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Organization of the MHC
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Organization of the MHC
The recent sequencing of the MHC as part of the genome project revealed numerous genes that function in antigen processing and other roles in the immune response, apart from the class I and class II MHC genes The MHC is a unique multigenic and polymorphic gene complex that regulates the adaptive immune response
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Genes with immune functions other than class I and II MHC
Olfactory Receptor HFe
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The MHC class I region contains additional class I genes other than the classic HLA-A, B and C
MHC class IB genes (Non-classic) Innate Immunity HLA-G the only MHC class I expressed on trophoblast and inhibits NK cell killing of fetus that would otherwise occur HLA-E binds leader peptide of classic class I molecules, HLA-A, B and C and inhibits NK cell killing of target cell by engagement of inhibitory CD94 / NKG2A receptor Limited polymorphism, restricted tissue expression
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MHC class IB genes MICA, MICB
Expressed in fibroblasts and intestinal epithelium Upregulated by cellular injury and stress, not g-IFN Engage stimulatory NK receptor NKG2D, activating NK cells Physiologic means of removing damaged/stressed cells
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Classical and non-classical MHC class II genes
Four intraspecies duplications resulted in four regions Classical MHC class II genes HLA-DR (DRA, DRB1) HLA-DQ (DQA1, DQB1) HLA-DP (DPA1, DPB1) Non-classical MHC class II genes DM primarily expressed in macrophages and DC DO primarily expressed in B cells
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Class I Class II
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Distinctive features of peptide binding to class II MHC molecules
Peptide binding groove open and no binding of N or C termini Peptide antigen length variable: amino acids and length not critical Pockets tether central portions of peptide and the pockets used vary considerably for loci and alleles Class II is a two chain molecule with both chains encoded in MHC and each contributes to peptide binding groove Trans combinations of chains from different HLA-DQ or DP haplotypes generate additional post translational diversity Polymorphism influences chain pairing and only certain gene pairs found=linkage disequilibrium
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Different rules for peptide binding to class II MHC molecules
Protein MHC Class I Same Protein 1 MHC Class II Same Protein 2 Same Protein 3 Peptides binding class II molecules vary in length, are anchored in the middle, but are also always oriented with NH2 termini to the left
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Peptide-MHC class II complex interactions with the CD4 T cell TCR
1 2 4 5 6 8 9 MHC class II peptide 7 Multiple hydrogen bonds, van der Waals and electrostatic interactions with the peptide backbone or side chains tether the middle of the peptide to MHC class II molecules, the ends are free, with length varying from amino acids
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HLA-DR1 (DRB1*0101) molecule
peptide-binding pockets Binding an ovalbumin peptide
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MHC class II molecule binding a peptide
Multiple bonds exist between peptide and MHC II
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Contrasting mode of binding of CD 8 and CD4 TCR to MHC I or II
CDR1b CDR2b CDR3b CDR1a CDR2a CDR3a CDR2b CDR1b CDR3a CDR3b CDR1a CDR2a MHC I-CD8 TCR MHC II-CD4 TCR The CD8 or CD4 TCR b-chain interacts with different portions of the MHC-peptide compex
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MHC I-CD8 TCR MHC II-CD4 TCR
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O Two strategies for polymorphism in MHC class II genes HLA-DR loci only have polymorphisms in b-chain, with DRA locus nearly monomorphic, similar to class I MHC HLA-DQ and -DP have polymorphisms in the genes encoding the a-chain and the b-chain and the resulting products are more intricate
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HLA-DR loci only have polymorphisms in b-chain, with DRA locus nearly monomorphic, similar concept to class I MHC
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Polygenic human MHC class II (HLA-DR) genes
Specificity (Antigen) Allele designation # of alleles MHC class II loci HLA-DRA a-chain HLA-DRB1 b-chain DR1, 2,… DRA*0101 DRB1*0101,… 3 440 Gene content here varies among haplotypes, too complex for now DRB5 DRB1 DRA DRB3 DRB4 0.5 1mb MHC class II region
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Codominant expression of MHC genes results in the presence of 2 different HLA- DR molecule allotypes on the cell surface DRB1*0401 DRA DRB1*0101 0.5 1mb Maternal haplotype Paternal haplotype MHC class II region
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HLA-DR Polymorphisms NNN alleles of DRB1 locus
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Nomenclature: Each allele is defined by its unique DNA nucleotide sequence
E.g. HLA-DRB1*0101 *0102 … *0112 *0401 *0402 *0403 *0424 “Specificities” HLA-DR1 HLA-DR4 But to make things “simpler”, structurally similar alleles are grouped in families that resemble those defined as “ serologic specificities”, e.g. HLA-DR1 or HLA-DR4, reflecting an old nomenclature when human alloantibodies were used to detect HLA “antigens”s
