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What do we mean by MHC molecule diversity? Does each human have a variety of MHC molecule isoforms?

What do we mean by MHC molecule diversity? Does each human have a variety of MHC molecule isoforms?


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I'm going to try and explain what I think I know

From what I understand, MHC/HLA molecules present peptides to T cells. To be able to present peptides from a wide variety of pathogens, they need to have diversity in their peptide binding domains. My lecture handout tell me that MHC diversity comes due to polygeny and polymorphism. Polygeny refers to there being 3/6 (handout says 3, textbook says 6) MHC class I loci leading to 3/6 class I isotypes, and 3/5 MHC class II loci leading to 3/5 class II isotypes. Polymorphism refers to multiple alleles of each gene, meaning a variety of allotypes produced from each gene. These processes lead to the generation of a wide variety of isoforms of MHC proteins in the human population. The textbook also states that there is no rearrangement or structural change of the genes encoding the MHC proteins.

So I get that in the population, there is huge diversity of MHC molecules. But in each human, since there is no rearrangement of genes as in the case of antibodies to generate antibody diversity, is there therefore only one type of MHC protein being encoded? So by MHC diversity, we are not referring to diversity in each human, rather in the entire population? And if so, how do our MHC molecules become capable of binding to any antigen from any pathogen?

Please could someone clarify for me if I've misunderstood something, and also if my above explanation is factually correct, with the appropriate use of terminology?


You're right that both polygeny and polymorphism contribute to the diversity of a given gene in the population correctly described what they mean individually.

However, you missed that the polygeny of MHC means that the human genome has 3 different loci/genes (called MHC-I A,B & C) in the haploid genome, meaning that any given human as actually 6 copies of the gene (i.e. 3 copies from each parent). All of these copies perform the same function of presenting peptides to CD8+ cells, but will have slightly different binding preferences for the peptides that they load. This is where the MHC diversity in a single human comes from.

Additionally each of the 3 MHC-I loci/isoforms is polymorphic, meaning that for each of them multiple alleles/variants exist in the human population. Since the number of these variants is pretty big (hundreds to thousands), most humans have different alleles on their paternal & maternal chromosomes and end up with 6 unique MHC-I genes.


MHC class I

MHC class I molecules are one of two primary classes of major histocompatibility complex (MHC) molecules (the other being MHC class II) and are found on the cell surface of all nucleated cells in the bodies of vertebrates. [1] [2] They also occur on platelets, but not on red blood cells. Their function is to display peptide fragments of proteins from within the cell to cytotoxic T cells this will trigger an immediate response from the immune system against a particular non-self antigen displayed with the help of an MHC class I protein. Because MHC class I molecules present peptides derived from cytosolic proteins, the pathway of MHC class I presentation is often called cytosolic or endogenous pathway. [3]

In humans, the HLAs corresponding to MHC class I are HLA-A, HLA-B, and HLA-C.


Chapter 6 - The Major Histocompatibility Complex

In this chapter, we describe the genes of the major histocompatibility complex (MHC) and their role in immune responses. The MHC class I and II genes encode surface proteins that present peptides to T cells. The corresponding MHC class I and II proteins are heterodimers with highly variant N-terminal domains forming a peptide-binding site. MHC class I is expressed on almost all cells and generally presents endogenous peptides. MHC class II is expressed by APCs and generally presents exogenous peptides. MHC class I interacts with CD8 on Tc cells and CTLs, while MHC class II interacts with CD4 on naïve and effector Th cells. The MHC genes are polygenic, polymorphic and expressed codominantly. Syngeneic individuals have the same MHC genotype, while allogeneic individuals have different MHC genotypes. Differences in MHC alleles between individuals are largely responsible for transplant rejection and variations in responses to pathogens. In addition, expression of particular MHC alleles is linked to autoimmune disease predisposition.


