organization of the mhc
DESCRIPTION
Organization of the MHC. 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. - PowerPoint PPT PresentationTRANSCRIPT
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Organization of the MHC
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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
Organization of the MHC
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
• Expressed in fibroblasts and intestinal epithelium
• Upregulated by cellular injury and stress, not -IFN
MICA, MICB
• 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
O
DM primarily expressed in macrophages and DC
DO primarily expressed in B cells
Non-classical MHC class II genes
Classical MHC class II genesHLA-DR (DRA, DRB1) HLA-DQ (DQA1, DQB1) HLA-DP (DPA1, DPB1)
Four intraspecies duplications resulted in four regions
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Class I Class II
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Distinctive features of peptide binding to class II MHC molecules
• Peptide antigen length variable: 12-24 amino acids and length not critical
• Pockets tether central portions of peptide and the pockets used vary considerably for loci and alleles
Peptide binding groove open and no binding of N or C termini
Class II is a two chain molecule with both chains encoded in MHC and each contributes to peptide binding groove
• Polymorphism influences chain pairing and only certain gene pairs found=linkage disequilibrium
• Trans combinations of chains from different HLA-DQ or DP haplotypes generate additional post translational diversity
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SameProtein 1
SameProtein 2
SameProtein 3
DifferentProtein
MHCClass I
MHCClass II
Peptides binding class II molecules vary in length, are anchored in the middle, but are also always oriented with NH2 termini to the left
Different rules for peptide binding to class II MHC molecules
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Peptide-MHC class II complex interactions with the CD4 T cell TCR
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 12-24 amino acids
TCR
1
2
4
5
6
8
9
MHC class II
peptide
7
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HLA-DR1 (DRB1*0101) molecule
peptide-binding pockets Binding an ovalbumin peptide
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P2
P7 P8
MHC class II molecule binding a peptide
Multiple bonds exist between peptide and MHC II
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CDR1
CDR2
CDR3
CDR1
CDR2
CDR3
Contrasting mode of binding of CD 8 and CD4 TCR to MHC I or II
MHC I-CD8 TCR MHC II-CD4 TCR
The CD8 or CD4 TCR -chain interacts with different portions of the MHC-peptide compex
CDR1
CDR2
CDR3CDR1
CDR2
CDR3
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MHC I-CD8 TCR MHC II-CD4 TCR
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Two strategies for polymorphism in MHC class II genes
HLA-DR loci only have polymorphisms in -chain, with DRA locus nearly monomorphic, similar to class I MHC
HLA-DQ and -DP have polymorphisms in the genes encoding the -chain and the -chain and the resulting products are more intricate
O
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HLA-DR loci only have polymorphisms in -chain, with DRA locus nearly monomorphic, similar concept to class I MHC
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MHC class II loci
HLA-DRA -chain
HLA-DRB1 -chain
Specificity(Antigen)
DR1, 2,…
Alleledesignation
DRA*0101
DRB1*0101,…
# ofalleles
3
440
0 0.5 1mb
DRB3DRB5
DRB4 DRADRB1
Polygenic human MHC class II (HLA-DR) genes
MHC class II region
Gene content here varies among haplotypes, too complex for now
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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 DRADRB1*0101 DRA
0 0.5 1mb
DRADRB1*0401
0 0.5 1mb
DRADRB1*0101
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
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
HLA-DR1
HLA-DR4
“Specificities”
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Polymorphic residues of the MHC class II -chain alleles of HLA-DR are predominantly in the antigen-binding cleft of the molecule
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HLASpecificity
DR1
DR2
DR3
DR4
DR4
DR4
DR5
pleated sheet in floor helical rim (P4)
Alleles are often generated by a patchwork process of gene conversion that alters pockets en bloc
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Amino acids forming P4 pocket in helical rim
MHC class II molecule
74 71
70
67The most important difference among the HLA-DR4 alleles is that their P4 pockets differ
Amino acids forming floor of antigen groove
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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
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
NQST
Pocket specificity and use varies with HLA-DR allotype
Residues in peptide available for TCR interaction vary
Pocket in HLA-DR molecule
(Hydrophobic Hydrophilic Negative Positive)
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DR1DR3DR4DR7DR8DR9DR10DR11DR12DR13DR14DR15DR16
DR15
DR4
DR9DR1
DR7
AMERINDIAN BLACK
CAUCASIAN ASIAN
Frequencies of HLA alleles differ markedly in different population groups
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HLA-DQ
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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
56 25
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A polymorphism at position 57 of the DQB1 -chain encodes either Asp or Ala or Val, a portion of pocket 9
When 57 is Asp, it can form a salt bridge with Asn at position 79 on the -chain
DQB1 alleles with 57Ala/Val confer susceptibility to type 1 diabetes mellitus, while 57Asp confers no susceptibility or resistance
DQB1*0201*0301*0302*0303*0401*0402*0501*0502*0503*0601*0602*0603*0604
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Codominant expression of HLA-DQ genes results in 4 different class II HLA-DQ molecules (allotypes) on the cell
DQA1*0501DQB1*0201
0 0.5 1mb
DQB1*0701 DQA1*0201
Maternal haplotype
0 0.5 1mb
DQB1*0201 DQA1*0501
Paternal haplotype
tran combination ciscis
DQA1*0501DQB1*0201DQA1*0201 DQA1*0201
DQB1*0701DQB1*0701
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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
This linkage disequilibrium is centrally involved in determining the genetic basis of susceptibility to celiac disease and to type 1 diabetes mellitus
In some instances gene pairs not represented fail to produce an intact HLA-DQ molecule
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
*0602
*0601
*0201
*0302
*0302
*0301
*0303
*0303
DQA1
*0102
*0103
*0501
*0301
*0301
*0301
*0301
*0201
DRB1
*1501
*1502
*0301
*0401
*0402
*0401
*0401
*0701
HLA-DR
DR2
DR2
DR3
DR4
DR4
DR4
DR4
DR7
DQB1
DQA1
DRB1 DRA
-
N
++
++
+
N
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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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)
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)
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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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Maximum number of different types of HLA molecules expressed on the cell surface
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
222000
6
Nucleated cells
Antigen presenting cells
222244
16
Each of these MHC molecules selects its own T cell repertoire that only recognizes peptides presented by that particular type of MHC molecule
(actually more)