004-05

Nashleanas, M., Kanaly, S., and Scott, P. (1998). Control of Leishmania major infection in mice lacking TNF receptors. J. Immunol. 160, 5506�.

Natoli, G., Costanzo, A., Ianni, A., Templeton, D. J., Woodgett, J. R., Balsano, C., et al. (1997). Activation of SAPK/JNK by TNF receptor 1 through a noncytotoxic TRAF2-dependent pathway. Science 275, 200�. doi: 10.1126/science.275.5297.200

Nomura, T., Abe, Y., Kamada, H., Shibata, H., Kayamuro, H., Inoue, M., et al. (2011). Therapeutic effect of PEGylated TNFR1-selective antagonistic mutant TNF in experimental autoimmune encephalomyelitis mice. J. Control Release 149, 8�. doi: 10.1016/j.jconrel.2009.12.015

Notley, C. A., McCann, F. E., Inglis, J. J., and Williams, R. O. (2010). ANTI-CD3 therapy expands the numbers of CD4+ and CD8+ Treg cells and induces sustained amelioration of collagen-induced arthritis. Arthritis Rheum. 62, 171�. doi: 10.1002/art.25058

Novrup, H. G., Bracchi-Ricard, V., Ellman, D. G., Ricard, J., Jain, A., Runko, E., et al. (2014). Central but not systemic administration of XPro1595 is therapeutic following moderate spinal cord injury in mice. J. Neuroinflammation 11:159. doi: 10.1186/s12974-014-0159-6

Okubo, Y., Mera, T., Wang, L., and Faustman, D. L. (2013). Homogeneous expansion of human T-regulatory cells via tumor necrosis factor receptor 2. Sci. Rep. 3:3153. doi: 10.1038/srep03153

Okubo, Y., Torrey, H., Butterworth, J., Zheng, H., and Faustman, D. L. (2016). Treg activation defect in type 1 diabetes: correction with TNFR2 agonism. Clin. Transl. Immunol. 5:e56. doi: 10.1038/cti.2015.43

Olleros, M. L., Vesin, D., Fotio, A. L., Santiago-Raber, M.-L., Tauzin, S., Szymkowski, D. E., et al. (2010). Soluble TNF, but not membrane TNF, is critical in LPS-induced hepatitis. J. Hepatol. 53, 1059�. doi: 10.1016/j.jhep.2010.05.029

Olleros, M. L., Vesin, D., Lambou, A. F., Janssens, J.-P., Ryffel, B., Rose, S., et al. (2009). Dominant-negative tumor necrosis factor protects from Mycobacterium bovis Bacillus Calmette Guérin (BCG) and endotoxin-induced liver injury without compromising host immunity to BCG and Mycobacterium tuberculosis. J. Infect Dis. 199, 1053�. doi: 10.1086/597204

Ortí-Casañ, N., Wu, Y., Naudé, P. J. W., Deyn, P. P., de Zuhorn, I. S., and Eisel, U. L. M. (2019). Targeting TNFR2 as a novel therapeutic strategy for Alzheimer’s disease. Front. Neurosci. 13:49. doi: 10.3389/fnins.2019.00049

Padutsch, T., Sendetski, M., Huber, C., Peters, N., Pfizenmaier, K., Bethea, J. R., et al. (2019). Superior Treg-expanding properties of a novel dual-acting cytokine fusion protein. Front. Pharmacol. 10:1490. doi: 10.3389/fphar.2019.01490

Patel, J. R., Williams, J. L., Muccigrosso, M. M., Liu, L., Sun, T., Rubin, J. B., et al. (2012). Astrocyte TNFR2 is required for CXCL12-mediated regulation of oligodendrocyte progenitor proliferation and differentiation within the adult CNS. Acta Neuropathol. 124, 847�. doi: 10.1007/s00401-012-1034-0

Pegoretti, V., Baron, W., Laman, J. D., and Eisel, U. L. M. (2018). Selective modulation of TNF-TNFRs signaling: insights for multiple sclerosis treatment. Front. Immunol. 9:925. doi: 10.3389/fimmu.2018.00925