Chapter 6 - Structural diversity of class I MHC-like molecules and its implications in binding specificities

The binding groove of class I major histocompatibility complex (MHC) class is essentially important for antigen binding and presentation on T cells. There are several molecules that have analogous conformations to class I MHC. However, they bind specifically to varying types of ligands and cell-surface receptors in order to elicit an immune response. To elucidate how such recognition is achieved in classical MHC-I like molecules, we have extensively analyzed the structure of human leukocyte antigen (HLA-1), neonatal Fc receptor (FcRn), hereditary hemochromatosis protein (HFE), cluster of differentiation 1 (CD1), gamma delta T cell receptor ligand (Τ22), zinc-α2-glycoprotein (ZAG), and MHC class I chain-related (MIC-A) proteins. All these molecules have analogous structural anatomy, divided into three distinct domains, where α1−α2 superdomains form a groove-like structure that potentially bind to certain ligand, while the α3 domain adopts a fold resembling immunoglobulin constant domains, and holds this α1−α2 platform and the light chain. We have observed many remarkable features of α1−α2 platform, which provide specificities to these proteins toward a particular class of ligands. The relative orientation of α1, α2, and α3 domains is primarily responsible for the specificity to the light chain. Interestingly, light chain of all these proteins is β2-microglobulin (β2M), except ZAG which has prolactin-induced protein (PIP). However, MIC-A is devoid of any light chain. Residues on β2M recognize a sequence motif on the α3 domain that is essentially restricted to specific heavy chain of MHC class I molecules. Our analysis suggests that the structural features of class I molecules determine the recognition of different ligands and light chains, which are responsible for their corresponding functions through an inherent mechanism.


Chromatin Remodelling and Immunity

Abstract

Major histocompatibility complex (MHC) class II molecules are essential for processing and presenting exogenous pathogen antigens to activate CD4 + T cells. Given their central role in adaptive immune responses, MHC class II genes are tightly regulated in a tissue- and activation-specific manner. The regulation of MHC class II gene expression involves various transcription factors that interact with conserved proximal cis-acting regulatory promoter elements, as well as MHC class II transactivator that interacts with a variety of chromatin remodeling machineries. Recent studies also identified distal regulatory elements within MHC class II gene locus that provide enormous insight into the long-range coordination of MHC class II gene expression. Novel therapeutic modalities that can modify MHC class II genes at the epigenetic level are emerging and are currently in preclinical and clinical trials. This review will focus on the role of chromatin remodeling, particularly remodeling that involves histone acetylation, in the constitutive and inducible regulation of MHC class II gene expression.


The Major Histocompatibility Complex

Ii) MHC Class II Peptide-Binding Site

The MHC class II peptide-binding groove is similar in overall structure to that of MHC class I molecules ( Fig. 6-4B ). However, the ends of the MHC class II groove are open, permitting the binding of much longer peptides (up to 30 amino acids). Nevertheless, the majority of peptides found in MHC class II grooves are 13–18 amino acids long. The open ends of the MHC class II groove also mean that binding does not depend on conserved anchor residues at the ends of the peptides but is instead mediated by hydrogen bonding between the peptide backbone and the sidechains of certain MHC amino acids. Researchers have found that antigenic peptides that are successfully bound to the floor of the MHC class II groove possess a particular conserved secondary structure (resembling a polyproline chain) in the portion of the peptide that aligns with critical acidic MHC residues located in the middle of the groove. As a result of this conformational requirement, MHC class II proteins generally bind a narrower range of proteins than do MHC class I proteins.


Discussion

Central players of the adaptive immune system are the groups of proteins encoded in the MHC. By binding short peptide segments (epitopes), MHC molecules guide both immune response against pathogens and tolerance to self-peptides. The genomic region encoding these MHC molecules is of special interest, for two reasons. It harbors more disease associations than any other regions in the human genome, including associations with infectious diseases, autoimmune disorders, tumors, and neuropsychiatric diseases [52, 53]. A growing body of literature is now revealing that certain MHC class I alleles can bind a wider range of epitopes than others, but the functional implications of this variation remain largely unknown [10]. By recognizing a larger variety of epitopes, such promiscuous MHC alleles promote immune response against a broader range of pathogens at the individual level. Therefore, promiscuous epitope binding of MHC molecules should be favored by selection in geographic regions where extracellular pathogen diversity is high. Importantly, this mechanism is conceptually distinct from the well-established concept of heterozygote advantage at the MHC [54], as it concerns individual alleles and not allele combinations or genotypes.

