MHCs

Overview – MHCs

Major Histocompatibility Complexes (MHCs) are cell surface glycoproteins that present antigenic peptides to T-cells. They are essential for T-cell recognition, antigen presentation, and immune activation. MHCs define “self” for the immune system and play a key role in both immunity and transplant rejection. MHC molecules come in two major classes—MHC-I and MHC-II—each with distinct expression profiles and functions.

What Are MHCs?

• Also known as HLA (Human Leucocyte Antigens)
• Encoded by MHC genes on chromosome 6
• Expressed as glycoproteins on cell surfaces
• Enable T-cells to recognise antigen in a restricted, MHC-dependent manner
• Account for transplant rejection due to their extensive genetic polymorphism
• Not expressed on red blood cells

MHC Molecular Structure

MHC Class I

• Expressed on all nucleated cells
• Consists of:
  • 1 alpha chain (with 3 domains: α1, α2, α3)
  • 1 β2-microglobulin (not MHC-encoded)
• Single intracellular domain
• Binds endogenous peptides (e.g. viral or tumour antigens)

MHC Class II

• Expressed only on APCs: macrophages, dendritic cells, B-cells
• Consists of:
  • α-chain and β-chain (both MHC-encoded)
• Two intracellular domains
• Binds exogenous peptides (e.g. phagocytosed pathogens)

MHC Diversity: Polygeny & Polymorphism

Polygeny

• Multiple genes encode each MHC class
• Class I genes: HLA-A, HLA-B, HLA-C
• Class II genes: HLA-DR, HLA-DP, HLA-DQ

Polymorphism

• Hundreds of alleles exist for each gene
• Expression is co-dominant
  • Each person expresses both maternal and paternal alleles
• Basis for MHC-based haplotypes, which are inherited as a unit
  • Explains similarity between 1st-degree relatives

MHC-I Functions

• Expressed on all nucleated cells & APCs
• Presents endogenous peptides (e.g. viral proteins)
• Activates CD8+ cytotoxic T-cells
• Enables thymic selection of CD8+ T-cells
• Allows cytotoxic targeting of cancerous or infected cells

MHC-II Functions

• Expressed only on APCs, semi-activated macrophages, and B-cells
• Presents exogenous peptides (e.g. phagocytosed pathogens)
• Activates CD4+ helper T-cells
• Required for:
  • Thymic selection of CD4+ T-cells
  • TH-cell help to activate macrophages and B-cells
  • Isotype switching and antibody secretion by B-cells

Antigen Processing & MHC Presentation

MHC-I Pathway (Endogenous Ags)

1. Cytosolic antigens (e.g. viruses, mutated proteins)
2. Degraded by proteasomes → peptide fragments
3. Peptides transported into ER via TAP transporters
4. Peptides loaded onto MHC-I (chaperones assist)
5. pMHC-I transported to cell surface
6. Recognised by CD8+ T-cells

Clinical Note:

• Some viruses & TAP mutations can disrupt this pathway to evade immunity

MHC-II Pathway (Exogenous Ags)

1. Extracellular antigens are phagocytosed
2. Phagosome fuses with lysosome → phagolysosome
3. Acid degrades antigen → peptide fragments
4. MHC-II molecules carry CLIP (invariant chain) to block premature peptide binding
5. In lysosome, HLA-DM removes CLIP → peptide loaded onto MHC-II
6. pMHC-II transported to surface for CD4+ T-cell recognition

MHC Restriction

• T-cell receptors (TCRs) only recognise antigen when presented with self MHC
• Two conditions must be met:
  1. Compatible MHC molecule
  2. Specific antigenic peptide
• Prevents inappropriate immune activation
• Basis for “self vs non-self” immune recognition

Superantigens

• Bacterial/viral antigens that bypass MHC restriction
• Bind outside the MHC-TCR cleft → trigger non-specific T-cell activation
• Lead to cytokine storm → ↑↑ IL-2, TNF-α, IFN-γ → Toxic Shock Syndrome

Clinical Features

• Fever, hypotension, tachycardia
• Myalgia, dizziness, rash

Management

• Aggressive antibiotic/antiviral therapy
• Symptomatic support

Summary – MHCs

MHCs are glycoproteins that present antigen to T-cells, enabling immune surveillance, thymic selection, and T-cell activation. MHC Class I presents endogenous antigens to CD8+ T-cells, while MHC Class II presents exogenous antigens to CD4+ T-cells. Their extreme polymorphism underpins transplant rejection and immune diversity. For more immunological concepts, visit our Immune & Rheumatology Overview.