Pfeffer, K., Matsuyama, T., Kündig, T. M., Wakeham, A., Kishihara, K., Shahinian, A., et al. (1993). Mice deficient for the 55 kd tumor necrosis factor receptor are resistant to endotoxic shock, yet succumb to L. monocytogenes infection. Cell 73, 457�. doi: 10.1016/0092-8674(93)90134-c

Probert, L., Akassoglou, K., Pasparakis, M., Kontogeorgos, G., and Kollias, G. (1995). Spontaneous inflammatory demyelinating disease in transgenic mice showing central nervous system-specific expression of tumor necrosis factor alpha. Proc. Natl. Acad. Sci. U.S.A. 92, 11294�. doi: 10.1073/pnas.92.24.11294

Proudfoot, A., Bayliffe, A., O’Kane, C. M., Wright, T., Serone, A., Bareille, P. J., et al. (2018). Novel anti-tumour necrosis factor receptor-1 (TNFR1) domain antibody prevents pulmonary inflammation in experimental acute lung injury. Thorax 73, 723�. doi: 10.1136/thoraxjnl-2017-210305

Ramani, R., Mathier, M., Wang, P., Gibson, G., Tögel, S., Dawson, J., et al. (2004). Inhibition of tumor necrosis factor receptor-1-mediated pathways has beneficial effects in a murine model of postischemic remodeling. Am. J. Physiol. Heart Circ. Physiol. 287, H1369–H1377. doi: 10.1152/ajpheart.00641.2003

Ranzinger, J., Krippner-Heidenreich, A., Haraszti, T., Bock, E., Tepperink, J., Spatz, J. P., et al. (2009). Nanoscale arrangement of apoptotic ligands reveals a demand for a minimal lateral distance for efficient death receptor activation. Nano Lett. 9, 4240�. doi: 10.1021/nl902429b

Rauert, H., Wicovsky, A., Müller, N., Siegmund, D., Spindler, V., Waschke, J., et al. (2010). Membrane tumor necrosis factor (TNF) induces p100 processing via TNF receptor-2 (TNFR2). J. Biol. Chem. 285, 7394�. doi: 10.1074/jbc.M109.037341

Richter, C., Messerschmidt, S., Holeiter, G., Tepperink, J., Osswald, S., Zappe, A., et al. (2012). The tumor necrosis factor receptor stalk regions define responsiveness to soluble versus membrane-bound ligand. Mol. Cell. Biol. 32, 2515�. doi: 10.1128/MCB.06458-11

Richter, F., Liebig, T., Guenzi, E., Herrmann, A., Scheurich, P., Pfizenmaier, K., et al. (2013). Antagonistic TNF receptor one-specific antibody (ATROSAB): receptor binding and in vitro bioactivity. PLoS One 8:e72156. doi: 10.1371/journal.pone.0072156

Richter, F., Seifert, O., Herrmann, A., Pfizenmaier, K., and Kontermann, R. E. (2019a). Improved monovalent TNF receptor 1-selective inhibitor with novel heterodimerizing Fc. MAbs 11, 653�. doi: 10.1080/19420862.2019.1596512

Richter, F., Zettlitz, K. A., Seifert, O., Herrmann, A., Scheurich, P., Pfizenmaier, K., et al. (2019b). Monovalent TNF receptor 1-selective antibody with improved affinity and neutralizing activity. MAbs 11, 166�. doi: 10.1080/19420862.2018.1524664

Rogers, R. C., and Hermann, G. E. (2012). Tumor necrosis factor activation of vagal afferent terminal calcium is blocked by cannabinoids. J. Neurosci. 32, 5237�. doi: 10.1523/JNEUROSCI.6220-11.2012

Rothe, J., Lesslauer, W., Lötscher, H., Lang, Y., Koebel, P., Köntgen, F., et al. (1993). Mice lacking the tumour necrosis factor receptor 1 are resistant to TNF-mediated toxicity but highly susceptible to infection by Listeria monocytogenes. Nature 364, 798�. doi: 10.1038/364798a0

