MHC Polymorphism: Page-by-Page Comprehensive Notes

Page 1

• Consequences of the MHC polymorphism: 1) MHC polymorphism 2) Peptide binding 3) The clinical consequences of the MHC polymorphism 4) Non-polymorphic MHC molecules

Page 2

• MHC stands for Major histocompatibility complex, also known as HLA (Human Leukocyte Antigen).

• Human terminology variants:

  • MHC = Major histocompatibility complex

  • HLA = Human Leukocyte Antigen

  • For class II MHC locus: DP, DQ, DR (referred to as “Class II” MHC locus)

• “Class III” is listed as a separate region in the MHC region.

• MHC locus structure (as presented):

  • Class I MHC locus: (C, A, TT, DM) [proteins involved include proteasome components and related processing factors]

  • Class III region includes: Complement proteins and Cytokines such as C4, LTα/β, TNF-α, LT (lymphotoxin)

• Proteasome genes and antigen processing components are part of the pathway to peptide presentation.

Page 3

• Polymorphic: MHC genes have multiple alleles in the population; MHC is the most polymorphic gene set in the human genome.

• Allotypes: different allelic products of MHC genes.

• MHC genes are the most polymorphic known.

• Classical MHC molecules have several alleles in the population.

• Heterozygous individuals possess two different alleles of the same gene.

• The diversity of peptides presented by MHC molecules within an individual is linked to polymorphism.

• Key phrases:

  • Polymorphism

  • One gene, different alleles

Page 4

• Recap: Codominant inheritance means MHC molecules have several different alleles in the population; heterozygous individuals express both alleles on the cell surface.

• The diversity of peptides presented by MHC molecules in the individual is driven by polymorphism.

• Reiteration of: One gene, different alleles.

Page 5

• Polygenic – encoded by multiple genes (evolutionary gene duplications) – ISOTYPES.

• Three major active MHC class I gene isotypes in humans: HLA-A, HLA-B, HLA-C.

• MHC class II molecule isotypes in humans: HLA-DP, HLA-DQ, HLA-DR.

• The diversity of peptides that can be presented by MHC molecules arises from:

  • One gene with alleles (for Class I) and

  • Multiple genes without alleles (for Class II isotypes and their combinations).

• All these genes are polymorphic.

Page 6

• HLA alleles and proteins identified up to 2016: source referenced as hla.alleles.org.

• The number of identified HLA alleles has been increasing year by year.

• Note: The slide shows a correlation between identified alleles and time, indicating ongoing discovery.

Page 7

• Nomenclature (how an allele is named):

  • Indicates HLA region and prefix for an HLA gene, e.g., HLA-DRB1.

  • A locus like DRB1 indicates a particular HLA locus i.e., DRB1.

  • HLA-DRB113 indicates a group of alleles encoding DR13 antigen or sequence homology to other DRB113 alleles.

  • HLA-DRB1*13:01 is a specific HLA allele.

  • HLA-DRB113:01:02 is an allele that differs by a synonymous mutation from DRB113:01:01.

  • HLA-DRB113:01:01:02 is an allele with a mutation outside the coding region from DRB113:01:01:01.

  • HLA-A*24:09N is a 'Null' allele (not expressed).

  • HLA-A*30:14L is an allele encoding a protein with reduced or low surface expression.

• Source: hla.alleles.org, etc.

Page 8

• Az MHC: Features include

  • Polymorphic

  • Polygenic

  • Codominant inheritance

Page 9

• Genotype expression: maternal and paternal contributions lead to expression of MHC class I on nucleated cells.

• Each nucleated cell in an individual expresses products of 6 MHC class I alleles on the cell surface.

• Population-level diversity estimate: approximately $6 imes 10^{15}$ possible allele combinations across individuals in the population.

Page 10

• All nucleated cells of an individual express the same set of 6 MHC class I alleles on the cell surface.

Page 11

• MHC class II: also polymorphic

  • Both alpha and beta chains are polymorphic; alpha chains are less polymorphic than beta chains.

  • Polygenic and codominant inheritance.

• Isotypes of MHC II molecules: Human: HLA-DP, HLA-DQ, HLA-DR.

Page 12

• Heterogeneity of the MHC II haplotypes (DR, DQ, DP):

  • Maternal haplotype and paternal haplotype show various A/B alpha beta chain pairings.

  • Alpha and beta chains can combine freely within the ER, generating intra-isotype combinations.

  • Not all combinations produce stable products; only preferred and frequent combinations are stable.

  • Normally 10-20 MHC II αβ combinations are expressed in a human cell.

  • All professional antigen-presenting cells (APCs) of an individual express the same 10-20 kinds of MHC II.

Page 13

• Inheritance of HLA follows a linked pattern: haplotype – allele combinations on a haploid chromosome, linked with each other.

Page 14

• Family genetics: number of offspring affects the probability of HLA-identical children.

• Because of haplotype inheritance, HLA-identical children can occur in families with a high number of offspring.

• Conceptual takeaway: identity by HLA can occur due to sharing of a haplotype in a family with multiple births.

