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19.2: Autoimmune Disorders - Biology


Learning Objectives

  • Explain why autoimmune disorders develop
  • Provide a few examples of organ-specific and systemic autoimmune diseases

In 1970, artist Walt Kelly developed a poster promoting Earth Day, featuring a character from Pogo, his daily newspaper comic strip. In the poster, Pogo looks out across a litter-strewn forest and says wryly, “We have met the enemy and he is us.” Pogo was not talking about the human immune system, but he very well could have been. Although the immune system protects the body by attacking invading “enemies” (pathogens), in some cases, the immune system can mistakenly identify the body’s own cells as the enemy, resulting in autoimmune disease.

Autoimmune diseases are those in which the body is attacked by its own specific adaptive immune response. In normal, healthy states, the immune system induces tolerance, which is a lack of an anti-self immune response. However, with autoimmunity, there is a loss of immune tolerance, and the mechanisms responsible for autoimmune diseases include type II, III, and IV hypersensitivity reactions. Autoimmune diseases can have a variety of mixed symptoms that flare up and disappear, making diagnosis difficult.

The causes of autoimmune disease are a combination of the individual's genetic makeup and the effect of environmental influences, such as sunlight, infections, medications, and environmental chemicals. However, the vagueness of this list reflects our poor understanding of the etiology of these diseases. Except in a very few specific diseases, the initiation event(s) of most autoimmune states has not been fully characterized.

There are several possible causes for the origin of autoimmune diseases and autoimmunity is likely due to several factors. Evidence now suggests that regulatory T and B cells play an essential role in the maintenance of tolerance and prevention of autoimmune responses. The regulatory T cells are especially important for inhibiting autoreactive T cells that are not eliminated during thymic selection and escape the thymus (see T Lymphocytes and Cellular Immunity). In addition, antigen mimicry between pathogen antigens and our own self antigens can lead to cross-reactivity and autoimmunity. Hidden self-antigens may become exposed because of trauma, drug interactions, or disease states, and trigger an autoimmune response. All of these factors could contribute to autoimmunity. Ultimately, damage to tissues and organs in the autoimmune disease state comes as a result of inflammatory responses that are inappropriate; therefore, treatment often includes immunosuppressive drugs and corticosteroids.

Organ-Specific Autoimmune Diseases

Some autoimmune diseases are considered organ specific, meaning that the immune system targets specific organs or tissues. Examples of organ-specific autoimmune diseases include celiac disease, Graves disease, Hashimoto thyroiditis, type I diabetes mellitus, and Addison disease.

Celiac Disease

Celiac disease is largely a disease of the small intestine, although other organs may be affected. People in their 30s and 40s, and children are most commonly affected, but celiac disease can begin at any age. It results from a reaction to proteins, commonly called gluten, found mainly in wheat, barley, rye, and some other grains. The disease has several genetic causes (predispositions) and poorly understood environmental influences. On exposure to gluten, the body produces various autoantibodies and an inflammatory response. The inflammatory response in the small intestine leads to a reduction in the depth of the microvilli of the mucosa, which hinders absorption and can lead to weight loss and anemia. The disease is also characterized by diarrhea and abdominal pain, symptoms that are often misdiagnosed as irritable bowel syndrome.

Diagnosis of celiac disease is accomplished from serological tests for the presence of primarily IgA antibodies to components of gluten, the transglutinaminase enzyme, and autoantibodies to endomysium, a connective tissue surrounding muscle fibers. Serological tests are typically followed up with endoscopy and biopsy of the duodenal mucosa. Serological screening surveys have found about 1% of individuals in the United Kingdom are positive even though they do not all display symptoms.1 This early recognition allows for more careful monitoring and prevention of severe disease.

Celiac disease is treated with complete removal of gluten-containing foods from the diet, which results in improved symptoms and reduced risk of complications. Other theoretical approaches include breeding grains that do not contain the immunologically reactive components or developing dietary supplements that contain enzymes that break down the protein components that cause the immune response.2

Disorders of the Thyroid

Graves disease is the most common cause of hyperthyroidism in the United States. Symptoms of Graves disease result from the production of thyroid-stimulating immunoglobulin (TSI) also called TSH-receptor antibody. TSI targets and binds to the receptor for thyroid stimulating hormone (TSH), which is naturally produced by the pituitary gland. TSI may cause conflicting symptoms because it may stimulate the thyroid to make too much thyroid hormone or block thyroid hormone production entirely, making diagnosis more difficult. Signs and symptoms of Graves disease include heat intolerance, rapid and irregular heartbeat, weight loss, goiter (a swollen thyroid gland, protruding under the skin of the throat [Figure (PageIndex{1})) and exophthalmia (bulging eyes) often referred to as Graves ophthalmopathy (Figure (PageIndex{2})).

The most common cause of hypothyroidism in the United States is Hashimoto thyroiditis, also called chronic lymphocytic thyroiditis. Patients with Hashimoto thyroiditis often develop a spectrum of different diseases because they are more likely to develop additional autoimmune diseases such as Addison disease (discussed later in this section), type 1 diabetes, rheumatoid arthritis, and celiac disease. Hashimoto thyroiditis is a TH1 cell-mediated disease that occurs when the thyroid gland is attacked by cytotoxic lymphocytes, macrophages, and autoantibodies. This autoimmune response leads to numerous symptoms that include goiter (Figure (PageIndex{1})), cold intolerance, muscle weakness, painful and stiff joints, depression, and memory loss.

Type 1 Diabetes

Juvenile diabetes, or type 1 diabetes mellitus, is usually diagnosed in children and young adults. It is a T-cell-dependent autoimmune disease characterized by the selective destruction of the β cells of the islets of Langerhans in the pancreas by CD4 TH1-mediated CD8 T cells, anti-β-cell antibodies, and macrophage activity. There is also evidence that viral infections can have either a potentiating or inhibitory role in the development of type 1 diabetes (T1D) mellitus. The destruction of the β cells causes a lack of insulin production by the pancreas. In T1D, β-cell destruction may take place over several years, but symptoms of hyperglycemia, extreme increase in thirst and urination, weight loss, and extreme fatigue usually have a sudden onset, and diagnosis usually does not occur until most β cells have already been destroyed.

Autoimmune Addison Disease

Destruction of the adrenal glands (the glands lying above the kidneys that produce glucocorticoids, mineralocorticoids, and sex steroids) is the cause of Addison disease, also called primary adrenal insufficiency (PAI). Today, up to 80% of Addison disease cases are diagnosed as autoimmune Addison disease (AAD), which is caused by an autoimmune response to adrenal tissues disrupting adrenal function. Disruption of adrenal function causes impaired metabolic processes that require normal steroid hormone levels, causing signs and symptoms throughout the body. There is evidence that both humoral and CD4 TH1-driven CD8 T-cell–mediated immune mechanisms are directed at the adrenal cortex in AAD. There is also evidence that the autoimmune response is associated with autoimmune destruction of other endocrine glands as well, such as the pancreas and thyroid, conditions collectively referred to as autoimmune polyendocrine syndromes (APS). In up to 80% of patients with AAD, antibodies are produced to three enzymes involved in steroid synthesis: 21-hydroxylase (21-OH), 17α-hydroxylase, and cholesterol side-chain–cleaving enzyme.3The most common autoantibody found in AAD is to 21-OH, and antibodies to any of the key enzymes for steroid production are diagnostic for AAD. The adrenal cortex cells are targeted, destroyed, and replaced with fibrous tissue by immune-mediated inflammation. In some patients, at least 90% of the adrenal cortex is destroyed before symptoms become diagnostic.

Symptoms of AAD include weakness, nausea, decreased appetite, weight loss, hyperpigmentation (Figure (PageIndex{3})), hyperkalemia (elevated blood potassium levels), hyponatremia (decreased blood sodium levels), hypoglycemia(decreased levels of blood sugar), hypotension (decreased blood pressure), anemia, lymphocytosis (decreased levels of white blood cells), and fatigue. Under extreme stress, such as surgery, accidental trauma, or infection, patients with AAD may experience an adrenal crisis that causes the patient to vomit, experience abdominal pain, back or leg cramps, and even severe hypotension leading to shock.

Exercise (PageIndex{1})

  1. What are the names of autoimmune diseases that interfere with hormone gland function?
  2. Describe how the mechanisms of Graves disease and Hashimoto thyroiditis differ.
  3. Name the cells that are destroyed in type 1 diabetes mellitus and describe the result.

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 “pins and needles”; 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:

Exercise (PageIndex{2})

  • 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.

Psoriasis

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-α (TNF-α). 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.

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–stranded 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.