Rothe, M., Pan, M. G., Henzel, W. J., Ayres, T. M., and Goeddel, D. V. (1995a). The TNFR2-TRAF signaling complex contains two novel proteins related to baculoviral inhibitor of apoptosis proteins. Cell 83, 1243�. doi: 10.1016/0092-8674(95)90149-3

Rothe, M., Sarma, V., Dixit, V. M., and Goeddel, D. V. (1995b). TRAF2-mediated activation of NF-kappa B by TNF receptor 2 and CD40. Science 269, 1424�. doi: 10.1126/science.7544915

Rothe, M., Wong, S. C., Henzel, W. J., and Goeddel, D. V. (1994). A novel family of putative signal transducers associated with the cytoplasmic domain of the 75 kDa tumor necrosis factor receptor. Cell 78, 681�. doi: 10.1016/0092-8674(94)90532-0

Ruddle, N. H. (2014). Lymphotoxin and TNF: how it all began-a tribute to the travelers. Cytokine Growth Factor Rev. 25, 83�. doi: 10.1016/j.cytogfr.2014.02.001

Saddala, M. S., and Huang, H. (2019). Identification of novel inhibitors for TNFα, TNFR1 and TNFα-TNFR1 complex using pharmacophore-based approaches. J. Transl. Med. 17, 215. doi: 10.1186/s12967-019-1965-5

Sarbassov, D. D., Guertin, D. A., Ali, S. M., and Sabatini, D. M. (2005). Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 307, 1098�. doi: 10.1126/science.1106148

Schliemann, M., Bullinger, E., Borchers, S., Allgöwer, F., Findeisen, R., and Scheurich, P. (2011). Heterogeneity reduces sensitivity of cell death for TNF-stimuli. BMC Syst. Biol. 5:204. doi: 10.1186/1752-0509-5-204

Schmid, T., Falter, L., Weber, S., Müller, N., Molitor, K., Zeller, D., et al. (2017). Chronic inflammation increases the sensitivity of mouse Treg for TNFR2 costimulation. Front. Immunol. 8:1471. doi: 10.3389/fimmu.2017.01471

Schmukle, A. C., and Walczak, H. (2012). No one can whistle a symphony alone - how different ubiquitin linkages cooperate to orchestrate NF-㮫 activity. J. Cell. Sci. 125, 549�. doi: 10.1242/jcs.091793

Schneider-Brachert, W., Tchikov, V., Neumeyer, J., Jakob, M., Winoto-Morbach, S., Held-Feindt, J., et al. (2004). Compartmentalization of TNF receptor 1 signaling: internalized TNF receptosomes as death signaling vesicles. Immunity 21, 415�. doi: 10.1016/j.immuni.2004.08.017

Scholz, J., and Woolf, C. J. (2007). The neuropathic pain triad: neurons, immune cells and glia. Nat. Neurosci. 10, 1361�. doi: 10.1038/nn1992

Selmaj, K., Papierz, W., Glabiński, A., and Kohno, T. (1995). Prevention of chronic relapsing experimental autoimmune encephalomyelitis by soluble tumor necrosis factor receptor I. J. Neuroimmunol. 56, 135�. doi: 10.1016/0165-5728(94)00139-f

Selmaj, K., Raine, C. S., and Cross, A. H. (1991). Anti-tumor necrosis factor therapy abrogates autoimmune demyelination. Ann. Neurol. 30, 694�. doi: 10.1002/ana.410300510

Sheng, Y., Li, F., and Qin, Z. (2018). TNF receptor 2 makes tumor necrosis factor a friend of tumors. Front. Immunol. 9:1170. doi: 10.3389/fimmu.2018.01170

Shibata, H., Yoshioka, Y., Abe, Y., Ohkawa, A., Nomura, T., Minowa, K., et al. (2009). The treatment of established murine collagen-induced arthritis with a TNFR1-selective antagonistic mutant TNF. Biomaterials 30, 6638�. doi: 10.1016/j.biomaterials.2009.08.041

