Notes on Major Histocompatibility Complex (MHC) and its Role in Immunity

Systems Biology: Introduction to MHC

Overview of Major Histocompatibility Complex (MHC)

  • MHC is a collection of genes and proteins responsible for immune system function.
  • Types of MHC:
    • MHC Class I (MHC I): Present on all nucleated cells; presents cytosolic antigens to cytotoxic T cells.
    • MHC Class II (MHC II): Expressed on antigen-presenting cells (APCs) only; presents extracellular antigens to helper T cells.

Structure of MHC Molecules

  • MHC I Structure:
    • Composed of α chain and β2-microglobulin.
    • Polymorphic: many alleles exist, co-dominantly expressed.
    • Transmembrane protein with hydrophobic amino acids for membrane anchoring.
    • Peptide-binding groove formed by a strand floor (β-strands) and α-helices.
  • MHC II Structure:
    • Composed of α and β chains.
    • Extracellular domains have a peptide-binding groove similar to MHC I but with a different structure.

Functions of MHC Molecules

  • Antigen Presentation: MHC molecules hold and display antigen fragments (peptides) to T cells, activating them for an immune response.
    • MHC I presents endogenous antigens (e.g., self or viral).
    • MHC II presents exogenous antigens (e.g., from bacteria).

Immune Evasion by Pathogens

  • Pathogens can mutate antigen genes to evade detection by T cells.
  • MHC diversity is advantageous for preventing immune evasion:
    • Individuals express multiple types of MHC molecules.
    • Extensive variability among individuals in MHC proteins supports survival.

MHC Genetics

  • HLA System: Human MHC is referred to as the Human Leukocyte Antigen (HLA) system.
  • MHC Gene Clusters:
    • Located on chromosome 6 in humans; contains both MHC I and MHC II genes.
    • MHC genes are polygenic and polymorphic, providing each individual with genetic diversity.
  • In mice, MHC is called H-2; rapid graft rejection based on MHC haplotypes highlights the importance of MHC compatibility.

Mechanism of T Cell Activation

  1. Pathogen Entry: Pathogen (e.g., bacteria) enters the body.
  2. Antigen Presentation:
    • APCs like dendritic cells engulf the pathogen via phagocytosis.
    • Dendritic cells migrate to lymph nodes and present peptide antigens via MHC II.
  3. T Cell Activation: T cells recognize peptide/MHC complexes through their T cell receptor (TCR), initiating a specific immune response and moving to the site of infection.

Peptide Binding Dynamics

  • MHC I can bind peptides of 8-10 amino acids; MHC II can bind peptides of 13-18 amino acids.
  • Promiscuous Binding:
    • A single MHC molecule can bind various peptides.
    • Broader specificity compared to T cells enhances immunological responses.

Conclusion

  • MHC plays a critical role in mediating immune responses by presenting antigens to T cells.
  • The structure of MHC molecules is intricately linked to their function, and their genetic diversity increases the immune system's capacity to recognize various pathogens and antigens.