Exercise (PageIndex{3})

  1. List the ways antibodies contribute to the pathogenesis of myasthenia gravis.
  2. Explain why rheumatoid arthritis is considered a type III hypersensitivity.
  3. Describe the symptoms of systemic lupus erythematosus and explain why they affect so many different parts of the body.
  4. What is recognized as an antigen in myasthenia gravis?
Table (PageIndex{1}) summarizes the causes, signs, and symptoms of select autoimmune diseases.Table (PageIndex{1}): Select Autoimmune Diseases
DiseaseCauseSigns and Symptoms
Addison diseaseDestruction of adrenal gland cells by cytotoxic T cellsWeakness, nausea, hypotension, fatigue; adrenal crisis with severe pain in abdomen, lower back, and legs; circulatory system collapse, kidney failure
Celiac diseaseAntibodies to gluten become autoantibodies that target cells of the small intestineSevere diarrhea, abdominal pain, anemia, malnutrition
Diabetes mellitus (type I)Cytotoxic T-cell destruction of the insulin-producing β cells of the pancreasHyperglycemia, extreme increase in thirst and urination, weight loss, extreme fatigue
Graves diseaseAutoantibodies target thyroid-stimulating hormone receptors, resulting in overstimulation of the thyroidHyperthyroidism with rapid and irregular heartbeat, heat intolerance, weight loss, goiter, exophthalmia
Hashimoto thyroiditisThyroid gland is attacked by cytotoxic T cells, lymphocytes, macrophages, and autoantibodiesThyroiditis with goiter, cold intolerance, muscle weakness, painful and stiff joints, depression, memory loss
Multiple sclerosis (MS)Cytotoxic T-cell destruction of the myelin sheath surrounding nerve axons in the central nervous systemVisual disturbances, muscle weakness, impaired coordination and balance, numbness, prickling or “pins and needles” sensations, impaired cognitive function and memory
Myasthenia gravisAutoantibodies directed against acetylcholine receptors within the neuromuscular junctionExtreme muscle weakness eventually leading to fatal respiratory arrest
PsoriasisCytokine activation of keratinocytes causes rapid and excessive epidermal cell turnoverItchy or sore patches of thick, red skin with silvery scales; commonly affects elbows, knees, scalp, back, face, palms, feet
Rheumatoid arthritisAutoantibodies, immune complexes, complement activation, phagocytes, and T cells damage membranes and bone in jointsJoint inflammation, pain and disfigurement, chronic systemic inflammation
Systemic lupus erythematosus (SLE)Autoantibodies directed against nuclear and cytoplasmic molecules form immune complexes that deposit in tissues. Phagocytic cells and complement activation cause tissue damage and inflammationFatigue, fever, joint pain and swelling, hair loss, anemia, clotting, a sunlight-sensitive "butterfly" rash, skin lesions, photosensitivity, decreased kidney function, memory loss, confusion, depression

Key Concepts and Summary

  • Autoimmune diseases result from a breakdown in immunological tolerance. The actual induction event(s) for autoimmune states are largely unknown.
  • Some autoimmune diseases attack specific organs, whereas others are more systemic.
  • Organ-specific autoimmune diseases include celiac disease, Graves disease, Hashimoto thyroiditis, type I diabetes mellitus, and Addison disease.
  • Systemic autoimmune diseases include multiple sclerosis, myasthenia gravis, psoriasis, rheumatoid arthritis, and systemic lupus erythematosus.
  • Treatments for autoimmune diseases generally involve anti-inflammatory and immunosuppressive drugs.

Footnotes

  1. 1 D.A. Van Heel, J. West. “Recent Advances in Coeliac Disease.” Gut 55 no. 7 (2006):1037—1046.
  2. 2 ibid.
  3. 3 P. Martorell et al. “Autoimmunity in Addison’s Disease.” Netherlands Journal of Medicine 60 no. 7 (2002):269—275.
  4. 4 C.C. Mok, C.S. Lau. “Pathogenesis of Systemic Lupus Erythematosus.” Journal of Clinical Pathology 56 no. 7 (2003):481—490.

Contributor

  • Nina Parker, (Shenandoah University), Mark Schneegurt (Wichita State University), Anh-Hue Thi Tu (Georgia Southwestern State University), Philip Lister (Central New Mexico Community College), and Brian M. Forster (Saint Joseph’s University) with many contributing authors. Original content via Openstax (CC BY 4.0; Access for free at https://openstax.org/books/microbiology/pages/1-introduction)


VEXAS syndrome in myelodysplastic syndrome with autoimmune disorder

VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is a newly-described adult-onset inflammatory syndrome characterized by vacuoles in myeloid and erythroid precursor cells and somatic mutations affecting methionine-41 (p.Met41) in UBA1. The VEXAS syndrome often overlaps with myelodysplastic syndromes (MDS) with autoimmune disorders (AD). By screening the UBA1 gene sequences derived from MDS patients with AD from our center, we identified one patient with a p.Met41Leu missense mutation in UBA1, who should have been diagnosed as MDS comorbid with VEXAS syndrome. This patient respond poorly to immune suppressive drugs. Patients with MDS and AD who have characteristic vacuoles in myeloid and erythroid precursor cells should be screened for UBA1 mutation, these patients are likely to have VEXAS syndrome and unlikely to improve with immunosuppressive drugs and should be considered for other alternative therapies.

Keywords: Autoimmune disorders Cytoplasmic vacuolation Myelodysplastic syndromes UBA1 mutation VEXAS syndrome.

Conflict of interest statement

The authors declare no competing financial interests.

Figures

The mutational profile of myelodysplastic…

The mutational profile of myelodysplastic syndromes (MDS) patients with autoimmune disorders (AD) and…


COVID-19 & Autoimmune Disease: What We Know Now

While the world at large is still getting a handle on exactly how the coronavirus spreads, what causes COVID-19, and why it affects some people with autoimmune disease, what we know now is still a far cry from what we knew at the start.

As the number of studies on autoimmune disease and the coronavirus increase, we are beginning to see the associations between the two and better understand why certain conditions are high risk. There are instances in which having an autoimmune disease increases vulnerability to COVID-19 complications, and other cases in which having a coronavirus infection may trigger autoimmune or other serious conditions.

What also holds true, is the distinctive way in which this virus impacts individuals – healthy or chronically ill, young or old. Like a fingerprint is unique to each person, your personal risk is unlike anyone else’s.

The High Risk List

The term “high risk” may be used to denote infection risk or complication risk. There is concern over the susceptibility to infection, as individuals with compromised immune systems are generally the first in line for pathogenic attacks. However, the most widely investigated topic – and the one explored in this article – is the risk of serious complications once infected by the virus.

The U.S. Centers for Disease Control and Prevention (CDC) released an updated list of high risk conditions (individuals who are at increased risk of serious illness from COVID-19).

The CDC’s list defines a primary group including cancer, chronic kidney disease, COPD, immunocompromised from organ transplant, obesity, serious heart conditions, smoking, sickle cell disease, and type 2 diabetes, and a secondary group that may signal an increased risk for COVID-19 complications, including asthma, cystic fibrosis, suppressed immune system, neurological conditions, liver disease, pulmonary fibrosis and type 1 diabetes. For the full list, visit the CDC’s website .

The CDC includes heart, lung, liver, and nervous system diseases on the high risk list. While there is limited data on the specific conditions affected in these categories, it is worthwhile to note the autoimmune or autoimmune-related instances of them. Some of the heart, lung, liver, and nervous system autoimmune diseases indicating a potentially increased risk (including systemic conditions) are:

Autoimmune myocarditis
Dressler’s syndrome
Subacute bacterial endocarditis
Cardiac sarcoidosis
Idiopathic pulmonary fibrosis
Autoimmune hepatitis
Multiple sclerosis
Guillain-Barre syndrome
Myasthenia gravis
Lupus
Rheumatoid arthritis
Scleroderma
Sjogren’s

Individuals on immunosuppressive medications such as corticosteroids are also at higher risk for severe COVID-19 complications. However, keeping conditions in check and avoiding debilitating flare-ups may greatly outweigh the potential risks of a suppressed immune system.

COVID-19 Disproportionately Affects People of Color

Adding to the list of higher risk groups, COVID-19 disproportionately impacts communities of color (as do autoimmune diseases like lupus and scleroderma). Regarding COVID-19 cases in the United States from January through May, roughly 33% of persons were Hispanic, 22% were black, and 1.3% were American Indian/Alaska Native (1), despite the fact that these groups are part of the country’s minority population.

These racial disparities are both a symptom and example of the systemic racism pervading American institutions. The high rates of underlying health conditions in communities of color, limited access to resources for COVID-19 testing and treatment, and economic hardships brought on by pandemic guidelines are all implicated in the added challenges faced by people of color (2, 3)

WHY ARE NON-RESPIRATORY DISEASES HIGH RISK?

We know that COVID-19 impacts the airways therefore, COPD and other serious respiratory illnesses appear to present a clear pathway to disaster. Individuals with these conditions need to be particularly vigilant. But how could other conditions also turn a coronavirus infection into a life threatening event?

Organ systems depend on each other.

Heart disease (like autoimmune myocarditis), for instance, presents itself as a likely factor for increased risk because normal operation of the heart is affected by other bodily functions. According to Dr. Maragakis, Senior Director of Infection Prevention at Johns Hopkins, the airways and lungs “work together with the heart to drive oxygen to the body’s tissues. When the lungs are overtaxed due to illness, the heart has to work harder” (4). This is a telling example of the vital connections between the different organ systems in our bodies.

The immune system’s response is the primary culprit.

We are learning that the source of the mayhem might not be the virus itself, but rather the immune system’s response to it. Severe COVID-19 cases may be associated with hyperactive immune responses in both chronically ill and healthy individuals. If you have an autoimmune disease, the immune system is already impaired – this may signal cause for concern.