Shibata, H., Yoshioka, Y., Ohkawa, A., Abe, Y., Nomura, T., Mukai, Y., et al. (2008a). The therapeutic effect of TNFR1-selective antagonistic mutant TNF-alpha in murine hepatitis models. Cytokine 44, 229�. doi: 10.1016/j.cyto.2008.07.003

Shibata, H., Yoshioka, Y., Ohkawa, A., Minowa, K., Mukai, Y., Abe, Y., et al. (2008b). Creation and X-ray structure analysis of the tumor necrosis factor receptor-1-selective mutant of a tumor necrosis factor-alpha antagonist. J. Biol. Chem. 283, 998�. doi: 10.1074/jbc.M707933200

Sicotte, N. L., and Voskuhl, R. R. (2001). Onset of multiple sclerosis associated with anti-TNF therapy. Neurology 57, 1885�. doi: 10.1212/wnl.57.10.1885

Siegemund, M., Schneider, F., Hutt, M., Seifert, O., Müller, I., Kulms, D., et al. (2018). IgG-single-chain TRAIL fusion proteins for tumour therapy. Sci. Rep. 8:7808. doi: 10.1038/s41598-018-24450-8

Sommer, C., Schmidt, C., and George, A. (1998). Hyperalgesia in experimental neuropathy is dependent on the TNF receptor 1. Exp. Neurol. 151, 138�. doi: 10.1006/exnr.1998.6797

Sorkin, L. S., and Doom, C. M. (2000). Epineurial application of TNF elicits an acute mechanical hyperalgesia in the awake rat. J. Peripher. Nerv. Syst. 5, 96�. doi: 10.1046/j.1529-8027.2000.00012.x

Sousa Rodrigues, M. E., de Houser, M. C., Walker, D. I., Jones, D. P., Chang, J., Barnum, C. J., et al. (2019). Targeting soluble tumor necrosis factor as a potential intervention to lower risk for late-onset Alzheimer’s disease associated with obesity, metabolic syndrome, and type 2 diabetes. Alzheimers Res. Ther. 12:1. doi: 10.1186/s13195-019-0546-4

Steed, P. M., Tansey, M. G., Zalevsky, J., Zhukovsky, E. A., Desjarlais, J. R., Szymkowski, D. E., et al. (2003). Inactivation of TNF signaling by rationally designed dominant-negative TNF variants. Science 301, 1895�. doi: 10.1126/science.1081297

Steeland, S., Gorlé, N., Vandendriessche, C., Balusu, S., Brkic, M., van Cauwenberghe, C., et al. (2018). Counteracting the effects of TNF receptor-1 has therapeutic potential in Alzheimer’s disease. EMBO Mol. Med. 10:e8300. doi: 10.15252/emmm.201708300

Steeland, S., Puimège, L., Vandenbroucke, R. E., van Hauwermeiren, F., Haustraete, J., Devoogdt, N., et al. (2015). Generation and characterization of small single domain antibodies inhibiting human tumor necrosis factor receptor 1. J. Biol. Chem. 290, 4022�. doi: 10.1074/jbc.M114.617787

Steeland, S., van Ryckeghem, S., van Imschoot, G., Rycke, R., de, Toussaint, W., Vanhoutte, L., et al. (2017). TNFR1 inhibition with a nanobody protects against EAE development in mice. Sci. Rep. 7:13646. doi: 10.1038/s41598-017-13984-y

Steinshamn, S., Bemelmans, M. H., van Tits, L. J., Bergh, K., Buurman, W. A., and Waage, A. (1996). TNF receptors in murine Candida albicans infection: evidence for an important role of TNF receptor p55 in antifungal defense. J. Immunol. 157, 2155�.

