4.1 Major Histocompatibility Complex (MHC) molecules

Major Histocompatibility Complex (MHC) molecules are crucial for immune recognition. They present peptides from inside and outside cells to T cells, enabling the immune system to detect threats. MHC's structure and genetics are key to its function.

MHC genes are highly diverse, with multiple variants in the population. This diversity helps protect against a wide range of pathogens. MHC molecules come in two main classes, each with specific roles in immune responses.

MHC Structure and Genetics

Structure and function of MHC molecules

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• MHC class I structure
  • Heavy chain with three domains (α1, α2, α3) forms peptide-binding groove and CD8 binding site
  • Non-covalently associated β2-microglobulin stabilizes structure and aids in peptide binding
  • Peptide-binding groove formed by α1 and α2 domains accommodates 8-10 amino acid peptides
• MHC class I function
  • Present peptides from intracellular proteins enables immune surveillance of infected or transformed cells
  • Interact with CD8+ T cells triggers cytotoxic responses against abnormal cells (virally infected, cancerous)
• MHC class II structure
  • Two chains: α and β, each with two domains create more open peptide-binding groove
  • Peptide-binding groove formed by α1 and β1 domains allows binding of longer peptides (13-25 amino acids)
• MHC class II function
  • Present peptides from extracellular proteins facilitates immune responses against extracellular pathogens
  • Interact with CD4+ T cells initiates helper T cell responses and antibody production

Genetic organization of MHC loci

• MHC gene location
  • Human chromosome 6 spans approximately 4 Mbp region
  • Mouse chromosome 17 shows synteny with human MHC
• Classical MHC genes
  • Class I: HLA-A, HLA-B, HLA-C (humans) encode cell surface glycoproteins
  • Class II: HLA-DP, HLA-DQ, HLA-DR (humans) encode α and β chains of class II molecules
• Polygenic nature
  • Multiple genes for each MHC class increases diversity of presented peptides
• Codominant expression
  • Both alleles expressed in heterozygous individuals enhances antigen presentation capabilities
• Extreme polymorphism
  • Numerous alleles for each gene in the population provides population-level resistance to pathogens
• Mechanisms of MHC diversity
  • Point mutations introduce single nucleotide changes
  • Gene conversion transfers genetic material between similar sequences
  • Recombination shuffles alleles during meiosis

MHC Function and Expression

MHC in antigen presentation

• Antigen processing
  • Intracellular antigens for MHC class I degraded by proteasome (cytosolic proteins, viral peptides)
  • Extracellular antigens for MHC class II processed in endosomes and lysosomes (bacterial proteins, allergens)
• Peptide loading
  • Endoplasmic reticulum for MHC class I involves TAP transporter and tapasin
  • Endosomal compartments for MHC class II facilitated by HLA-DM and HLA-DO molecules
• T cell recognition
  • MHC-peptide complex interacts with T cell receptor forms immunological synapse
  • Co-receptor binding (CD8 or CD4) stabilizes interaction and enhances signaling
• Immune response initiation
  • T cell activation and proliferation leads to clonal expansion
  • Cytokine production shapes immune response (Th1, Th2, Th17)
  • Effector function development includes cytotoxicity, B cell help, and macrophage activation

Expression patterns of MHC classes

• MHC class I expression
  • Nearly all nucleated cells allows for constant immune surveillance
  • High levels on lymphocytes and macrophages facilitates rapid immune responses
• MHC class II expression
  • Professional antigen-presenting cells (APCs) specialize in antigen presentation
    • Dendritic cells most potent APCs, initiate primary immune responses
    • Macrophages present antigens from phagocytosed pathogens
    • B cells present antigens captured by surface immunoglobulins
  • Thymic epithelial cells crucial for T cell selection during development
  • Activated T cells (in humans) can present antigens to other T cells
• Regulation of MHC expression
  • Constitutive vs inducible expression allows for dynamic immune responses
  • Cytokine-mediated upregulation enhances antigen presentation during infections (IFN-γ)
• Tissue-specific variations in expression levels adapt immune responses to different environments
• Altered expression in disease states
  • Viral infections often downregulate MHC class I to evade detection
  • Tumors may lose MHC expression to escape immune recognition