“I HAVE AN AUTOIMMUNE DISEASE. AM I HIGH RISK?”

It remains unclear if having autoimmune disease automatically puts you at high risk for severe complications.

However, many sources point to no – unless you are also on immunosuppressive medication, are over 60 years old, or have one of the listed high risk conditions (like heart disease or obesity) in addition to autoimmune disease (5).

Many people with autoimmune disease and COVID-19 are asymptomatic or have mild to moderate symptoms and recover, some experience flare-ups or lingering effects, and others are hospitalized.

Apart from type 1 diabetes, most autoimmune diseases are not yet considered high risk by the CDC.

1. We do not have enough data

Studying autoimmune diseases in general is a daunting task, as there is still much unknown about these conditions and their etiology, or causes. Therefore, untangling a relevant relationship between autoimmune disease and COVID-19 is a tall order.

2. From the data we do have, there are mixed outcomes

One review laid out the complicated forces at play in certain autoimmune diseases, demonstrating the need for further study and precaution. In systemic lupus erythematosus (SLE), the overexpression of a protein called ACE2 may be involved in severe COVID-19 cases. Researchers investigating the correlation between COVID-19 and rheumatic disease explain that ACE2 is a “functional receptor for the viral spike [of] glycoprotein, that allows the entry of SARS-CoV-2 into cells.” In some lupus patients, this phenomenon may correlate with increased susceptibility (6).

A review and meta-analysis on the association between severe COVID-19 and autoimmune disease “ showed that autoimmune disease was slightly associated with increased risk of severity and mortality of COVID-19” (7). They do clarify that the statistical difference was not significant, but that these findings do not quell the threat and more research is needed.

3. The impact of autoimmune disease and the behavior of the immune system are different in different people

While those living with autoimmune disease do experience altered immune system function, the ability to fight off pathogens is not necessarily weakened rather the response is misguided.

Some people are more vulnerable to harmful bacteria and viruses because their bodies are busy attacking their own tissues – or they are living with suppressed immune systems. For others, hyper-vigilant immune systems may prevent them from getting sick often. A body that overreacts to benign substances, like foods or harsh chemicals, may actually continue putting up a good fight when it comes to the real enemies: pathogenic microbes like the coronavirus (8, 9). It depends on the individual.

It is possible for symptoms of COVID-19 to linger in people with chronic illnesses , despite a lack of severe symptoms and hospitalization. Both the CDC and a survey conducted by the Indiana University School of Medicine found that chronically ill patients who contracted the virus experienced a particularly long road to recovery, with lingering symptoms like fatigue and cough, as well as skin and neurological problems (10, 11). To read more about lingering symptoms, scroll down to the section: “Long COVID”

Have you been feeling anxious and fatigued lately? Or experiencing more autoimmune flare-ups? Even if you’re not at high risk for serious COVID-19 complications, having a chronic illness means that stress is often a symptom trigger. And the pandemic, in and of itself, can feel like an endless symphony of worry, isolation, life changes, and other stressors. You’re not alone. After surveying arthritis patients, Creaky Joints reports that 42% of patients are experiencing an increase in fatigue during the pandemic.

AUTOIMMUNE SYMPTOM CONFUSION

It is not uncommon that some of your autoimmune symptoms mimic those of COVID-19 . You may be wondering how to tell them apart. One telltale sign you might have coronavirus is the loss of taste and smell, which is not a common autoimmune symptom .

However, the data is still limited and there’s no hard-and-fast rule about which symptoms – like shortness of breath, fever, or fatigue – would signal presence of the virus and which would belong to an autoimmune flare-up.

Below are a few thoughts from rheumatologists – thanks to the Global Healthy Living Foundation and Creaky Joints :

  1. Rheumatic conditions (lupus, rheumatoid arthritis, scleroderma) do not seem to experience increased rates of infection or severe complications
  2. If you experience a coronavirus-like symptom (like fever), be aware of other symptoms that may indicate patterns consistent with a flare-up
  3. Notice if your dry cough, fever, fatigue, etc. is typical for your condition, or if it feels like something new

WHY ARE HEALTHY PEOPLE AFFECTED?

A seemingly healthy individual may, in fact, be living with undetected issues in the body.

A preexisting – and possibly genetic – issue with the immune system may enable the virus to move from the nose and throat, and into the lungs (12, 13). Unable to produce the antibodies responsible for barring the virus entry into certain cells, which is how coronavirus multiplies, the body is thrown into submission and develops complications like pneumonia and acute respiratory distress syndrome (ARDS) (12).

Other undetected issues with the immune system, in conjunction with a COVID-19 infection, can give rise to events known as cytokine storms. The ensuing events can land otherwise healthy people in the hospital.

Cytokine storm is a general descriptor for any number of “hyperactive immune response[s] characterized by the release of interferons, interleukins, tumor-necrosis factors, chemokines, and several other mediators,” explain researchers in their JAMA article, “Is a ‘Cytokine Storm’ Relevant to COVID-19?” Sky-high numbers of these molecules (generally lumped together under the umbrella term of cytokines) are released and can wreak havoc on the body.

The intensity of these hyperactive responses does not mean that the immune system is particularly good at fighting off the coronavirus. Rather, the off switch just doesn’t work. A bloated army of proinflammatory cytokines will remain on high alert and ready to fire well after the threat is over. Consequently, the immune system becomes chronically on-edge, which triggers actions against the body’s own cells. Herein lies the potentially deadly outcome, as it can eventually lead to multiple organ damage.

The use of the term “cytokine storm” to describe the pathophysiology of severe COVID-19 complications is still debated. However, the theory has taken hold throughout the public and the scientific community. It brings a modicum of attention to immune-mediated events like autoimmunity, as w e also see the cytokine storm phenomena in some autoimmune diseases, such as lupus and rheumatoid arthritis (14).

Thankfully, severe complications in healthy individuals continue to be rare, and researchers are testing various drugs to dampen hyperactive immune responses. Biologics used for many autoimmune diseases and affecting specific cytokine receptors and are currently being trialed as potential treatments for COVID-19 (15).

CAN COVID-19 TRIGGER AUTOIMMUNE DISEASE OR ILLNESS?

The body’s immune response to the virus is the center of the story here, as well.

Some healthy individuals have experienced COVID-19 complications that do not result in immediate lung disease or death, but in the triggering and potential development of autoimmune conditions.

In a University College of London Hospital’s study of 43 patients previously infected with the coronavirus, eight acquired Guillain-Barre syndrome and nine acute disseminated encephalomyelitis (ADEM), both autoimmune diseases. The researchers suggest that this outcome was the result of the body’s immune response, rather than the virus itself.

Other studies have identified an overproduction of multiple autoantibodies in some COVID-19 patients. According to researchers investigating “The Correlation Between SARS-CoV-2 Infection and Rheumatic Disease” , such an event “is an important marker of autoimmune tolerance deficiency,” and may therefore signal a future of autoimmunity for those patients.

It is possible for COVID-19 to trigger the development of autoimmune disease or other post-infection fallout. After all, other pathogens – Epstein-Barr virus (EBV), Parvovirus B19, Rubella virus – have been implicated in the development of autoimmune diseases (13). Nevertheless, the numbers are small, and further research is needed to understand the true impact and substantiate this theory.

Long Covid

Another possibility is long covid – an extension of symptoms beyond the absence of infection. The National Institute for Health and Care Excellence defines it as “signs and symptoms that develop during or following an infection consistent with COVID-19, continuing for more than 12 weeks and are not explained by an alternative diagnosis. It usually presents with clusters of symptoms, often overlapping, which can fluctuate and change over time and can affect any system in the body.” Symptoms many people with the condition can also experience are pain, fatigue, high temperature, and mental health conditions (17).

In individuals with long covid, coronavirus tests often come back negative. As a result, healthcare providers must lean more on patients’ personal experiences and symptoms, rather than evidence by way of test results. This different way of approaching health concerns could mean better care for people with chronic illness and autoimmune disease in the long-run.

Other terms used to describe long COVID, like post-COVID syndrome and chronic COVID-19, actually “risk delegitimizing suffering…and that will make it harder for people to access care,” the authors of Nature editorial state (16). Long COVID is coming into the spotlight as more and more researchers and doctors search for answers. If you or a loved one is experiencing long COVID, groups like LongCovidSOS are providing support and information.

The Autoimmune COVID-19 Research Project

One way we’re understanding more about the effects of COVID-19 on autoimmune disease is through patient-centered initiatives like the Autoimmune COVID-19 Project , developed by the Global Healthy Living Foundation and Creaky Joints.

The authors of this longitudinal study are using online surveys to gather a broad spectrum of perspectives from individuals with autoimmune disease. Information requested includes symptoms, experiences with testing, telehealth, concerns about immunosuppressive therapy, and preferred sources of information about the virus.

Analyzing this data will produce a better understanding of the impact COVID-19 is having on quality of life. In this type of initiative, the experience of the patient is highly valued. Harnessing the expertise of researchers plus the power of patient voices will add a unique kind of knowledge to the conversation surrounding infectious disease today, as well as for future pandemics.