Sun, S.-C. (2017). The non-canonical NF-㮫 pathway in immunity and inflammation. Nat. Rev. Immunol. 17, 545�. doi: 10.1038/nri.2017.52

Suvannavejh, G. C., Lee, H. O., Padilla, J., Dal Canto, M. C., Barrett, T. A., and Miller, S. D. (2000). Divergent roles for p55 and p75 tumor necrosis factor receptors in the pathogenesis of MOG(35-55)-induced experimental autoimmune encephalomyelitis. Cell. Immunol. 205, 24�. doi: 10.1006/cimm.2000.1706

Tam, E. M., Fulton, R. B., Sampson, J. F., Muda, M., Camblin, A., Richards, J., et al. (2019). Antibody-mediated targeting of TNFR2 activates CD8+ T cells in mice and promotes antitumor immunity. Sci. Transl. Med. 11:eaax0720. doi: 10.1126/scitranslmed.aax0720

Tan, R., and Cao, L. (2018). Cannabinoid WIN-55,212-2 mesylate inhibits tumor necrosis factor-α-induced expression of nitric oxide synthase in dorsal root ganglion neurons. Int. J. Mol. Med. 42, 919�. doi: 10.3892/ijmm.2018.3687

Taoufik, E., Tseveleki, V., Chu, S. Y., Tselios, T., Karin, M., Lassmann, H., et al. (2011). Transmembrane tumour necrosis factor is neuroprotective and regulates experimental autoimmune encephalomyelitis via neuronal nuclear factor-kappaB. Brain 134, 2722�. doi: 10.1093/brain/awr203

Thoma, B., Grell, M., Pfizenmaier, K., and Scheurich, P. (1990). Identification of a 60-kD tumor necrosis factor (TNF) receptor as the major signal transducing component in TNF responses. J. Exp. Med. 172, 1019�. doi: 10.1084/jem.172.4.1019

Tomita, K., Tamiya, G., Ando, S., Ohsumi, K., Chiyo, T., Mizutani, A., et al. (2006). Tumour necrosis factor alpha signalling through activation of Kupffer cells plays an essential role in liver fibrosis of non-alcoholic steatohepatitis in mice. Gut 55, 415�. doi: 10.1136/gut.2005.071118

Torres, D., Janot, L., Quesniaux, V. F. J., Grivennikov, S. I., Maillet, I., Sedgwick, J. D., et al. (2005). Membrane tumor necrosis factor confers partial protection to Listeria infection. Am. J. Pathol. 167, 1677�. doi: 10.1016/S0002-9440(10)61250-3

Torrey, H., Butterworth, J., Mera, T., Okubo, Y., Wang, L., Baum, D., et al. (2017). Targeting TNFR2 with antagonistic antibodies inhibits proliferation of ovarian cancer cells and tumor-associated Tregs. Sci. Signal. 10:eaaf8608. doi: 10.1126/scisignal.aaf8608

Torrey, H., Khodadoust, M., Tran, L., Baum, D., Defusco, A., Kim, Y. H., et al. (2019). Targeted killing of TNFR2-expressing tumor cells and Tregs by TNFR2 antagonistic antibodies in advanced Sézary syndrome. Leukemia 33, 1206�. doi: 10.1038/s41375-018-0292-9

Tracey, D., Klareskog, L., Sasso, E. H., Salfeld, J. G., and Tak, P. P. (2008). Tumor necrosis factor antagonist mechanisms of action: a comprehensive review. Pharmacol. Ther. 117, 244�. doi: 10.1016/j.pharmthera.2007.10.001

Tsakiri, N., Papadopoulos, D., Denis, M. C., Mitsikostas, D.-D., and Kollias, G. (2012). TNFR2 on non-haematopoietic cells is required for Foxp3+ Treg-cell function and disease suppression in EAE. Eur. J. Immunol. 42, 403�. doi: 10.1002/eji.201141659

Uysal, K. T., Wiesbrock, S. M., and Hotamisligil, G. S. (1998). Functional analysis of tumor necrosis factor (TNF) receptors in TNF-alpha-mediated insulin resistance in genetic obesity. Endocrinology 139, 4832�. doi: 10.1210/endo.139.12.6337

