MHC

Major Histocompatibility Complex (MHC)

Overview

  • MHC is a cluster of genes present in all studied mammalian species.

  • Plays vital roles in intercellular recognition and immune response.

  • Essential for distinguishing self from nonself in immune reactions.

Role in Immune Responses

  • Cell-Mediated Immunity: T cells recognize antigens only when presented with MHC molecules.

  • Humoral Immunity: Antibodies can react with free antigens, but T cells require MHC.

  • Antigen Presentation: MHC molecules present processed antigens to T helper (TH) and T cytotoxic (TC) cells, influencing individual's immune response and susceptibility to diseases.

MHC Structure and Inheritance

Historical Context

  • Origin of MHC research traced back to Peter Gorer in the 1930s and George Snell in the 1940s-50s.

  • Identified blood group antigens within histocompatibility genes, which are now classified as H-2 in mice and HLA in humans.

Gene Classes

  • MHC genes are categorized into three major classes:

    • Class I: Glycoproteins on nucleated cells; present antigens to TC cells.

    • Class II: Primarily on antigen-presenting cells; present to TH cells.

    • Class III: Encode various immune function proteins, including components of the complement system.

Detailed Genomic Organization

Class I MHC Genes

  • Encoded by A, B, C regions (humans) and K, D, L regions (mice).

  • Class I molecules are found in almost all nucleated cells, playing a critical role in presenting antigens from endogenous proteins.

Class II MHC Genes

  • Encoded by DP, DQ, DR regions in humans; IA, IE regions in mice.

  • Primarily expressed on macrophages, dendritic cells, and B cells.

Class III MHC Genes

  • Located between Class I and II regions; encode complement components and inflammatory cytokines.

MHC Genetics and Polymorphism

Inheritance Patterns

  • MHC genes exhibit high polymorphism with many alleles at each locus.

  • Inheriting MHC alleles occurs in linked groups called haplotypes (one allele from each parent).

Concordance in Inbred and Outbred Populations

  • Inbred strains are homozygous, while outbred populations are often heterozygous at many loci, leading to diverse MHC expression.

MHC Functionality

Structure of MHC Molecules

  • Class I molecules consist of a glycoprotein heavy chain and a light chain (β2-microglobulin).

  • Class II molecules have two non-identical chains associated noncovalently; exhibit peptide-binding clefts that capture antigens.

Peptide Binding Characteristics

  • Class I MHC binds shorter peptides (8–10 amino acids);

  • Class II MHC accommodates longer peptides (13–18 amino acids).

  • Both types can bind various peptides, classified as having 'promiscuous' binding capability.

MHC and Immune Responsiveness

Immune Response Variability

  • MHC haplotypes influence the ability to mount an immune response.

  • Different MHC alleles affect the capacity to bind and present specific antigens.

MHC Polymorphism and Disease Susceptibility

  • Certain MHC alleles correlate with higher disease susceptibility, particularly autoimmune diseases.

  • Variability in MHC expression shapes the immune response to environmental pathogens.

Genetic and Environmental Factors

  • Autoimmune diseases are influenced by genetic predispositions from MHC, while environmental factors also play a role.

Practical Considerations

MHC in Transplant Medicine

  • Matching donor and recipient MHC types is crucial for transplant success; mismatch may lead to rejection.

  • The polymorphic nature complicates finding compatible matches in organ transplantation.