If you have been diagnosed with an autoimmune or related condition like rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, or vasculitis, you may participate in this study to help researchers gain more insight into the relationship between COVID-19 and autoimmune disease.

Our knowledge of autoimmune and the coronavirus is only going to increase, especially as the world gains a greater interest in the experiences and perspectives of the patients themselves.

REDUCING RISK

Just as nutrition and lifestyle factors can have profound impacts on our chronic conditions, so can they affect the way our bodies react when faced with COVID-19. The forms of prevention we’re almost too familiar with – hand washing, face masks, social distancing, testing, contact tracing – are not our only tools.

The seemingly benign factors of nutrition and lifestyle are powerful enough to steer us towards either health or disease. Practices such as proper nutrition and hydration contribute to optimal immune system function and that of other body systems, which helps prevent the virus from triggering severe complications. If we are able to make more healthful choices, then we can take some power back from the virus.

It is important to keep in mind, however, that many people are living without access to fresh foods, support, financial stability, comfortable housing, and resources to manage their autoimmune diseases, let alone incorporate diet and lifestyle changes. This is one reason why all the other methods we’re using to combat the coronavirus (yes, like face masks!) are equally important.

As always, risk should be assessed on a case-by-case basis. Outcomes depend on whether or not your disease is under control, you have multiple conditions, you’re taking medications, you experience racial inequities, you have access to quality care and resources, and a host of other factors with which we aren’t yet familiar.


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Autoimmune Disorders

Symptoms vary depending on which disorder develops and which part of the body is affected.

Several blood tests are often used to check for an autoimmune disorder.

Treatment depends on the type of autoimmune disorder and often involves drugs that suppress the activity of the immune system.

The immune system must first recognize foreign or dangerous substances before it can defend the body against them. Such substances include bacteria, viruses, parasites (such as worms), certain cancer cells, and even transplanted organs and tissues. These substances have molecules that the immune system can identify and that can stimulate a response by the immune system. These molecules are called antigens. Antigens may be contained within cells or on the surface of cells (such as bacteria or cancer cells) or be part of a virus. Some antigens, such as pollen or food molecules, exist on their own.

Cells in a person's own tissues also have antigens. But normally, the immune system reacts only to antigens from foreign or dangerous substances, not to antigens from a person's own tissues. However, the immune system sometimes malfunctions, interpreting the body's own tissues as foreign and producing antibodies (called autoantibodies) or immune cells that target and attack particular cells or tissues of the body. This response is called an autoimmune reaction. It results in inflammation and tissue damage. Such effects may constitute an autoimmune disorder, but many people produce such small amounts of autoantibodies that an autoimmune disorder does not occur. Having autoantibodies in the blood does not mean that a person has an autoimmune disorder.

There are many autoimmune disorders. Some of the more common autoimmune disorders include Graves disease, rheumatoid arthritis, Hashimoto thyroiditis, type 1 diabetes mellitus, systemic lupus erythematosus (lupus), and vasculitis. Additional disorders that are believed to be autoimmune include Addison disease, polymyositis, Sjögren syndrome, progressive systemic sclerosis, many cases of glomerulonephritis (inflammation of the kidneys), and some cases of infertility.


Autoimmune disease

In autoimmune diseases, the body attacks normal, healthy tissues. The cause is unknown. It is probably a combination of a person&rsquos genes and something in the environment that triggers those genes.

Three common autoimmune diseases are:

Type 1 diabetes. The immune system attacks the cells in the pancreas that make insulin. Insulin removes sugar from the blood to use as energy.

Rheumatoid arthritis. This type of arthritis causes swelling and deformities of the joints. An auto-antibody called rheumatoid factor is in the blood of some people with rheumatoid arthritis.

Lupus. This disease that attacks body tissues, including the lungs, kidneys, and skin. Many types of auto-antibodies are found in the blood of people with lupus.

No one knows exactly what causes autoimmune diseases, but many factors seem to be involved. If you have an immune system disorder, learn as much as you can about it. And work closely with your healthcare providers to manage it.

#TomorrowsDiscoveries: Understanding the Immune System — Dr. Joel Pomerantz


Autoimmune Disorders

Introduction

Autoimmune disorders arise when physiological tolerance to “self” antigens is lost. Although several mechanisms may be involved in this pathogenic process, dysregulation of T-cell and B-cell activation and of pathways leading to inflammation are logical candidates. Susceptibility to autoimmune diseases has been associated with multiple factors including genetics, epigenetics, and the environment. While the modest concordance rate in monozygotic twins suggests that environmental factors are major players in most autoimmune diseases, increased heritability within families and the decrease in risk with degree of relatedness all argue in favor of genetic factors. With the advent of high-throughput genomic and other ’omic technologies, massive amounts of genetic data are being produced and reported almost on a monthly basis. Although considerable insight has been gained from each of these individual studies, a detailed comparative analysis will likely identify both unique and common pathways operating in autoimmunity. This kind of analysis may set the basis for more targeted and rational therapeutic approaches.

Certain autoimmune disorders co-occur significantly in a single individual or within nuclear families more often than expected, suggesting the presence of genetic variants that predispose to or protect against autoimmunity generally [ Barcellos et al., 2006 International Multiple Sclerosis Genetics Consortium (IMSGC), 2009 Lin et al., 1998 Tait et al., 2004 ]. In a recent analysis, Rzhetzky and colleagues reviewed 1.5 million medical records involving 161 diseases, and computed pairwise correlations of disease co-occurrences ( Rzhetsky et al., 2007 ). Indeed, several autoimmune disorders co-occurred in the same individuals more often than expected by chance. Type 1 diabetes (T1D) most often correlated with the presence of type 2 diabetes (T2D), but also with rheumatoid arthritis (RA) and psoriasis. Similarly, multiple sclerosis (MS) correlated with systemic lupus erythematosus (SLE), T1D, T2D and psoriasis, while RA strongly correlated with SLE, ankylosing spondylitis, T1D, T2D, Sjogren’s syndrome, and psoriasis. Although these data were derived from medical records and not from genetic analyses, the results strongly suggest that common genetic and pathologic mechanisms may be at play in different autoimmune diseases (AID).

Genetic polymorphisms are heritable sequence variants in the genome that contribute to phenotypic variability and can modulate the expression and/or function of genes, thus affecting the behavior of biological pathways, potentially underlying the magnitude of one’s susceptibility to diseases. Modern genomics developments have made available miniaturization and automation of genotyping platforms, and more than 200 genome-wide association studies (GWAS) have been performed in different diseases to date [ Hindorff et al., 2009 National Human Genome Research Institute (NHGRI), 2009 ] including 31 studies in seven common AID that are the focus of this chapter [SLE, T1D, MS, RA, psoriasis, Crohn’s disease (CD) and celiac disease (CeD)].

In this chapter, I will summarize the findings of these studies, elaborate hypotheses about the possible pathogenic mechanisms implicated in each disorder, and provide a global view of shared and specific genes that characterize them.


Our Approach

Scientists at La Jolla Institute are investigating what causes immune cells to turn on the body—and how we can intervene.

LJI Professor Hilde Cheroutre, Ph.D. , is studying how autoreactive T cells mistakenly learn to recognize “self” in an organ called the thymus. These “educated” autoreactive T cells can actually help the body by regulating immune responses to cancer cells or infected cells. But under the wrong circumstances, a naïve T cell may encounter a self-antigen and spark an autoimmune response. Dr. Cheroutre and her team are working with doctors at Rady Children’s Hospital-San Diego to better understand how this process goes wrong. The team hopes to be able to identify the signs that an infant might be susceptible to autoimmune diseases and perhaps even prevent autoimmunity altogether.

LJI Professor Pandurangan Vijayanand, M.D. Ph.D. , is studying genomic data from patients to see which commonly found genetic variants are more prevalent in people with different autoimmune diseases. Dr. Vijayanand and his LJI colleagues have built a database called DICE (Database of Immune Cell Expression, Expression of quantitative trait loci, and Epigenomics), which scientists can use to study the effects of different genetic variants in different immune cells. In 2018, the team published data from 91 healthy donors showing profiles of genetic activity for the 15 most abundant types of immune cells found in human blood. Because autoimmune diseases usually arise from combinations of variants in many different genes, some of which are common and also found in individuals without autoimmune disease, the database gives scientists a guide for comparing variants more often associated with health compared to disease-associated variants.

LJI Associate Professor Sonia Sharma, Ph.D. , is studying inflammatory and autoimmune diseases that affect the vascular endothelium, the cells lining the blood vessels. Her laboratory integrates cutting-edge genetics, biochemistry, cell biology, computational and translational approaches to define the key genetic mechanisms regulating cellular innate immunity—and determine how these factors can trigger autoimmune disease. Dr. Sharma was also instrumental in establishing the Institute’s Functional Genomics Center, which she directs.

LJI Professor Michael Croft, Ph.D. , studies molecules involved in causing atopic dermatitis, severe asthma and fibrotic diseases caused by chronic inflammation. He has partnered successfully with several companies and his work has led to clinical trials for asthma and atopic dermatitis.