Uysal, K. T., Wiesbrock, S. M., Marino, M. W., and Hotamisligil, G. S. (1997). Protection from obesity-induced insulin resistance in mice lacking TNF-alpha function. Nature 389, 610�. doi: 10.1038/39335

van der Most, R. G., Currie, A. J., Mahendran, S., Prosser, A., Darabi, A., Robinson, B. W. S., et al. (2009). Tumor eradication after cyclophosphamide depends on concurrent depletion of regulatory T cells: a role for cycling TNFR2-expressing effector-suppressor T cells in limiting effective chemotherapy. Cancer Immunol. Immunother. 58, 1219�. doi: 10.1007/s00262-008-0628-9

van Hauwermeiren, F., Vandenbroucke, R. E., Grine, L., Lodens, S., van Wonterghem, E., de Rycke, R., et al. (2015). TNFR1-induced lethal inflammation is mediated by goblet and Paneth cell dysfunction. Mucosal. Immunol. 8, 828�. doi: 10.1038/mi.2014.112

van Oosten, B. W., Barkhof, F., Truyen, L., Boringa, J. B., Bertelsmann, F. W., von Blomberg, B. M., et al. (1996). Increased MRI activity and immune activation in two multiple sclerosis patients treated with the monoclonal anti-tumor necrosis factor antibody cA2. Neurology 47, 1531�. doi: 10.1212/wnl.47.6.1531

Vanamee, ÉS., and Faustman, D. L. (2017). TNFR2: a novel target for cancer immunotherapy. Trends Mol. Med. 23, 1037�. doi: 10.1016/j.molmed.2017.09.007

Vanamee, ÉS., and Faustman, D. L. (2018). Structural principles of tumor necrosis factor superfamily signaling. Sci. Signal. 11:eaao4910. doi: 10.1126/scisignal.aao4910

Vanden Berghe, T., Linkermann, A., Jouan-Lanhouet, S., Walczak, H., and Vandenabeele, P. (2014). Regulated necrosis: the expanding network of non-apoptotic cell death pathways. Nat. Rev. Mol. Cell. Biol. 15, 135�. doi: 10.1038/nrm3737

Vogel, C., Stallforth, S., and Sommer, C. (2006). Altered pain behavior and regeneration after nerve injury in TNF receptor deficient mice. J. Peripher. Nerv. Syst. 11, 294�. doi: 10.1111/j.1529-8027.2006.00101.x

Wagner, R., and Myers, R. R. (1996). Endoneurial injection of TNF-alpha produces neuropathic pain behaviors. Neuroreport 7, 2897�. doi: 10.1097/00001756-199611250-00018

Wajant, H., Henkler, F., and Scheurich, P. (2001). The TNF-receptor-associated factor family: scaffold molecules for cytokine receptors, kinases and their regulators. Cell. Signal. 13, 389�. doi: 10.1016/s0898-6568(01)00160-7

Wajant, H., Pfizenmaier, K., and Scheurich, P. (2003). Tumor necrosis factor signaling. Cell Death Differ 10, 45�.

Wajant, H., and Scheurich, P. (2011). TNFR1-induced activation of the classical NF-㮫 pathway. FEBS J. 278, 862�. doi: 10.1111/j.1742-4658.2011.08015.x

Wandrer, F., Liebig, S., Marhenke, S., Vogel, A., Manns, M. P., Teufel, A., et al. (2020). TNF-receptor-1 inhibition reduces liver steatosis, hepatocellular injury and fibrosis in NAFLD mice. Cell Death Dis. 11:212. doi: 10.1038/s41419-020-2411-6

Wang, J., Ferreira, R., Lu, W., Farrow, S., Downes, K., Jermutus, L., et al. (2018). TNFR2 ligation in human T regulatory cells enhances IL2-induced cell proliferation through the non-canonical NF-㮫 pathway. Sci. Rep. 8:12079. doi: 10.1038/s41598-018-30621-4

Wellen, K. E., and Hotamisligil, G. S. (2005). Inflammation, stress, and diabetes. J. Clin. Invest. 115, 1111�.