To test this hypothesis, we combined data on the geographic distribution of human MHC class II alleles and prevalence of extracellular pathogens, empirical/computational estimates of epitope-binding promiscuity, and phylogenetic analyses. Our main findings, strongly supporting our hypothesis, are as follows.

First, in geographical regions of high extracellular pathogen diversity, human HLA-DRB1 alleles have exceptionally high epitope-binding repertoires. This suggests that the geographical distribution of promiscuous HLA-DRB1 alleles has been shaped by the diversity of extracellular pathogens. The HLA-DRB1*12:02 allele highlights this point. HLA-DRB1*12:02 is a promiscuous allele that has been associated with protection from certain infectious diseases (S5 Data). As expected, this allele is especially prevalent in regions of Southeast Asia with elevated pathogen load (Fig 2B).

It is well established that antigens presented by HLA class II molecules derive mainly from extracellular proteins [1]. However, HLA class II molecules have well-established roles in controlling immune response against viruses [55, 56]. Additionally, viral peptides are reported to be processed and presented also by the HLA class II pathway [57]. Therefore, it remains to be established why intracellular pathogen diversity has no major impact on the global distribution of HLA-DRB1 alleles.

Notably, the relationship between pathogen load and epitope-binding promiscuity may be more general, as similar results hold for the HLA-A locus: we found a positive correlation between local intracellular pathogen diversity and the HLA-A promiscuity level of the corresponding human populations (S9A and S9B Fig, S3 Data).

Second, a phylogenetic analysis revealed major differences in promiscuity levels of very closely related HLA-DRB1 alleles. This suggests that high promiscuity level in HLA-DRB1 has evolved rapidly and repeatedly during human evolution. Finally, amino acid positions with a prominent role in shaping HLA-DRB1 promiscuity level are especially variable in human populations and tend to be under positive selection. In sum, we conclude that HLA promiscuity level is a human trait with paramount importance during adaptation to local pathogens.

Our work has important ramifications for future studies. MHC is the most variable region of the human genome, and the variation is associated with numerous infectious and immune-mediated diseases [52, 53, 58–62]. The impact of MHC promiscuity level on population allelic diversity is an interesting area for future research. In a similar vein, MHC allelic diversity is associated with olfaction-based mating preferences in human and other animals [63]. The roles of MHC promiscuity in mating success and mating preferences are a terra incognita.

We note that the most promiscuous HLA-DRB1 alleles are rare in certain human populations (S1 Table S2 Data). This suggest that these alleles are not particularly favored by natural selection in these areas. Why should it be so? First, high promiscuity may not be able to cope with the rise of novel and highly virulent pathogens. In such cases, displaying a particular epitope might be the most efficient way to achieve resistance, and high promiscuity might be suboptimal due to a reduced specificity [9, 10]. Second, high promiscuity level may elevate the risk of immune reactions against host tissues and non-harmful proteins [9, 64]. Clearly, future work should elucidate the evolutionary trade-offs between protection from pathogens and genetic susceptibility to autoimmune diseases. This will require high-throughput experimental methods to determine epitope-binding repertoire [65], and HLA transgenic mice studies on the role of promiscuity in immune response [66].

Finally, genetic variation within particular MHC genes influences vaccine efficacy [67], rejection rates of transplanted organs [68], susceptibility to autoimmune diseases [49], and antitumor immunity [28, 69, 70]. Our work raises the possibility that, by altering the maturation and functionality of the immune system, the size of the epitope-binding repertoire of MHC alleles itself could have an impact on these processes. The exact role of MHC promiscuity in these crucial public health issues is an exciting future research area.


Results

HLA class I dissimilarity relates to partnership and sexual satisfaction

Partnership and sexual satisfaction were significantly related to HLA class I match. For both, partnership and sexual satisfaction, there was a significant interaction effect of HLA class and HLA similarity (partnership satisfaction: F(249, 1) = 14.1, p < 0.001 sexual satisfaction F(249, 1) = 5.1, p = 0.023). HLA class I dissimilarity was significantly associated with higher partnership satisfaction (F(249, 1) = 18.7, p < 0.001) and higher sexual satisfaction (F(496, 2) = 6.9, p = 0.008), while no such effect was found for HLA class II. Sex specific analysis revealed that overall HLA class I dissimilarity was related to higher partnership satisfaction in women (F(1, 249) = 9.9 p = 0.002) as well as in men (men: F(1, 240) = 8.8, p = 0.003), while overall HLA class I dissimilarity was related to higher sexual satisfaction in women only (F(1, 240) = 7.9, p = 0.005).