LJI Professor Matthias von Herrath, M.D. , has participated in the Network of Pancreatic Organ Donors to track the immune system in the pancreas of patients with type I and type II diabetes. He is committed to clinical translation of immune-based interventions in autoimmune diseases, with a focus on type 1 diabetes. His experimental research can guide early phase I/II clinical trials and move promising therapies toward phase 3 trials and drug approval. His work spans from fundamental studies to clinical trials, facilitated through his affiliation with NovoNordisk.

LJI Professor Mitchell Kronenberg, Ph.D. , is investigating how surface molecules and intracellular signaling pathways regulate immune cells that reside in the intestine. These immune cells have a unique challenge because they must co-exist with a highly diverse microbiome. He studies how these cells maintain this peaceful co-existence while responding to pathogens. The loss of tolerance of good bacteria is a key step involved in the pathogenesis of inflammatory bowel diseases (IBD), such as Crohn’s disease and ulcerative colitis.

The lab of LJI Professor Alessandro Sette, Dr. Biol. Sci., is investigating autoimmune diseases from two angles. First, the team is looking at the possible role of autoreactive T cells in causing Parkinson’s disease. Dr. Sette has found that T cells can target misfolded clumps of alpha-synuclein protein in the brain, potentially triggering damage to vulnerable brain cells very early in the disease onset. This research could make it possible to someday detect Parkinson’s disease before the onset of debilitating motor symptoms—and potentially intervene with therapies to slow the disease progression.


Coping

Most autoimmune conditions are relapsing-remitting disorders. It can be hard to predict when you will feel well and when you won't. In addition, many people with these disorders appear outwardly healthy, sometimes leading to less understanding and support from friends and loved ones.

That said, there are many things that people with autoimmune disease can do themselves to better cope with the day to day frustration and symptoms:

  • Eat a healthy diet: For those who have celiac disease or diabetes, monitoring diet is critical. Yet for others with an autoimmune disease, it's important to learn about how to have healthy gut bacteria.
  • Practice good sleep hygiene: Get an adequate amount of rest every night, and try to wake up and go to sleep at the same time each day.
  • Exercise: Mild to moderate exercise is important for most people, but not pushing it and knowing when to stop is equally important.
  • Practice stress management: Stress management is helpful when coping with any medical condition, and especially important with a stressful condition such as autoimmune disease.
  • Know your triggers: With some conditions, there are triggers that are associated with flares of the disease. It's helpful to identify them and then look at ways to reduce your exposure.

Support

Anyone coping with a serious medical condition needs support, but this is even more true for those living with "invisible diseases." In-person support groups and online support communities can be helpful, as they provide an opportunity to connect with others who are similarly coping with an unpredictable and often misunderstood condition.

Some groups are based on specific conditions, whereas others are symptom-based. The National Coalition of Autoimmune Patient Groups is a good place to begin when looking for these communities.


19.2: Autoimmune Disorders - Biology

An autoimmune disorder is a condition that occurs when the immune system mistakenly attacks and destroys healthy body tissue perceiving it to be “non-self”. There are more than 80 different types of autoimmune disorders.

Normally the immune system’s white blood cells help protect the body from antigens such as bacteria, viruses, toxins, cancer cells, and blood or tissues from another person or species. The immune system produces antibodies that destroy these harmful substances.

In patients with an autoimmune disorder, the immune system perceives the body’s own tissues as antigens and attacks them. The result is an immune response that destroys normal body tissues. This response is a hypersensitivity reaction similar to the response in allergic conditions. In allergies, the immune system reacts to an outside substance that it normally would ignore. With autoimmune disorders, the immune system reacts to normal body tissues that it would normally ignore.

What causes the immune system to no longer tell the difference between healthy body tissues and antigens is unknown. One theory is that some microorganisms (such as bacteria or viruses) or drugs may trigger some of these changes, especially in people who have genes that make them more likely to get autoimmune disorders. The possibility that microorganisms might trigger the pathology of auto-immunity is interesting because I believe that Latent Heat is often at the root of autoimmune diseases. Moreover, in my view, immunizations have a lot to do with the development of Latent Heat.


An autoimmune disorder may result in:
- The destruction of one or more types of body tissue
- Abnormal growth of an organ
- Changes in organ function
- An autoimmune disorder may affect one or more organ or tissue types.

Organs and tissues commonly affected by autoimmune disorders include:
- Blood vessels
- Connective tissues
- Endocrine glands such as the thyroid or pancreas
- Joints
- Muscles
- Red blood cells
- Skin
A person may have more than one autoimmune disorder at the same time.

Symptoms
Symptoms of an autoimmune disease vary enormously based on the disease and location of the abnormal immune response. Symptoms that often occur with autoimmune diseases include:
Fatigue
Fever
General ill-feeling (malaise)
From a Chinese perspective these three symptoms could be symptoms of Yin Fire or Latent Heat.
Before discussing the possible interpretation of autoimmune diseases from the Chinese perspective, I would like to discuss the Chinese medicine correspondent of the immune system or, to put it differently, what parts of Chinese Vital Substances and functions influence the immune system.

COMPONENTS OF IMMUNE SYSTEM IN CHINESE MEDICINE
Wei Qi
Ying Qi
Blood
Kidney (Yin and Yang)
Bone marrow
Yuan Qi
Jing
Stomach and Spleen

It would be easy to identify the function of the immune system as a Yang function (protection, immune cells constantly moving and hunting for antigens) but it would be wrong. The whole humoral part of the immune system relies on Blood and Yin.

Wei Qi
It is a very common misconception to attribute the immune response to Wei Qi which is natural since it is indeed the “protective” or “defensive” Qi that protects from exterior pathogenic factors. The following is the Chinese ideogram for "Wei".


The inside part is phonetic (wei) while the two outer parts together are xing, i.e. to move. Separately, they are the left and the right footprint and some say they suggest two guards patrolling back to back, hence Wei Qi being defensive Qi

These two parts together form the character xing 行 which means "to move" (and it also the character for "Element" as in the "5 Elements". The modern, simplified character for "wei" 卫 does not mean anything.

Chapter 18 of the Ling Shu says: “Ying Qi comes from the Middle Burner Wei Qi comes from the Lower Burner.” This may come as a surprise to some as we are used to think of the Wei Qi being associated with the Lungs and therefore the Upper Burner, which it is. However, it is said that the Wei Qi comes from the Lower Burner because it is associated with Kidney-Yang. Of course, it is also true that the Wei Qi is diffused in the Upper Burner by the Lungs, but its origin is in the Lower Burner.

Zhang Yuan Su (ca. 1151-1234) in the Yi Yuan “Origin of Medicine” says very clearly that the Wei Qi comes from the Lower Burner and the context can leave no doubt because he lists the three Burners, from Upper to Middle to Lower and therefore the third one (for the Wei Qi) could not but be the Lower Burner.

He says: “Zong Qi accumulates in the Upper Burner Ying Qi comes out in the Middle Burner Wei Qi comes out in the Lower Burner. Ying Qi follows the Zong Qi in the channels [mai] the Wei Qi cannot follow the Zong Qi and cannot enter the channels. It therefore stays outside the channels, penetrating the space between the skin and muscles in the head, eyes, hands and feet.”

He also says: “Ying Qi is clear, Wei Qi turbid Ying moves in the channels, Wei moves outside the channels. The Upper Burner is like a mist the Middle Burner like a cauldron the Lower Burner like a ditch. Wei Qi depends on the Yang part of the Yin of the Lower Burner, it rises to the other two Burners [because it is Yang], but it comes from the Lower Burner.”

Ying Qi is Yin, Wei Qi is Yang. We are used to think of Ying Qi as the one corresponding to food, nutrition and that is why it is called “Nutritive Qi”. However, Wei Qi is also related to food and nutrition. In fact the Su Wen says: “Wei Qi is the rough [han] Qi of water and grains.” The Su Wen uses the word “fierce, ferocious” [han 悍] that I translate as “rough”.

The Ying Qi is also connected to “water and grains”: “Ying Qi is the essence [jing Qi] of water and grains which enters the channels [mai].”

Although stemming from the Lower Burner, Wei Qi influences the Upper Burner, the Lungs, the Exterior, the Cou Li space, the pores and sweating.

Wu Qian says in the The Golden Mirror of Medicine (Yi Zong Jin Jian 1746): “Both Ying and Wei Qi derive from Gu Qi. The clear part of Qi forms Ying Qi, the turbid part forms Wei Qi. The Qi of Wei Qi is “rough”[“fierce”, “ferocious”] the Blood of Ying Qi is an essence. In terms of location, we talk of Qi and Blood in terms of movement, they are Wei and Ying. Ying Qi moves in the vessels [mai] and is Yin Wei Qi moves outside the vessels and is Yang. The movement of Ying and Wei relies on the Pre-Natal Qi of the Kidneys.”

He also says: “There are three Qi in the body: the Wei Qi exits in the Upper Burner and the Ying Qi in the Middle Burner: these are two Qi. These two Qi coalesce in Heart and Lungs to form the Zong Qi. Ying Qi is in the vessels and is close to Blood: Wei Qi is outside the vessels and is close to fluids. As Ying Qi is close to Blood, it is affected by Blood stasis: as Wei Qi is close to fluids, it is affected by fluid retention. To treat Blood, one must move and transform Ying Qi to treat fluids, one must warm and move Wei Qi.”