Page 15

• Mechanisms of MHC polymorphism (summary):

  • Allele variations exist in the population, driven by combinations of thousands of alleles.

  • Practically, an individual has a pair of inherited haplotype combinations that change infrequently by recombination.

  • Large allele numbers lead to heterozygosity, and genes on homologous chromosomes are expressed codominantly, effectively doubling isotype variation.

  • MHC gene/molecule isotypes:

  • 3 polymorphic MHC I isotypes: HLA-A, HLA-B, HLA-C.

  • 3 polymorphic MHC II isotypes alpha chains: HLA-DPA1, HLA-DQA1, HLA-DRA (considered monomorphic in many contexts) and beta chains: HLA-DPB1, HLA-DQB1, HLA-DRB1.

  • α- and β-chain combinations of MHC II yield 10-12 frequent αβ combinations within the intra-isotype set, and about 40 principal combinations via mixed isotype αβ combinations; however, mixed isotype combinations are less frequent due to incompatibilities.

Page 16

• Summary facts about Az MHC:

  • Polymorphic

  • Polygenic

  • Codominant inheritance

  • Linked inheritance

  • Individuals express (max) 6 MHCI isotypes

  • All nucleated cells of an individual express the same 6 MHCI alleles on the cell surface

  • Different persons express different MHC allotypes

Page 17

• Recap of the four main topics:
  1) MHC polymorphism 2) Peptide binding 3) The clinical consequences of MHC polymorphism 4) Non-polymorphic MHC molecules

Page 18

• Structural schematic (Janeway’s Immunobiology, 8th ed.):

  • MHC I has α1 and α2 domains; MHC II has α1 and β1 domains; peptides bind in the groove.

  • The peptide is held by the MHC via intermolecular weak forces.

  • Peptides located in the MHC peptide-binding groove.

Page 19

• MHC-bound peptides show shared motifs: common sequence parts called motifs.

• Anchoring amino acids are located at specific positions within the core peptide sequence that fit into MHC binding pockets.

• Peptides from different variants of MHC I can have different sequences but share similar anchoring motifs or properties (e.g., aromatic residues Y/F; hydrophobic residues V/L/I).

• Example: Eluted peptides from two different MHC I variants show shared motif features for anchoring.

Page 20

• MHC II characteristics:

  • Open peptide-binding groove allowing peptide ends to extend beyond the ends of the peptide core.

  • Peptides bound by MHC II can have their anchoring amino acids distributed along the core sequence.

  • Different length peptides can bind to the same MHC II molecule if they share the same core sequence and motif.

Page 21

• Simplified structural model of MHC binding sites:

  • MHC I typically has a hydrophobic pocket for the peptide's C-terminal hydrophobic residue.

  • The terminal -NH3+ and -COO- groups can participate in anchoring (ionic interactions).

  • Peptides of different lengths can be accommodated in the binding site.

  • Anchoring side chains of the peptide core fit into distributed pockets within the binding groove.

  • For MHC II, the long peptide ends can extend from the open binding groove.

Page 22

• A given MHC molecule can bind many different peptides: roughly about $10^4$ different peptides.

• However, a given MHC molecule cannot bind all possible peptides; binding is selective.

• General property: peptide-binding specificity is constrained by the binding pockets; not every peptide fits.

Page 23

• Polymorphic residues of MHC molecules are located in the peptide-binding site and clustered there.

• MHC polymorphism influences peptide binding: different allelic variants bind different peptides with different efficiency (motifs!).

• This variability impacts T cell activation.

• Source: Fundamental Immunology (6th ed., 2008).

Page 24

• Simplified model of MHC restriction:

  • TCR (T cell receptor) recognizes a combined surface of peptide-MHC complex.

  • APC presents peptide with MHC to T cell.

  • Diagrammatic representation of the TCR recognizing the peptide-MHC complex on APC.

• Key idea: The TCR binds to the composite surface of peptide + MHC.

Page 25

• Reiteration of binding principles:

  • A given MHC molecule can bind different peptides effectively.

  • A given MHC molecule cannot bind all kinds of peptides.

• Peptide-binding pockets of a given MHC molecule restrict the set of peptides that can be presented.

Page 26

• Continuation of the general properties:

  • Different MHC variants bind peptides with different motifs.

  • Efficient antigen presentation benefits from the presence of multiple MHC molecule variants simultaneously.

  • The set of peptides presented by different MHC molecules includes overlapping and distinct peptides.

Page 27

• Summary of expression patterns:

  • All nucleated cells express the same max 6 MHC I isotypes, and these are the products of the same 6 MHC I alleles on the cell surface.

  • A defined MHC variant can bind various peptides with different sequences but similar motifs.

  • A single MHC variant cannot bind all possible peptides.

  • The peptide-binding domains show the greatest polymorphism.

  • Other MHC variants bind peptides with different motifs.

• Overall: A given individual has a unique immune response profile due to MHC polymorphism.

