Major Histocompatibility

Complex
 CONTENT

 General Organization and Inheritance of the MHC

 MHC Molecules and Genes
 Detailed Genomic Map of MHC Genes
 Cellular Distribution of MHC Molecules
 Regulation of MHC Expression
 MHC and Disease Susceptibility
 MHC

 Major Histocompatibility Complex

 Cluster of genes found in all mammals
 Its products play role in discriminating self/non-self
 Participant in both humoral and cell-mediated immunity
 MHC Act As Antigen Presenting Structures
 In Human MHC Is Found On Chromosome 6
 Referred to as HLA complex
 In Mice MHC Is Found On Chromosome 17
 Referred to as H-2 complex
 MHC

Genes Of MHC Organized In 3 Classes

 Class I MHC genes
 Glycoproteins expressed on all nucleated cells
 Major function to present processed Ags to TC cells
 Class II MHC genes
 Glycoproteins expressed on(macrophages, dendritic cells and B cells)
 Major function to present processed Ags to TH cells
 Class III MHC genes
 Products that include secreted proteins that have immune functions
 Ex. Complement system, inflammatory molecules
Class I, II and III MHC

 Class I MHC Genes Found In Regions A, B and C In Humans (K and D In

Mice)
 Class II MHC Genes Found In Regions DR, DP and DQ (IA and IE In Mice)
 Class I and Class II MHC Share Structural Features
 Both involved in APC
 Class III MHC Have No Structural Similarity To Class I and II
 Ex. TNF, heat shock proteins, complement components
 MHC Genes Are Polymorphic

 MHC loci are highly polymorphic

 Vary considerably from person to person

 However, Crossover Rate Is Low about 0.5%

 presence of many alternative forms of the gene or allele in the population

 Inherited as 2 sets (one from father, one from mother)

 Haplotype: set of alleles present in each parental chromosome (two sets)

 New haplotypes are generated by recombination

Inheritance Of HLA Haplotypes
 Class I MHC Molecule.

 Comprised of 2 molecules
  chain (45 kDa), transmembrane
 2-microglobulin (12 kDa)
 Non-covalently associated with each other
 Association Of  Chain and 2 Is Required For Surface Expression
  Chain Made Up Of 3 Domains (1, 2 and 3)
 2-microglobulin Similar To 3
 Class I MHC cannot be expressed without β2-microglobulin
 1 And 2 Form Peptide Binding Cleft
 3 Interacts with CD8 (TC) molecule
MHC Molecule
 Class II MHC Molecule

 Comprised of  and  chains

  chain and  chain associate non-covalently

  and  chains Made Up Of Domains

 1 and 2 ( chain)

 1 and 2 ( chain)

 1and 1 Form Antigen Binding Cleft

 CD4 Molecule Binds 2/2 domains

Peptide binding by class I and class II MHC molecules
Exhibit Polymorphism

Class I MHC Peptides.

 Peptides Presented Thru MHC I Are Endogenous Proteins
 As Few As 100 Peptide/MHC Complex Can Activate TC
 Peptide Features
 size 8-10 a/a
 Peptides Bind MHC Due To Presence Of Specific a/a Found At The
Ends Of Peptide. Ex. Glycine @ Position 2
 Class II MHC Peptides

 Peptides Presented Thru MHC II Are Exogenous

 Processed thru endocytic pathway
 Peptides Are Presented To TH
 Peptides Are 13-18 a/a Long
 Binding Is Due To Central 13 a/a
 MHC I Peptides Fit Exactly, Not The Case With MHC II Peptides
 Class I And II Specificity

 Several Hundred Allelic Variants Have Been Identified In Humans

 However, up to 6 MHC I And 12 MHC II Molecules Are Expressed In An
Individual
 Enormous Number Of Peptides Needs To Be Presented Using These MHC
Molecules
 MHC Molecules Are Not Very Specific For Peptides (Unlike TCR and BCR)
Promiscuous Binding Occurs
 A peptide can bind a number of MHC
 An MHC molecule can bind numerous peptides
 Class I And II Diversity And Polymorphism

 MHC Is One Of The Most Polymorphic Complexes

 large number of different alleles at each locus
 Alleles differ in their DNA sequences 5% to 10%
 Alleles Can Differ Up To 20 a/a
 Class I Alleles In Humans: 240 A, 470 B, 110 C
 Class II Alleles In Humans: HLA-DR 350 , 2 !
 HLA-DR
  genes vary from 2-9 in different individuals!!!
 DRA chain is highly conserved, with only 2 different alleles
MHC Expression

 Expression Is Regulated By Many Cytokines

 IFN, IFN, IFN and TNF Increase MHC expression
 Transcription Factors That Increase MHC gene Expression
 Some Viruses Decrease MHC Expression
 CMV, HBV, Ad12
 Reduction Of MHC May Allow For Immune System Evasion
 MHC and Disease Susceptibility

 TABLE 7-4 Some significant associations of HLA alleles with increased risk for various diseases
 Disease Associated HLA allele Relative risk*

 Ankylosing spondylitis B27 90

 Goodpasture’s syndrome DR2 16
 Gluten-sensitive enteropathy DR3 12
 Hereditary hemochromatosis A3 9.3
 B14 2.3
 A3/B14 90
 Insulin-dependent diabetes mellitus DR4/DR3 20
 Multiple sclerosis DR2 5
 Myasthenia gravis DR3 10
 Narcolepsy DR2 130
 Reactive arthritis (Yersinia, Salmonella, Gonococcus) B27 18
 Reiter’s syndrome B27 37
 Rheumatoid arthritis DR4 10
 Sjogren’s syndrome Dw3 6
 Systemic lupus erythematosus DR3 5
 SUMMARY

 MHC ,Cluster of genes found in all mammals

 Referred to as HLA complex in human and H-2 complex in mice
 Genes Of MHC Organized In 3 Classes ,Class I,II,III MHC genes
 MHC class I Glycoproteins expressed on all nucleated cells
 Class II MHC Glycoproteins expressed on APC
 MHC loci are highly polymorphic
 Class I MHC Genes Found In Regions A, B and C In Humans
 Class II MHC Genes Found In Regions DR, DP and DQ
 Peptide binding by class I and class II MHC molecules
Exhibit Polymorphism
 MHC Expression Is Regulated By Many Cytokines
 Some HLA alleles occur at a much higher frequency in those suffering from certain diseases.