Please note that the statement here that the Wei Qi exits in the Upper Burner is not in contradiction with the earlier one (Zhang Yuan Su) that stated that the Wei Qi comes from the Lower Burner. Wei Qi originates from the Lower Burner but it exits in the Upper Burner where it is controlled by the diffusing of Lung-Qi.

Wei Qi and Lungs
Wei Qi goes to the Upper Burner and the Lungs “diffuses” it like an aerosol spray to the Upper Burner, the skin and the Cou Li space. Although we stress a lot the descending of Lung-Qi, the diffusing of Lung-Qi [xuan 宣] has an ascending movement.

Acupuncture: LU-7 Lieque, L.I.-4 Hegu, BL-12 Fengmen.

Wei Qi and Exterior
The “Exterior” is the space of the body that is outside the Zangfu and also outside the Main channels. It is the space where the Luo channels are. The Luo channels are the channels through which external pathogenic factors penetrate the body and the Wei Qi flows in the Luo channels performing its function of protection from external pathogenic factors.

Acupuncture: LU-7 Lieque, L.I.-4 Hegu, BL-13 Feishu.

Wei Qi and Cou Li Space
The term Cou Li is difficult to translate. Cou means “cavity” while Li means “texture” as in the texture or grain of wood. Although Cou refers to any cavity of the body, some large, some small, the term Cou Li is usually used (although not strictly correct) to indicate the space between the skin and muscles.

This is not literally and anatomically the space between skin and muscles but it must be interpreted energetically as a superficial space of the body, actually, apart from the skin itself, the most superficial. This is the space where the smaller and more superficial Luo channels flow [sun mai and fu mai].

The Cou Li 腠 理 space is the space between skin and muscles. The Luo channels are more superficial than the Main channels and they run in all directions, horizontally rather than vertically. Amongst other spaces, they fill the Cou Li space, i.e. the space between skin and muscles.

Acupuncture: LU-7 Lieque, L.I.-4 Hegu, BL-13 Feishu.

Wei Qi, pores and sweating
The Wei Qi influences the pores on the skin and therefore sweating. Sweat is in the Cou Li space. Th is space is regulated by the balance of Ying and Wei in it. When these are regulated, sweating is normal, i.e. normal sweating on exercise or when it is hot.

The Cou Li space may be “too tight” which means the pores are closed and the person does not sweat on exercise or when it is hot. It also means that if this person gets an invasion of Wind, they will not sweat and one must use Ma Huang Tang Ephedra Decoction.

The Cou Li space may also be “too relaxed” in which case the pores are open and the person sweats spontaneously. It also means that if they get an invasion of Wind, there will be slight sweating, which is actually due to a deficiency of Ying Qi in the Cou Li space one uses Gui Zhi Tang Ramulus Cinnamomi Decoction to regulate Ying and Wei in the Cou Li space.

Acupuncture: LU-7 Lieque, L.I.-4 Hegu, BL-13 Feishu.

Ying Qi
Ying Qi, the “nutritive” Qi is inseparable from Wei Qi. Although the two are always contrasted with each other, they are actually closely connected. The Wei Qi could not exist without Ying Qi.
The Ying Qi is called “Nutritive” because it comes from “water and grains”: “Ying Qi is the essence [jing Qi] of water and grains which enters the channels [mai].” However, Wei Qi also derives from water and grains except that its Qi is more “coarse”: “Wei Qi is the rough [han] Qi of water and grains.”
Ying Qi also keeps the Cou Li space “consolidated” if the Cou Li space is not "consolidated" it is prone to invasions of Wind. If the Ying Qi is weak in this space, there is slight sweating during an invasion of Wind.

Acupuncture: ST-36 Zusanli, Ren-12 Zhongwan, BL-20 Pishu, BL-21 Weishu.

Blood
The Su Wen relates resistance to disease to Blood in many passages. “When the Qi of Blood is not harmonized, 100 diseases can arise.” Blood influences resistance to disease also due to its relationship with Ying Qi.
The point BL-11 Dashu is the point of the Upper Sea of Blood of the Chong Mai. I use it with direct moxa, also to stimulate resistance to disease and to external pathogenic factors.

Acupuncture: BL-11 Dashu, BL-17 Geshu (with direct moxa), Ren-4 Guanyuan, KI-3 Taixi, SP-6 Sanyinjiao, ST-36 Zusanli.

Kidneys
The Kidneys play a big role in the immune system and resistance to disease. First of all, Kidney-Yang is the root of the Wei Qi which stems from the Lower Burner. Resistance to disease from a Chinese perspective depends on Qi and Qi is movement and movement is Yang. Kidney-Yang is the root of the Yang of the whole body.

If we think of the B cells, T cells, macrophages, neutrophils etc, and how they move in the blood stream and the cells we get an idea of the need for Yang, i.e. movement (although the medium where it all happens is blood which is Yin). If we consider that the B cells produce highly specific antibodies at a rate of as many as 2000 molecules per second for four to five days, we get a very good idea of why it is a Yang process.
The Kidneys play a role in the immune system also due to Yuan Qi and bone marrow which will be discussed separately.

Acupuncture: BL-23 Shenshu, Ren-4 Guanyuan.

Bone Marrow
Bone marrow depends on the Kidneys, more Yin than Yang. Jing is the organic foundation for the production of Marrow. “Marrow” (sui 髓) does not correspond to bone marrow of Western Medicine. “Marrow” in Chinese Medicine is a substance which is the common matrix of bones, bone marrow, brain and spinal cord.

The Ling Shu says in chapter 36: “The five flavours and fluids amalgamate to form Fat: this irrigates the cavities inside the bones, it tonifies the Brain and the Marrow and flows to the thighs”. 1

This statement is interesting in its reference to a form of “fat” formed by food and drink which goes to form bone-marrow and the spinal cord and brain. Therefore the bone-marrow, spinal cord and brain (all manifestations of “Marrow”) are a dense, material type of Qi which the Ling Shu calls “Fat”. Another interesting aspect of the above statement is the reference to the Marrow flowing to the thighs: therefore the ancient Chinese seem to have grasped the fact that long bones contain bone-marrow.

The Marrow is also the basis for the formation of bone marrow which nourishes the bones. Thus the Kidneys also govern the bone marrow and bones. The “Simple Questions” in chapter 17 says: “The bones are the Fu [organ] of the Marrow”. 2

The Kidneys store Jing which produces marrow: this, in turn, generates bone marrow which contributes to making Blood. A doctor of the Qing dynasty, Zhang Lu, in his book Medical Transmission of the Zhang Family (1695), says: ‘If Qi is not exhausted, it returns essences to the Kidneys to be transformed into Jing if Jing is not depleted, it returns to the Liver to be transformed into Blood.’ 3

It seems remarkable that the Chinese account of the blood-forming function of bone marrow, so similar to that given by Western physiology, was formulated during the Qing dynasty before the introduction of Western medicine into China. Lin Pei Qin, a doctor of the Qing dynasty, formulated the theory that ‘Liver and Kidneys have the same source’ and that Blood is transformed from Kidney Jing.

The connection between bone marrow and Blood is a primordial understanding of the role of bone marrow in the immune system since both B cells and T cells derive from bone marrow.

Acupuncture: BL-11 Dashu, G.B.-39 Xuanzhong, BL-17 Geshu, BL-23 Shenshu.

Yuan Qi
The Yuan Qi emerges from between the Kidneys. Chapter 66 of the Nan Jing is one of the earliest descriptions of the Yuan Qi. It says: “The Yuan Qi is the Motive Force [Dong Qi] situated between the two kidneys, it is life-giving and it is the root of the 12 channels.” 4

Yuan Qi can be seen as the dynamic motive force that arouses and moves the functional activity of all the organs. It does so because, like Jing, it is the foundation of vitality and stamina. As a form of Qi, it circulates all over the body, in the channels. It could be said to be the link between Jing, which is more fluid-like and related to slow, long-term cycles and changes, and the day-to-day Qi, which is Qi-like and is related to short-term cycles and changes.

Yuan Qi also facilitates the transformation of Gu Qi into Blood in the Heart. This is another way in which the Kidneys participate in the production of Blood.

Chapter 8 of the Nan Jing: "Sometimes the Cun Kou is normal and yet the patient dies. Why is that? The pulses of the 12 channels all originate from the Yuan Qi. This Yuan Qi is the root of the 12 channels, it is the Motive Force (Dong Qi 动 气) between the Kidneys, the root of the 5 Zang and 6 Fu and of the 12 channels, the gate of breathing and the origin of the Triple Burner. It is the spirit that guards against pathogenic factors (or evil influences). Such Qi is the root of humankind if the root is cut stalks and leaves wither. When the Cun Kou is normal but the patient dies, it means that the Yuan Qi has been cut off internally."

This chapter establishes some very important principles. First, it talks about the Yuan Qi 原 气: this is essentially the meaning of the expression “Sheng Qi Zhi Yuan” which can be translated as the “Origin of Life’s Qi” or “Origin that generates Qi”. It says that Yuan Qi is between the Kidneys (like the Ming Men) and that it is the root of the 12 channels, the Triple Burner and the 5 Zang and 6 Fu.