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Polymorphic residues of the MHC class II b-chain alleles of HLA-DR are predominantly in the antigen-binding cleft of the molecule
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HLA Specificity DR1 DR2 DR3 DR4 DR5 b pleated sheet in floor a helical rim (P4) Alleles are often generated by a patchwork process of gene conversion that alters pockets en bloc
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MHC class II molecule Amino acids forming floor of antigen groove 71 67 74 The most important difference among the HLA-DR4 alleles is that their P4 pockets differ 70 Amino acids forming P4 pocket in helical rim
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What the actual sequence of some DRB1 alleles looks like
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Unrooted tree relationship of HLA-DR alleles
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Peptide binding motifs of some prototypic HLA-DR allotypes
DRB1 Allotype *0101 *0301 *0401 *0402 *0701 *1501 Pocket in HLA-DR molecule P1 YFVLI LIFMV FYVIL VILM FILV LVI P2 P3 P4 LAIVM DNQT DFWIL KRHY FYI P5 P6 AGST KR NSTQHR NSTQK NST P7 ILV P8 L P9 LAIV YLF NQST (Hydrophobic Hydrophilic Negative Positive) Pocket specificity and use varies with HLA-DR allotype Residues in peptide available for TCR interaction vary
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Frequencies of HLA alleles differ markedly in different population groups
DR1 DR9 DR1 DR3 DR4 DR7 DR8 DR4 DR9 AMERINDIAN BLACK DR10 DR11 DR12 DR15 DR13 DR14 DR15 DR16 DR7 CAUCASIAN ASIAN
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HLA-DQ
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Most common HLA-DQ alleles
56 25 DQB1 DQA1 DRB1 DRA DQB1 *0201 *0301 *0302 *0303 *0401 *0402 *0501 *0502 *0503 *0601 *0602 *0603 *0604 DQA1 *0101 *0102 *0103 *0104 *0201 *0301 *0401 *0501 *0601 Most common HLA-DQ alleles
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A polymorphism at position 57 of the DQB1 b-chain encodes either Asp or Ala or Val, a portion of pocket 9 DQB1 *0201 *0301 *0302 *0303 *0401 *0402 *0501 *0502 *0503 *0601 *0602 *0603 *0604 When 57b is Asp, it can form a salt bridge with Asn at position 79 on the a-chain DQB1 alleles with 57bAla/Val confer susceptibility to type 1 diabetes mellitus, while 57bAsp confers no susceptibility or resistance
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Codominant expression of HLA-DQ genes results in 4 different class II HLA-DQ molecules (allotypes) on the cell 0.5 1mb DQB1*0701 DQA1*0201 Maternal haplotype DQB1*0201 DQA1*0501 Paternal haplotype tran combination cis DQB1*0201 DQA1*0501
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Most common HLA-DQ alleles
DQB1 DQA1 DRB1 DRA DQB1 *0201 *0301 *0302 *0303 *0401 *0402 *0501 *0502 *0503 *0601 *0602 *0603 *0604 DQA1 *0101 *0102 *0103 *0104 *0201 *0301 *0401 *0501 *0601 Most common HLA-DQ alleles
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Only certain combinations of DQA1 and DQB1 alleles are found
20 linkage disequilibrium haplotypes Expect 107 pairs if random combination of DQA1 and DQB1 alleles Caucasians
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Polymorphism of DQA1 and DQB1 influences chain pairing and only certain gene pairs are found together In some instances gene pairs not represented fail to produce an intact HLA-DQ molecule This linkage disequilibrium is centrally involved in determining the genetic basis of susceptibility to celiac disease and to type 1 diabetes mellitus The linkage disequilibrium extends throughout the class II region and sometimes across the entire MHC
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Alleles of major DQ-DR haplotypes that exhibit linkage disequilibrium
DQB1 DQA1 DRB1 DRA DQB1 *0602 *0601 *0201 *0302 *0301 *0303 DQA1 *0102 *0103 *0501 *0301 *0201 DRB1 *1501 *1502 *0301 *0401 *0402 *0701 HLA-DR DR2 DR3 DR4 DR7 - N ++ + T1DM T1DM susceptibility also influenced by DQA1 and DRB1 alleles
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Some clinically important instances of linkage disequilibrium relevant to disease reflect a variable duplication in class III genes HLA-A1-B8-DR3-DQA1*0501-DQB1*0201 haplotype has a deletion of 25kb of DNA including the C4B gene, which decreases the C4 level by ~half
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Mispairing of class III regions that have one or two modules of C4 during cross over can result in an additional loss of CYP21B(A2) CYP21B(A2) encodes steroid 21 hydroxylase and its absence results in congenital adrenal hyperplasia, a recessive disease due to a failure to synthesize cortisol; this results in androgenic precursor over- production Androgen excess leads to ambiguous genitalia in females, rapid somatic growth during childhood in both sexes with premature closure of the epiphyses and short adult stature (Infant Hercules)
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The haplotype HLA-A25-B18-DR2 contains a defective gene for C2 with a 28bp deletion
No hemolytic activity in classic pathway Associated with autoimmune disease (SLE)
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Antigen presenting cells
Maximum number of different types of HLA molecules expressed on the cell surface Nucleated cells Antigen presenting cells Class I (HLA-A) Class I (HLA-B) Class I (HLA-C) Class II (HLA-DR) Class II (HLA-DQ) Class II (HLA-DP) Total 2 6 2 4 16 (actually more) Each of these MHC molecules selects its own T cell repertoire that only recognizes peptides presented by that particular type of MHC molecule
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