Sex and HLA type specific analysis revealed that sexual satisfaction in women was related to HLA-B dissimilarity (F(1, 240) = 14.5 pcorr < 0.001). Partnership satisfaction in women was related to HLA-B (F(1, 240) = 8.3 pcorr = 0.01) as well as HLA-C (F(1, 240) = 6.6 pcorr = 0.03). In men, higher partnership satisfaction was related to HLA-C dissimilarity (pcorr = 0.033, d = 0.25). Further, HLA-B dissimilarity was related to enhanced sexual satisfaction in men (pcorr = 0.027, d = 0.32). despite the lack of an overall HLA class I effect. No effect was observed for HLA-A (Fig. 1, Supplementary Table 1).

In general, HLA class I (HLA,–C) dissimilar couples expressed higher satisfaction, body odour attractiveness and a stronger wish for children. HLA,B dissimilarity significantly related to sexual satisfaction in women: pcorr = 0.003 and men: pcorr = 0.027. HLA–C dissimilarity contributed to partnership satisfaction in men p corr = 0.033, in women also HLA–C p corr = 0.027 as well as HLA,B p corr = 0.003. No effect was observed for HLA,A and class II. Women with a HLA–C-dissimilar partner expressed higher longing for children pcorr = 0.027. The error bar indicates the standard mean error.

Control for relationship duration did not impact the results. The impact of HLA class I on partnership satisfaction was stable after control of partnership sexuality (F(249, 1) = 14.7, p < 0.001). However, HLA class I dissimilarity did not significantly increase sexual satisfaction, after control of partnership satisfaction.

Women are more likely to want children with HLA class I dissimilar partners

HLA class I dissimilarity was significantly related to a positive answer to the question of whether participants wanted to have (more) children with their partner (Chi 2 = 11.3, p = 0.003). No such effect was observed for HLA class II. However, while sex specific analysis revealed a preference of HLA dissimilarity in women (Chi 2 = 16.6, p < 0.001), no such effect was observed for men. Within the group of women, dissimilarity in HLA class I allele B and C was related to the wish to have children with their partner, though after Bonferroni correction, only the impact of HLA-C remained significant (Chi 2 = 8.9, pcorr = 0.03, compare Fig. 1 and Supplementary Table 1). Exclusion of participants who already had children, did not impact the results.

HLA class I dissimilar partners are preferred in terms of body odor attractiveness

There was a significant interaction between the HLA similarity and HLA class (F(249, 1) = 6.3, p = 0.012), indicating that only HLA class I dissimilarity was significantly associated with higher body odor attractiveness (F(249, 1) = 8.2, p = 0.004). No such effect was observed for HLA class II (F(1, 1.5) = 0.4, p = 0.55). Sex specific analysis revealed, that HLA class I dissimilarity was related to women’s rating of partner body odor pleasantness (F(249, 1) = 4.2, p = 0.04, compare Fig. 1 and Supplementary Table 1), while no such effect was observed for men. Within the group of women, dissimilarity in HLA-B and -C class I alleles were related to higher body odor attractiveness rating of the respective partner, however those effects did not hold after Bonferroni correction.

There was no significant interaction between HLA similarity and HLA class (F(249, 1) = 0.1, p = 0.8) on body odor attraction after control for relationship duration and partnership satisfaction.

HLA-heterozygote people are not preferred over HLA-homozygote

Heterozygosity was more frequent than homozygosity for each of the HLA alleles (compare Supplementary Table 2). However sexual and partnership satisfaction, were independent of whether people were in a relationship with HLA heterozygote or homozygote partners. Similarly, no significant effects were obtained for the partner’s body odor attractiveness. Further, the desire for children was not affected by homozygote or heterozygote partners.