This chapter also establishes the idea that the Yuan Qi (and therefore the Kidneys) is the root of the 5 Zang and 6 Fu, of the 12 channels and of the Triple Burner.

Secondly, this passage establishes the principle that the Yuan Qi (and therefore the Kidneys) play a role in the resistance to pathogenic factors. Interestingly, it calls the Yuan Qi the Shen that protect from pathogenic factors (or evils).

This is of huge clinical significance because it means that our resistance to pathogenic factors depends not only on the Wei Qi and therefore Lungs but also on the Kidneys and the Yuan Qi (and also Jing due to the extraordinary vessels). In any case, Wei Qi stems from the Lower Burner.

This is of clinical significance not only in resistance to pathogenic factors but also in the pathology of allergic asthma and allergic rhinitis, the root of which is also in the Kidneys, the Jing and the Yuan Qi.

As we shall see, a deficiency of the Kidneys also plays a role in the formation of Latent Heat and a deficiency of Yuan Qi plays a role in the formation of Yin Fire which are often at the base of auto-immune disorders.

Chapter 66 of the Nan Jing also discusses the Yuan Qi: “Below the umbilicus and between the kidneys there is a Throbbing Qi [Dong Qi 动 气] which constitutes a person’s life [sheng ming 生 命]. This [Throbbing Qi] is the root of the 12 channels, also called Yuan Qi [原 气]. The Triple Burner is the envoy of the Yuan Qi [or it allows the Yuan Qi to separate into its different functions]. It is responsible for the passage of the three types of Qi in the 5 Zang and 6 Fu.

The “three Qi” mentioned here are the Yuan Qi, Ying Qi and Wei Qi of Lower, Middle and Upper Burner respectively. Yuan Qi is part of a triad of types of Qi, all which play a role in resistance to disease in the three Burners: Yuan Qi in the Lower, Ying Qi in the Middle and Wei Qi in the Upper Burner.

Acupuncture: Ren-4 Guanyuan, BL-23 Shenshu, Du-4 Mingmen.

Jing
We are used to think of Jing as the precious Essence that we inherit from the parents, that determines our constitution and that resides in the Lower Dan Tian. When described like that, the Jing sounds like an inert essence but, in reality, Jing circulates in the channels and plays an important role in resistance to disease.

It circulates in the channels through the extraordinary vessels. The influence of the Extraordinary Vessels on the space between skin and muscles implies their important role in protection from pathogenic factors. As the Extraordinary Vessels circulate the Kidney-Jing, this means that Jing plays a role in many physiological functions and, in particular, in the protection against external pathogenic factors.

A deficiency of Jing plays a role in the formation of Latent Heat and, in my opinion, in the aetiology of allergic diseases such as allergic asthma, allergic rhinitis and atopic eczema and of auto-immune disorders. Indeed, it is in my opinion the aetiology of atopy itself.

The "Study of the Eight Extraordinary Vessels" by Li Shi Zhen says: ". when the Qi of the channels overflows, it flows into the extraordinary vessels where it is turned into irrigation, warming the organs internally and irrigating the space between skin and muscles externally."
The Qi of the Extraordinary Vessels “irrigates” the space between the skin and muscles where Defensive Qi circulates to prevent invasion of pathogenic factors.

Because all the Extraordinary Vessels derive directly or indirectly from the Kidneys, they play an important role in the defence against exterior pathogenic factors.

Acupuncture
- Du Mai: SI-3 Houxi with BL-62 Shenmai, BL-23 Shenshu, Du-4 Mingmen, Du-14 Dazhui.
- Ren Mai: LU-7 Lieque with KI-6 Zhaohai, Ren-4 Guanyuan.

Stomach and Spleen
Finally, the Stomach and Spleen also play a role in the resistance to disease. This is quite obvious since they are the origin of nutrition and of Gu Qi which is the basis for both Ying and Wei Qi.
The Stomach and Spleen play a particularly important role in the immune system of children. Dr Shen used to say that there are only two aetiological factors in children: external Wind and nutrition (Stomach and Spleen). He then added that, the younger the child, the more there is only one aetiological factor and that is the Stomach and Spleen because they determine resistance to external pathogenic factors.

Acupuncture: Ren-12 Zhongwan, ST-36 Zusanli, BL-20 Pishu, BL-21 Weishu.

THE IMMUNE SYSTEM AND THE 6 STAGES AND 4 LEVELS
The 6 Stages were developed by Zhang Zhong Jing in his book "A Discussion of Diseases from Cold Injury" (Shang Han Lun, ca. AD 220) while the 4 Levels were developed much later by Ye Tian Shi in his book "A Discussion of Warm Diseases" (Wen Bing Lun, 1742).

The patterns of both of these theories describe the progression of fevers from external invasions of Wind. Although these two theories are often contrasted to each other, they have many points in common as illustrated in the diagram below. The patterns in this diagram are colour-coded to show the connections between the patterns of the 6 Stages with those of the 4 Levels. In particular, there is a strong connection between the Yang Ming Stage and the Qi Level and many of the prescriptions used by Ye Tian Shi for the Qi Level are the same as those for the Yang Ming Stage in the Shang Han Lun.

I have been thinking about these ancient patterns and it occurred to me that they could be seen as a picture of the immune system and this idea is illustrated in the diagram below. For example, if we fall ill with a fever of external origin (we can think of influenza, for example) and, after the initial stage, we develop a higher fever, it indicates that the body is reacting and fighting the pathogenic factor: this is a good state of the immune system and it corresponds to the Qi Level of the 4 Levels or the Yang Ming stage of the 6 Stages.

Allergy, such as in allergic asthma and allergic rhinitis, represents a hyper-activity of the immune system that is reacting to allergens to which it should not: this could be represented by the Wei Level pattern in the 4 Levels or the Tai Yang Stage in the 6 Stages.

In chronic fatigue syndrome, the immune system is reacting to a viral infection, but not enough, so that the disease has a chronic course: this corresponds to the Gall-Bladder-Heat pattern of the 4 Levels or the Shao Yang Stage of the 6 Stages.

If our immune system is greatly debilitated, it may succumb to cancer and this corresponds to the Blood Level of the 4 Levels or the three Yin Stages of the 6 Stages.

In autoimmune diseases, the immune system has a deep dysfunction that leads it to attack the cells of the body, mistaking them for "other": this often (but not always) corresponds to Latent Heat.



AUTOIMMUNE DISEASES in CHINESE MEDICINE
In my view, the presence of an auto-immune dysfunction of the immune system indicates an aetiological factor that is at a deep energetic level and that is different from normal exterior pathogenic factors. It indicates a more insidious form of pathogenic factor. The immune dysfunction also indicates a pathology of the Yin aspects of the immune system, i.e. Blood, bone marrow, Kidneys.

However, auto-immune diseases are so many and so disparate that it is impossible to prescribe a blanket treatment method for them. For example, the pathology of Hashimoto’s thyroiditis and MS are so different that they really have very little in common.

The only thing they might have in common is the aetiology. In many, but not all, auto-immune diseases the aetiology is Latent Heat. This is the case especially when there are symptoms of Heat, with lassitude and possibly fever, they have something in common in their pathology. In other cases of autoimmune diseases, the main pathology may also be Yin Fire. Also, if we know we are dealing with an auto-immune disease, it gives us an important pointer from the point of view of prognosis.

However, there is an interesting common feature of some auto-immune diseases and that is the pulse. I have noticed this especially in MS, RA, Hashimoto's thyroiditis and Crohn’s disease. The pulse is of the Leather [ge 革] quality, i.e. it is superficial and “stretched” like a drum but empty at the deep level: it feels hard on the outside but empty inside, like a drum. The Leather pulse indicates severe deficiency of Blood, Essence or Yin. It also indicates Qi floating upwards because it is not rooted by Blood. This would indicate that the root of these autoimmune diseases is a Kidney deficiency.

APPROACH TO TREATMENT OF AUTO-IMMUNE DISEASES
- No Chinese theory obviously.

- All diseases are very different and must be treated according to their specific pathology and patterns (e.g.
MS and Hashimoto’s thyroiditis have nothing in common from Chinese perspective).

- Being auto-immune affects ease (or difficulty) of treatment and prognosis. They are more difficult to treat.

- Compare hyperthyroidism and Graves' Disease: latter has more severe symptoms and will be more
difficult to treat.

- In late stages of auto-immune diseases, there seems to be a common pulse, i.e. the Leather pulse which is
superficial but empty at the deep level. The surface is kind of “broad” and feels kind of stretched like a
drum. This indicates a severe Kidney deficiency.

- Must grasp aetiology, pathology and patterns of the disease ignoring its auto-immune nature. For _ example, Sjogren’s Syndrome, Hashimoto thyroiditis, Crohn’s Disease, MS and RA have very little or _ nothing in common in terms of pathology.
______ Sjogren’s Syndrome: Yin Xu of Stomach and Liver
______ Hashimoto's Thyroiditis: Phlegm, Spleen-Qi Xu, Kidney-Yang Xu
______ Crohn’s Disease: Damp-Heat in Intestines
______ MS: Dampness, Stomach-Spleen Xu, Liver-Kidneys Xu
______ RA: Damp-Heat in joints

- Must treat the Kidneys which are the root of the auto-immune process. This can be Kidney-Yang,
Kidney-Yin, Jing, Yuan Qi, Minister Fire.