Williams, S. K., Fairless, R., Maier, O., Liermann, P. C., Pichi, K., Fischer, R., et al. (2018). Anti-TNFR1 targeting in humanized mice ameliorates disease in a model of multiple sclerosis. Sci. Rep. 8:13628. doi: 10.1038/s41598-018-31957-7

Williams, S. K., Maier, O., Fischer, R., Fairless, R., Hochmeister, S., Stojic, A., et al. (2014). Antibody-mediated inhibition of TNFR1 attenuates disease in a mouse model of multiple sclerosis. PLoS One 9:e90117. doi: 10.1371/journal.pone.0090117

Yang, L., Lindholm, K., Konishi, Y., Li, R., and Shen, Y. (2002). Target depletion of distinct tumor necrosis factor receptor subtypes reveals hippocampal neuron death and survival through different signal transduction pathways. J. Neurosci. 22, 3025�. doi: 10.1523/JNEUROSCI.22-08-03025.2002

Yang, S., Xie, C., Chen, Y., Wang, J., Chen, X., Lu, Z., et al. (2019). Differential roles of TNFα-TNFR1 and TNFα-TNFR2 in the differentiation and function of CD4+Foxp3+ induced Treg cells in vitro and in vivo periphery in autoimmune diseases. Cell Death Dis. 10:27. doi: 10.1038/s41419-018-1266-6

Ye, L.-L., Wei, X.-S., Zhang, M., Niu, Y.-R., and Zhou, Q. (2018). The significance of tumor necrosis factor receptor type II in CD8+ regulatory T cells and CD8+ effector T cells. Front. Immunol. 9:583. doi: 10.3389/fimmu.2018.00583

Yli-Karjanmaa, M., Clausen, B. H., Degn, M., Novrup, H. G., Ellman, D. G., Toft-Jensen, P., et al. (2019). Topical administration of a soluble TNF inhibitor reduces infarct volume after focal cerebral ischemia in mice. Front. Neurosci. 13:781. doi: 10.3389/fnins.2019.00781

Zalevsky, J., Secher, T., Ezhevsky, S. A., Janot, L., Steed, P. M., O𠆛rien, C., et al. (2007). Dominant-negative inhibitors of soluble TNF attenuate experimental arthritis without suppressing innate immunity to infection. J. Immunol. 179, 1872�. doi: 10.4049/jimmunol.179.3.1872

Zeng, X.-Y., Zhang, Q., Wang, J., Yu, J., Han, S.-P., and Wang, J.-Y. (2014). Distinct role of tumor necrosis factor receptor subtypes 1 and 2 in the red nucleus in the development of neuropathic pain. Neurosci. Lett. 569, 43�. doi: 10.1016/j.neulet.2014.03.048

Zettlitz, K. A., Lorenz, V., Landauer, K., Münkel, S., Herrmann, A., Scheurich, P., et al. (2010). ATROSAB, a humanized antagonistic anti-tumor necrosis factor receptor one-specific antibody. MAbs 2, 639�. doi: 10.4161/mabs.2.6.13583

Zhang, L., Berta, T., Xu, Z.-Z., Liu, T., Park, J. Y., and Ji, R.-R. (2011). TNF-α contributes to spinal cord synaptic plasticity and inflammatory pain: distinct role of TNF receptor subtypes 1 and 2. Pain 152, 419�. doi: 10.1016/j.pain.2010.11.014

Zhang, X., Yin, N., Guo, A., Zhang, Q., Zhang, Y., Xu, Y., et al. (2017). NF-㮫 signaling and cell-fate decision induced by a fast-dissociating tumor necrosis factor mutant. Biochem. Biophys. Res. Commun. 489, 287�. doi: 10.1016/j.bbrc.2017.05.149

Keywords : TNF, TNFR1, TNFR2, therapy, inflammation, tissue regeneration

Citation: Fischer R, Kontermann RE and Pfizenmaier K (2020) Selective Targeting of TNF Receptors as a Novel Therapeutic Approach. Front. Cell Dev. Biol. 8:401. doi: 10.3389/fcell.2020.00401

Received: 06 February 2020 Accepted: 01 May 2020
Published: 26 May 2020.

Olivier Micheau, Université de Bourgogne, France

David MacEwan, University of Liverpool, United Kingdom
Nathalie Grandvaux, Université de Montrບl, Canada
Patrick Legembre, INSERM U1262 CRIBL, France

Copyright © 2020 Fischer, Kontermann and Pfizenmaier. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.