The Major Histocompatibility Complex (MHC) · A B C Paternal A, B, C Maternal A, B, C MHC class I...
Transcript of The Major Histocompatibility Complex (MHC) · A B C Paternal A, B, C Maternal A, B, C MHC class I...
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The Major Histocompatibility Complex Histocompatibility Complex
(MHC)
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ch6p
(MHC)
Human Leucocyte Antigens(HLA)
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Map of the human MHC (short arm Chr 6)
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Map of the human MHC (short arm Chr 6)
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Map of the human MHC (short arm Chr 6)
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Maps of human and murine MHC loci
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Maps of human and murine MHC loci
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Maps of human and murine MHC loci
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ch6p
(MHC)
Human Leucocyte Antigens(HLA)
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MHC
polygenic: 9 main genes (DP⟨ / , DQ⟨ / , DR⟨ / , B, C, A)polygenic: 9 main genes (DP⟨ / , DQ⟨ / , DR⟨ / , B, C, A)
polymorphic: multiple alleles for each gene
codominant: both maternal and paternal alleles expressed
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HLA-A locus: 580HLA-B locus: 921HLA-C locus: 312
HLA-DPα locus: 23HLA-DPβ locus: 127
Allelic polymorphism
HLA-DPβ locus: 127
HLA-DQα locus: 34HLA-DQβ locus: 86
HLA-DRα locus: 3 (~ monomorphic)HLA-DRβ locus: 577
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A
B
C
Paternal A, B, CMaternal A, B, C
MHC class I
Co-dominance
both paternal and maternal MHC alleles are expressed
A
B
C
A
A
B
B
C
C
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All nucleated cells Antigen Presenting Cells(Dendritic cells, macrophages, monocytes,B lymphocytes, Langherans cells)
Expression of human MHC molecules
Class I Class I + Class II
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Haplotypethe set of inherited MHC alleles on each chromosome
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n. codom α+β + loci TOT
Class I 3 x2 - - = 6
Number of different MHC moleculeson each cell
mix extra
Class II 3 x2 x2 +x ~ 18-20
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MHC/peptide - TCR interaction
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Structure of a Class I MHC molecule
46 kD
12 kD
46 kD
bindsCD8
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Structure of a Class II MHC molecule
33 kD 30 kD
bindsCD4
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Polymorphic residues in MHC molecules
Non-polymorphic regions: Class I α3 binds CD8, Class II β2 binds CD4
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Peptides
- Peptides loaded on MHC molecules are normally self peptides
- Each individual MHC molecule can bind different peptides
- Slow on-rate (15-30 min) and extremely slow off-rate (days)
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Viral peptide in a Class I groove
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Antigenic peptides in the MHC pockets
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Allelic polymorphism dictates peptide specificity
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peptide recognition by the TCR isMHC - "restricted"
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Alloantigens: non-self MHC molecules. 1-10% of all T lymphocytes recognizes allogenic MHC - transplant rejection
Superantigens: bacterial or viral proteins/lipid/sugars that associate extracellularly with the MHC-II and are recognized by 5-10% of all T lymphocytes - endotoxic shock
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Alloreactivity Superantigens
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Features of MHC molecules
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γγγγIFN enhances MHC class II expression
Mediated by Class II transactivator(CIITA)
γIFN also enhances the expression of TAP genes and proteasome genes,such as LMP-2 and LMP-7
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MHC-Ib recognition by NK cells
• MICA and MICB on epithelial cells are recognized by the complex DAP10/NKG2D on NK cells (activatory DAP10/NKG2D on NK cells (activatory signal)
• HLA-G and HLA-E are recognized by the complex CD94/NKG2A on NK cells (inhibitory signal)