- Must treat inflammation with at least one or two anti-inflammatory herbs.

- Check if there is Latent Heat or Yin Fire and treat them accordingly.

LIST OF ANTI-INFLAMMATORY CHINESE HERBS 5
Ba Ji Tian Radix Morindae officinalis
Bai Shao Radix Paeoniae alba
Bai Zhi Radix Angelicae dahuricae
Can Er Zi Fructus Xanthii
Cao Wu Radix Aconiti Kusnezoffi
Chai Hu Radix Bupleuri
Chi Shao Radix Paeonia rubra
Chuan Xin Lian Herba Andrographis
Da Huang Radix et Rhizoma Rhei
Da Qing Ye Folium Isatidis
Dan Shen Radix Salviae miltiorrhizae
Dang Gui Radix Angelicae sinensis
Dang Shen Radix Codonopsis
Di Yu Radix Sanguisorbae
Du Huo Radix Angelicae pubescentis
Du Zhong Cortex Eucommiae
Fang Feng Radix Saposhnikoviae
Fu Zi Radix Aconiti Lateralis preparata
Hong Hua Flos Carthami
Hei Zhi Ma Semen Sesami nigri
Hu Zhang Rhizoma Polygoni cuspidati
Huai Hua Flos Sophorae
Huang Lian Rhizoma Coptidis
Huang Qi Radix Astragali
Huang Qin Radix Scutellariae
Jiang Huang Rhizoma Curcumae longae
Jie Geng Radix Platycodonis
Jin Qian Cao Herba Lysimachiae
Jin Yin Hua Flos Lonicerae
Jing Jie Herba Schizonepetae
Ku Shen Radix Sophorae flavescentis
Kuan Dong Hua Flos Farfarae
Lei Gong Teng Radix Tripterygii wilfordii
Lian Qiao Fructus Forsythiae
Lu Hui Aloe
Lu Lu Tong Fructus Liquindambaris
Man Jing Zi Fructus Viticis
Mao Dong Qing Radix Ilicis pubescentis
Mu Dan Pi Cortex Moutan
Nu Zhen Zi Fructus Ligustri lucidis
Pi Pa Ye Folium Eriobotryae
Qiang Huo Rhizoma et Radix Notopterygii
Qin Jiao Radix Gentianae macrophyllae
Qin Pi Cortex Fraxini
San Qi Radix Notoginseng
Shan Dou Gen Radix Sophorae tonkinensis
Sheng Ma Radix Cimicifugae
Tao Ren Semen Persicae
Tian Ma Rhizoma Gastrodiae
Wu Jia Pi Cortex Acanthopanacis
Xi Xian Cao Herba Siegesbeckiae
Xi Xin Herba Asari
Xia Ku Cao Spica Prunella
Xian Mao Rhizoma Curculiginis
Xiang Fu Rhizoma Cyperi
Xiao Ji Herba Cirisii
Xu Chang Qing Radix Cynanchi Paniculati
Xue Jie Sanguis Draconis
Xue Yu Tan Crinis Carbonisatus
Xun Gu Feng Herba Aristolochiae Mollissimae
Ye Ju Hua Flos Chysanthemi Indici
Yin Yang Huo Herba Epimedii
Yu Xing Cao Herba Houttuyniae
Ze Xie Rhizoma Alismatis
Zhi Zi Fructus Gardeniae
Zi Cao Gen Radix Lithospermi

As one can see, this list is so extensive that practically every formula we use will have some anti-inflammatory herb in it. I believe it is very important to use some anti-inflammatory herbs in the treatment of autoimmune diseases. I especially use Mu Dan Pi Cortex Moutan. It is worth also noting that the anti-inflammatory herbs are found in many different categories of herbs, not just those that clear Heat: thus having an anti-inflammatory effect does not necessarily involve clearing Heat from the Chinese perspective. Indeed, it is very interesting (and somewhat surprising) that even Fu Zi and Cao Wu (extremely hot herbs) are anti-inflammatory.

http://news.harvard.edu/gazette/story/2012/02/secrets-of-ancient-chinese-remedy-revealed/
The following is an online article from Harvard University about the effect of the Chinese herb Chang Shan Radix Dichroae febrifugae on autoimmune diseases.
For roughly 2,000 years, Chinese herbalists have treated malaria using a root extract, commonly known as Tu Chang Shan, from a type of hydrangea that grows in Tibet and Nepal. More recent studies suggest that halofuginone, a compound derived from this extract’s bioactive ingredient, could be used to treat many autoimmune disorders as well. Now, researchers from the Harvard School of Dental Medicine have discovered the molecular secrets behind this herbal extract’s power.

It turns out that halofuginone (HF) triggers a stress-response pathway that blocks the development of a harmful class of immune cells, called Th17 cells, which have been implicated in many autoimmune disorders.
“HF prevents the autoimmune response without dampening immunity altogether,” said Malcolm Whitman, a professor of developmental biology at Harvard School of Dental Medicine and senior author on the new study. “This compound could inspire novel therapeutic approaches to a variety of autoimmune disorders.”

" This study is an exciting example of how solving the molecular mechanism of traditional herbal medicine can lead both to new insights into physiological regulation and to novel approaches to the treatment of disease,” said Tracy Keller, an instructor in Whitman’s lab and the first author on the paper.

This study, which involved an interdisciplinary team of researchers at Harvard-affiliated Massachusetts General Hospital and elsewhere, will be published online Feb. 12 in Nature Chemical Biology.
Prior research had shown that HF reduced scarring in tissue, scleroderma (a tightening of the skin), multiple sclerosis, scar formation, and even cancer progression. “We thought HF must work on a signaling pathway that had many downstream effects,” said Keller.

In 2009, Keller and colleagues reported that HF protects against harmful Th17 immune cells without affecting other beneficial immune cells. Recognized only since 2006, Th17 cells are “bad actors,” implicated in many autoimmune diseases such as inflammatory bowel disease, rheumatoid arthritis, multiple sclerosis, and psoriasis.

The researchers found that minute doses of HF reduced multiple sclerosis in a mouse model. As such, it was one of a new arsenal of drugs that selectively inhibits autoimmune pathology without suppressing the immune system globally. Further analysis showed that HF was somehow turning on genes involved in a newly discovered pathway called the amino acid response pathway, or AAR.

Scientists have only recently appreciated the role of the nutrient sensing-AAR pathway in immune regulation and metabolic signaling. There is also evidence that it extends life span and delays age-related inflammatory diseases in animal studies on caloric restriction.

AAR lets cells know when they need to preserve resources. For example, when a cell senses a limited supply of amino acids for building proteins, AAR will block signals that promote inflammation because inflamed tissues require lots of protein.

“Think about how during a power outage we conserve what little juice we have left on our devices, foregoing chats in favor of emergency calls,” said Whitman. “Cells use similar logic.”For the current study, the researchers investigated how HF activates the AAR pathway, looking at the most basic process that cells use to translate a gene’s DNA code into the amino acid chain that makes up a protein.

The researchers were able to home in on a single amino acid, called proline, and discovered that HF targeted and inhibited a particular enzyme (tRNA synthetase EPRS) responsible for incorporating proline into proteins that normally contain it. When this occurred, the AAR response kicked in and produced the therapeutic effects of HF treatment.

Providing supplemental proline reversed the effects of HF on Th17 cell differentiation, while adding back other amino acids did not, establishing the specificity of HF for proline incorporation. Added proline also reversed other therapeutic effects of HF, inhibiting its effectiveness against the malaria parasite as well as certain cellular processes linked to tissue scarring. Again, supplementation with other amino acids had no such effect. Such mounting evidence clearly demonstrated that HF acts specifically to restrict proline.

The researchers think that HF treatment mimics cellular proline deprivation, which activates the AAR response and subsequently impacts immune regulation. Researchers do not yet fully understand the role that amino acid limitation plays in disease response or why restricting proline inhibits Th17 cell production.
Nevertheless, “[the] AAR pathway is clearly an interesting drug target, and halofuginone, in addition to its potential therapeutic uses, is a powerful tool for studying the AAR pathway,” said Whitman.


END NOTES
1. 1981 Spiritual Axis (Ling Shu Jing). People’s Health Publishing House, Beijing, p. 77.
2. Simple Questions, p. 100.
3. Zhang Lu Medical Transmission of the Zhang Family (Zhang Shi Yi Tong), cited in Syndromes and Treatment of the Internal Organs (Zang Fu Zheng Zhi). Tianjin Scientific Publishing House, Tianjin, 1981, p.27.
4. Nanjing College of Traditional Chinese Medicine 1979 A Revised Explanation of the Classic of Difficulties (Nan Jing Jiao Shi). People’s Health Publishing House, Beijing, p. 144.
5. Chen JK, Chen TT, "Chinese Medical Herbology and Pharmacology", Art of Medicine Press, City of Industry, CA, 2001.