7Plasma cells secrete antibody at a high rate but can no longer respond to antigen or helper T cells.
8The Major Histocompatibility Complex Cellular and Molecular ImmunologyChapter 4
9MHC - The Major Histocompatibility Complex Originally identified in mice as blood cell antigens by R.A. Gorer and G.D. Snell in 1930s, and defined on the basis of tissue graft rejection Nobel prize awarded to Snell.Work by Rolf Zinkernagel and Peter Doherty in the 1970s revealed that it is the complex of MHC molecule plus antigen that is recognized by T cells (MHC restriction of T cell responses) Nobel PrizeTwo classes of MHC molecule: Class I (single MHC a chain + b2-microglobulin) and Class II (a chain plus b chain) - more Ig-superfamily members (Ig-C domains)
12Peptide Binding to MHC Molecules: Class I vs. II Class I Class II• Generated by proteasome (cytosol) • Generated in endosomes/lysosomes• Transported to ER by TAP1/2 • Bind in specialized vessicles (MIIC)• Restricted length, 8-9 residues • Any length, extend from MHC• Binding energy from N, C termini • Binding energy from backbone• “Anchor” residues fill specific pockets • “Anchor” residues fill specific pockets
14Fig. 3.27 The T-cell receptor binding to the MHC:peptide complex (Ian Wilson).
15The Major Histocompatibility Complex MHC Class I and Class II genes are encoded in a large (>4 Mb, >200 genes) tightly linked gene cluster: the MHCThe MHC is similarly organized in mice (Ch17) and humans (Ch6) - syntenicKnown in humans as HLA (human leukocyte antigen) genes; in mouse as H-2 (histocompatibility group 2) genesGenes are highly polymorphic (many alleles)Class I: HLA-A, -B, -C (human); H-2K, -2D, -2L (mouse)Class II: HLA-DP, -DQ, -DR (human), I-A, I-E (mouse)
16b2-microglobulin is located on a different chromosome. HumanMHC class I: HLA-A, -B, -CMHC class II: HLA-DR, -DP, -DQMouseMHC class I: H2-K, -D, -LMHC class II H2-A, -E (I-A, I-E)b2-microglobulin is located on a different chromosome.
17MHC Encodes a Variety of Other Genes Class I region: “Non-classical” Class I molecules (share sequence homology, bind b2m, but non-polymorphic), also called Class IB genesH2-M3 (mouse) binds N-formylated peptidesMIC genes interact with activating receptors on NK (and some T) cellsHLA-E and HLA-G interact with inhibitory receptors on NK cellsHFE is involved in iron metabolism
18MHC Encodes a Variety of Other Genes Class II region: other genes involved in antigen processingTAP1 and TAP2 - transporter for Class I peptidesTapasin - involved in loading peptides into Class I moleculesLMP2 and LMP7 - inducible proteasome subunitsHLA-DM (H-2M in mouse) and HLA-DO (H-2O) - control loading of peptides into Class II molecules (DM+, DO-)Gene expression (except DOb) is coordinately regulated by IFN-g induction of Class II Transactivator (CIITA)
19MHC Encodes a Variety of Other Genes Class III region: miscellaneous assortment of genes - some immunologically related, others notComplement C4, C2, and factor BTumor necrosis factor (TNF) and lymphotoxin (LT)21-hydroxylase (enzyme involved in steroid biosynthesis)
21MHC Polymorphism MHC Class I and Class II molecules have many alleles Diversity ensures that a wide range of peptides can be presented within the population (even if a much more limited set is presented by any individual)For Class II, both a and chains are polymorphic (except DRa in humans and Ea in mice), adding more diversity
22Fig. 5.13 Human MHC genes are highly polymorphic.
23Fig. 5.16 Allelic variation occurs at specific sites within the MHC molecules. The polymorphism of MHC guarantees a sufficient number of different MHC molecules in a single individual to present a variety of peptides.
24MHC PolymorphismMHC Class I and Class II molecules have many alleles (point mutations, gene conversion, gene recombination)Diversity ensures that a wide range of peptides can be presented within the population (even if a much more limited set is presented by any individual)For Class II, both a and chains are polymorphic (except DRa in humans and Ea in mice), adding more diversityCollection of Class I + Class II alleles on one chromosome is called the haplotypeMHC molecules are expressed co-dominantly: alleles from both chromosomes are expressed in each cell
25MHC-Linked DiseasesDefects in MHC gene expression lead to immunodeficiencies (MHC molecules are required for both T cell development and activation)Some MHC alleles are associated with susceptibility or resistance to autoimmune diseases
26MHC-Linked Immunodeficiencies Bare Lymphocyte Syndromes lead to loss of MHC molecule expression:Defects in TAP genes prevent MHC Class I protein surface expression (even though MHC proteins are normal), so no CD8+ T cells - surprisingly mild immunodeficiency (respiratory and skin infections)Defects in TF’s controlling Class II gene expression (CIITA, RFXANK, RFX5, RFXAP) block CD4+ T cell development - result in SCID (severe combined immunodeficiency)
27Fig. 13.20 Associations of HLA serotype and sex with susceptibility to autoimmune disease.