Page 28

• The four consequences of MHC polymorphism, as framed in the lecture: (1) MHC polymorphism, (2) Peptide binding, (3) The clinical consequences of MHC polymorphism, (4) Non-polymorphic MHC molecules.

Page 29

• Why so many MHC variants?

  • Pathogens replicate faster than human reproduction, and pathogens mutate frequently to evade antigen presentation.

  • The MHC has evolved many variants to counteract this pathogen diversity.

  • Some variants may not protect against a given pathogen, but at population level there will be variants that confer protection against some pathogens.

  • Result: multiple MHC variants provide a broader defense portfolio via different peptide-binding pockets and specificities.

Page 30

• Beneficence of MHC polymorphism (population-level perspective):

  • If only a single MHC type existed (MHC X), the population would be vulnerable to pathogens capable of evading it.

  • A heterogeneous population with diverse MHC types is better protected against diverse pathogens.

  • Conceptual model showing that heterogeneity reduces risk of widespread susceptibility.

Page 31

• Tissue rejection differences due to MHC allotypes:

  • Allogeneic APCs in a graft display allogeneic MHC.

  • Allogeneic MHC can be immunogenic, leading to alloreactive T cell responses.

  • The non-self MHC molecule may be immunogenic with any peptide presented.

Page 32

• The clinical consequences of MHC polymorphism (summary):

  • The efficiency of the antigen-specific immune response varies across individuals depending on their MHC alleles.

  • Vaccination efficacy can differ between individuals with different MHC haplotypes.

  • The frequency of certain HLA haplotypes correlates with disease frequency in populations, in either protective or susceptibility directions (e.g., autoimmune diseases or hypersensitivity disorders).

  • Tissue rejection risk varies with MHC compatibility.

Page 33

• Natural selection can shift allele frequencies in populations exposed to endemic pathogens.

• Some MHC alleles may confer superior protection against specific pathogens.

• Examples:

  • HLA-B53 serotype is associated with recovery from lethal malaria in regions where malaria is endemic.

  • HLA-B27 and B57 serotypes are more frequent among HIV controllers.

Page 34

• Key conceptual takeaways:

  • One MHC variant can bind various peptides with different sequences but similar motifs.

  • Other MHC variants bind different peptides; peptides with the most common motifs are more likely to be presented.

  • Because of MHC polymorphism, each individual has a unique immune response profile.

  • Immune responses to infections, tumors, and vaccinations can differ between individuals, including the probability of autoimmune and hypersensitivity reactions.

  • Transplantation requires similar (same) allotypes between donor and recipient.

Page 35

• Reiteration of the four main concepts:
  1) MHC polymorphism 2) Peptide binding 3) The clinical consequences of the MHC polymorphism 4) Non-polymorphic MHC molecules

Page 36

• In addition to the polymorphic classical peptide-presenting MHC molecules, there exist non-polymorphic MHC-like molecules:

  • MHC class I-like and MHC class II-like molecules

  • MHC region encoded molecules and molecules encoded outside the MHC region

  • They have diverse functions

Page 37

• Non-polymorphic MHC class I-like molecules outside the MHC region include:

  • HLA-G: expressed on placental trophoblast cells; can inhibit NK cell activation by interacting with inhibitory NK receptor LILRB1; virus-infected and tumor cells can also express HLA-G to evade immune responses; HLA-G also supports placental development via cytokine-producing NK cells during pregnancy.

  • HLA-E: expressed on most tissues; can be presented on the cell surface by binding signal peptide sequences of HLA-A, B, C; inhibits NK cell activation via NKG2A:CD94 receptor.

  • MICA/MICB: MHC class I-related sequences (no associated β2-microglobulin); stress-induced proteins that can activate NK cells via lectin-like receptor NKG2D; these are modulated during infections.

Page 38

• Some MHC class Ib proteins encoded outside the MHC region:

  • MHC class I-like, non-polymorphic molecules encoded outside the MHC region.

  • They have MHC I-like structure (β2-microglobulin-associated). Some possess antigen-presenting function; some do not.

Page 39

• CD1 molecules (CD1a, CD1b, CD1c, CD1e, CD1d):

  • Usually expressed by professional APCs.

  • Present self and microbial lipids (glycolipids, lipopeptides) including both exogenous and endogenous lipids.

  • Contribute to antibacterial immunity (e.g., immunity against mycobacteria within phagocytes).

  • Approximately 5% of T cells in the body are specific for non-peptide epitopes presented by non-polymorphic MHC-like molecules.

Page 40

• MR1 (MHC Related-1): expressed on various cell types, with a polar antigen-binding site; presents microbial riboflavin (vitamin B2) metabolic products to mucosa-associated invariant T cells (MAIT);

  • Corbet et al. (Nature, 2014) details.

  • MAIT cells detect riboflavin metabolites produced by bacteria and yeast; mammals cannot synthesize riboflavin, so MAIT cells use these metabolites as infection signals.

Page 41

• Cytotoxic T cells (TC cells, or CTLs) destroy virally infected cells and tumor cells.

• T helper cells (TH cells) assist other white blood cells in immunologic processes.