MHC

  • Introduction to MHC:

    • The Major Histocompatibility Complex (MHC) is a cluster of genes located on chromosome 6 in humans.

    • MHC genes encode proteins that play a crucial role in intercellular recognition and discrimination between self and non-self.

    • MHC molecules are involved in both humoral and cell-mediated immune responses.

  • Classes of MHC Molecules:

    • Class I MHC: Expressed on nearly all nucleated cells. They present endogenous peptides (e.g., viral proteins) to CD8+ T cells (cytotoxic T cells).

    • Class II MHC: Expressed primarily on antigen-presenting cells (APCs) like macrophages, dendritic cells, and B cells. They present exogenous peptides to CD4+ T cells (helper T cells).

    • Class III MHC: Encodes proteins involved in immune functions, such as complement components and inflammatory cytokines (e.g., TNF-α).

  • Structure of MHC Molecules:

    • Class I MHC: Composed of an α chain (45 kDa) and β2-microglobulin (12 kDa). The α chain forms a peptide-binding cleft that binds peptides of 8-10 amino acids.

    • Class II MHC: Composed of α and β chains, both of which form a peptide-binding cleft that can accommodate longer peptides (13-18 amino acids).

  • Polymorphism of MHC Molecules:

    • MHC molecules are highly polymorphic, meaning there are many allelic variants in the population.

    • Each individual expresses a limited number of MHC molecules (up to 6 Class I and 12 Class II), but these can bind a wide variety of peptides, allowing the immune system to respond to diverse antigens.

  • Cellular Distribution of MHC Molecules:

    • Class I MHC: Expressed on most nucleated cells, with high levels on lymphocytes and low levels on liver hepatocytes and neural cells.

    • Class II MHC: Constitutively expressed on APCs (macrophages, dendritic cells, B cells). Expression can be upregulated by cytokines like IFN-γ.

  • Regulation of MHC Expression:

    • Cytokines: IFN-α, IFN-β, IFN-γ, and TNF-α increase Class I MHC expression. IFN-γ also induces Class II MHC expression via the CIITA (Class II transactivator).

    • Viral Infections: Some viruses (e.g., CMV, HBV) downregulate MHC expression to evade immune detection.

  • MHC and Disease Susceptibility:

    • Certain MHC alleles are associated with increased susceptibility to diseases, including:

      • Autoimmune diseases: Rheumatoid arthritis (HLA-DR4), Type 1 Diabetes (HLA-DR3/DR4).

      • Infectious diseases: Ankylosing spondylitis (HLA-B27).

      • Neurological disorders: Multiple sclerosis (HLA-DR2).

    • The relative risk of developing a disease is higher in individuals with specific MHC alleles.