Chapter 7 The MHC

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Chapter 7 The MHC

• Major Histocompatibility Complex
• named for role in transplant rejection
• gene complex on CS 6 (humans)
• 3 classes of genes MHC-I MHC-II MHC-III
• code for MHC proteins
• called HLA in humans, H-2 in mice

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• MHC-I
• expressed on membrane of most nucleated cells
• present peptide Ags to TC cells
• gene regions called ABC in humans, KD in mice
• proteins HLA-A / B / C humans, H-2K / D / L
  mice
• non-classical MHC-I E, F, G, etc.

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• MHC-II
• expressed on antigen-presenting cells (APC)
• i.e. B cells, macrophages, dendritic cells
• (MHC-I and MHC-II both present peptides, but only
  cells with MHC-II are called APC)
• Present Ags to TH cells
• genes / proteins DP, DQ, DR humans,
• IA, IE mice
• non-classical MHC-II code for proteasomes,
  proteins involved in Ag processing

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• MHC-III
• not Ag-presenting molecules
• genes code for complement, heat-shock proteins,
  cytokines, etc.
• usually secreted proteins vs membrane molecules

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• MHC genes are closely linked on the CS
• many alleles at each locus
• inherited as a unit haplotype
• get 1 haplotype from each parent
• both haplotypes are expressed codominant
• (no allelic exclusion like Ig genes)
• learned about MHC from inbred mice (syngeneic)
• all mice in a strain are genetically identical
• all have the same haplotype

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Inbred mouse strains

• e.g., strains CBA and C3H are H-2k
• BALB/c DBA/2 are H-2d
• a cross between CBA x BALB/c ? H-2d/k

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MHC Crosses identified by transplant rejection

• F1 hybrids express both parental haplotypes
• dont reject grafts from either parent
• but parents reject grafts from F1 hybrids
• see non-self MHC
• humans are all hybrids (except identical twins)
• haplotypes are mixture of alleles inherited from
  both parents
• we reject transplants because everbody else is
  nonself

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Human Haplotypes

• genotype (tissue type) is two sets of MHC genes
  one from each parent
• e.g. A2 B12 C8 DP2 DQ4 DR7 (mom)
• A6 B1 C21 DP5 DQ12 DR3 (dad)

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Congenic Mice

• 2 strains identical at all but one locus (MHC)
• breed / backcross syngeneic mouse strains
• e.g., make a mouse thats all A except at MHC
• A x B ? AB (half A, half B)
• AB x AB ? AA AB AB BB
• select for BB MHC by grafting with A skin
• backcross BB x AA ? AB
• new AB x AB select BB by transplant
• eventually, mouse BB is all A genes except for
  its BB MHC (called A.B)

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Structure of Class I MHC Molecules

• Ig superfamily
• 1 chain (a) with 3 domains
• a-1 and a-2 domains form groove for Ag peptide
• many different alleles for a chains
• assoc. with ß2-microglobulin
• ß2M gene not in MHC
• conserved (same in everybody)
• required for expression of MHC-I
• MHC-I anchored in membrane by hydrophobic tail

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MHC-I found on most nucleated cells

• lymphocytes have the most (500K / cell)
• few on liver, muscle, fibroblasts
• none on neurons, developing sperm
• each cell has 2 different A, 2B, 2C types
  (codominance)

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Class II MHC

• 2 chains, a and ß, 2 domains each (no ß2-M)
• peptide groove between a-1 and ß -1
• crystallized form is dimer-dimer
• MHC-II proteins on B cells, macs, dend. cells
  (professional APC)
• some other cell types can express MHC-II sometimes

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Inheritance / Expression of MHC-II genes

• more complex than for MHC-I
• (2 chains like Igs, but no allelic exclusion)
• individual expresses both parental molecules
• can also have hybrids with one of each

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how MHC proteins bind antigens

• Class I binding site is closed hole that holds a
  peptide of 8-10 amino acids
• peptide anchored at ends, bulges in center
• anchor aas common to all Ags that fit in
  groove
• MHC-I peptides come from endogenous proteins that
  get digested in cytosol (not vesicles)

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how MHC proteins bind antigens

• Class II MHC groove is open at both ends
• holds peptides of 13-18 amino acids
• MHC-II peptides come from exogenous proteins
  degraded in endocytic vesicles

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how MHC proteins bind antigens

• Ag-MHC binding has broad specificity
• vs. fine specificity of Ag-Ab
• each Ab generally binds only 1 Ag epitope
• each MHC protein can fit / present many peptides
• Diversity of MHC due to polymorphism
• (vs. DNA rearrangements for Abs)
• many alleles at each locus
• MHC repertoire fixed by inheritance
• (Ab repertoire changes with every B cell)

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Regulation of MHC gene expression

• Transcription factors bind gene promoters
• positive or negative regulation
• bare lymphocyte syndrome ? no MHC-II
• Cytokines can regulate MHC expression
• IL-4 ? increased MHC-II on B cells
• IFN-? ? downregulates
• some viruses (CMV, HBV) may ? decreased MHC-I
  expression

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MHC and disease susceptibility

• some MHC alleles correlate with increased
  susceptibility to certain diseases
• relative risk see allele more often in people
  with disease than in general population
• relative risk 1 means that allele is expessed in
  as many patients with disease as in general
  population
• high relative risk does not mean MHC genes cause
  the disease

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The End

• Questions 1-6, 8, 11, 12
• NB transfecting genes means adding a gene to
  whats already there