Immunology: Chapter 5 practice quiz

Later, as MHC class II is processed in the Golgi, the invariant chain gets degraded and only a small peptide, CLIP, blocks access to the peptide-binding groove of MHC class II.

a) refers to a locus that encodes an alpha and beta chain of MHC class I

b) refers to a locus that encodes an alpha and beta chain of MHC class II

c) refers to a gene that encodes the alpha chain of MHC class II

d) refers to a gene that encodes the beta chain of MHC class II

a) Different MHC alleles have different peptide binding specificity

b) MHC allele expression is subject to allelic exclusion: only one allele of MHC gene is used in one cell (False)

c) MHC allele expression is subject to gene exclusion: only the two alleles of one of the genes in a MHC gene family is used one cell (False)

d) MHC allele expression is co-dominant: all alleles are expressed simultaneously in one cell

i) What are the genes shown in the figure above encoding (different alleles at the HLA-DRA and HLA-DRB1 genes are shown as boxes of different shades) ?

ii) How many isoforms of MHC class II can this particular locus produce ?

ii) There are two different alpha chain alleles and three different beta alleles that can combine to form 2 X 3 = 6 different isoforms.

a) In the human population, there are hundreds of alleles of the MHC class I gene families.

b) In the human population, there are dozens to hundreds of alleles of the MHC class II gene families

c) The MHC class I family consists of 3 genes

d) The MHC class II gene family consists of three loci of two or more genes

e) HLA-DM is one of the loci encoding a MHC class II gene (false)

If an individual were homozygous for all three genes (very unlikely), only three isoforms would be expressed.

a) Organ rejection is usually due to the recipient's T cells

b) Differences in MHC alleles between organ donor and recipient can lead to organ rejection

c) The combination of MHC alleles that you inherited from one of your parents constitutes a haplotype

d) MHC haplotypes tend to be inherited and passed on with little recombination

e) Your father or mother has about a 50% chance of matching all your MHC alleles

f) Your brother or sister has about a 25% chance of matching all your MHC alleles

g) MHC polymorphism is a problem during organ transplant

h) MHC restriction means that our T cell receptors only recognize foreign peptides when presented by our own MHC isoforms

i) Organs are best "matched" to a recipient, if the donor and recipient share many of the same MHC alleles

j) Some of our T cells can attack cells expressing a foreign MHC isoform

k) Odds are that your kids will carry an MHC haplotype that is very similar to either one of your father's haplotype or one of your mother's haplotype


Evidence for selection maintaining MHC diversity in a rodent species despite strong density fluctuations

Strong spatiotemporal variation in population size often leads to reduced genetic diversity limiting the adaptive potential of individual populations. Key genes of adaptive variation are encoded by the immune genes of the major histocompatibility complex (MHC) playing an essential role in parasite resistance. How MHC variation persists in rodent populations that regularly experience population bottlenecks remains an important topic in evolutionary genetics. We analysed the consequences of strong population fluctuations on MHC class II DRB exon 2 diversity in two distant common vole (Microtus arvalis) populations in three consecutive years using a high-throughput sequencing approach. In 143 individuals, we detected 25 nucleotide alleles translating into 14 unique amino acid MHC alleles belonging to at least three loci. Thus, the overall allelic diversity and amino acid distance among the remaining MHC alleles, used as a surrogate for the range of pathogenic antigens that can be presented to T-cells, are still remarkably high. Both study populations did not show significant population differentiation between years, but significant differences were found between sites. We concluded that selection processes seem to be strong enough to maintain moderate levels of MHC diversity in our study populations outcompeting genetic drift, as the same MHC alleles were conserved between years. Differences in allele frequencies between populations might be the outcome of different local parasite pressures and/or genetic drift. Further understanding of how pathogens vary across space and time will be crucial to further elucidate the mechanisms maintaining MHC diversity in cyclic populations.

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Present address: Institute of Immunology, Hannover Medical School, Hannover, D-30625, Germany

Affiliations

Center for Immunology and Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, 55455, USA

Hristo Georgiev, Changwei Peng, Matthew A. Huggins, Stephen C. Jameson & Kristin A. Hogquist

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Contributions

H.G. and K.A.H. designed experiments. H.G., C.P., and M.A.H. performed experiments. H.G., S.C.J., and K.A.H. analyzed experiments and interpreted the findings. H.G. wrote the manuscript. K.A.H. and S.C.J. edited the manuscript. K.A.H. directed the research and is the guarantor of its integrity.

Corresponding author