Major Histocompatibility Complex

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• Chapter 8
• Major Histocompatibility Complex

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• Antibodies can recognize antigen alone
• T-cell receptors can only recognize antigen that
  has been processed and presented by Major
  Histocompatibility Complex (MHC)
• Involves
• Antigen processing
• Antigen presentation

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Inheritance of MHC

• MHC coded by cluster of genes
• Rejection of foreign tissue is due to immune
  response against cell surface molecules,
  histocompatibility antigens

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Inheritance of MHC

• Collection of genes on chromosome 6 in humans
  (HLA complex) and chromosome 17 in mice (H-2
  complex)
• Class I MHC genes
• Encode glycoproteins expressed on all nucleated
  cells
• Class II MHC genes
• Encode glycoproteins expressed on
  antigen-presenting cells (macrophages, B cells,
  dendritic cells)
• Class III MHC genes
• Encode various products involved in complement
  and inflammation

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Inheritance of MHC
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Inheritance of MHC

• Many different alleles exist at each locus among
  the population
• Each set of alleles is called a haplotype
• Genes of MHC lie close together so crossing over
  during meiosis occurs infrequently
• Individual inherits one haplotype from mom, one
  from dad
• Many in the population are heterozygous
• Alleles are codominant so expressed simultaneously

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Inheritance of MHC

• Inbred strains will express identical haplotypes
  homozygous
• Inbred mice are solid colors

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Inheritance of MHC
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MHC molecules

• Both Class I and Class II are membrane-bound
  glycoproteins
• Antigen-presenting molecules

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• Class I MHC
• Alpha a chain
• Transmembrane
• Encoded by A, B, and C regions in human MHC
  complex
• Beta ß2-microglobulin
• Encoded by highly conserved gene on different
  chromosome

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• Class II Molecule
• a1 and a2 chain
• Transmembrane
• ß1 and ß2 chain
• transmembrane

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Figure b shows top View of peptide cleft
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• Every individual expresses small number of
  different Class I and Class II
• Limited number of MHC must be able to present
  enormous array of different antigens
• MHC does not display specificity of Antibodies
• MHC is promiscuous ?

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Peptide Interactions with MHC
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• Generation of B-cell receptors (antibodies) and
  T-cell receptors is dynamic, changing over-time
• Gene rearrangement
• In contrast, MHC molecules are fixed in the genes
• Differences in population due to large number of
  alleles
• In humans, 370 A alleles, 660 B alleles, 190 C
  alleles

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Location of genes

• Human
• Class I MHC are red
• Telomeric end of HLA complex
• Class II MHC are blue
• Centromeric end of HLA complex

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Cellular Expression of MHC
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• MHC Diversity
• Diversity (polymorphism) helps to protect a
  species from wide range of infectious diseases
• Certain alleles make individuals more susceptible
  to diseases
• Example, polymorphism in
  cheetah is limited, due to
  bottleneck effect

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MHC Restriction

• CD8 Tc cells are MHC Class I restricted
• Can only recognize antigen presented by MHC Class
  I molecules
• Therefore, cells with MHC Class I are called
  taget cells, killed by cytotoxic T cells
• CD4 TH cells are MHC Class II restricted
• Cells with MHC Class II are called
  antigen-presenting cells (APCs)

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MHC Restriction

• Mice immunized with lymphocytic choriomenigitis
  virus (LCM)
• Animals spleen cells were extracted (containing
  Tc cells)

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Antigen Presenting Pathways

• Cystolic Pathway
• Endogeneous antigens produced in cell, in
  infected cell
• Antigens presented on MHC Class I to Tc cells
• Endocytic Pathway
• Exogeneous antigen taken in by endocytosis by
  antigen-presenting cells and presented to TH
  cells by MHC Class II

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Cystolic PathwayEndogenous

• Figure below
• (a) shows degradation of misfolded proteing
• (b) shows intact proteins linked to ubiquitin to
  be degraded

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Endocytic PathwayExogenous
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