The Major Histocompatibility Complex (MHC) — termed the Human Leukocyte Antigen (HLA) system in humans—is a genetically complex region critical for adaptive immunity. It governs antigen presentation, transplant compatibility, and susceptibility to autoimmune disorders. Located on chromosome 6p21.3, the MHC encompasses over 200 genes, many immune-related, organized into three classes: I, II, and III.

1. The MHC spans roughly 3.6 Mb on chromosome 6, encoding MHC class I and II molecules, along with complement proteins, cytokines, and heat shock proteins in class III.
2. Its origin dates back approximately 450 million years, conserved across jawed vertebrates with similar locus organization.

MHC Class I

1. Encodes HLA-A, HLA-B, and HLA-C. These molecules are present on virtually all nucleated cells and present endogenous peptides (8–10 amino acids long) to CD8⁺ cytotoxic T lymphocytes.
2. They are composed of a polymorphic α chain and non-polymorphic β₂-microglobulin.
3. Peptide loading involves proteasomal degradation, translocation via the TAP complex, and assembly in the endoplasmic reticulum.

MHC Class II

1. Includes HLA-DR, DQ, and DP molecules, expressed on professional antigen-presenting cells (APCs) like B cells, dendritic cells, and macrophages.
2. They present exogenous peptides—processed in endocytic compartments—to CD4⁺ helper T cells.
3. HLA-DM plays a key role in editing the peptide repertoire by exchanging CLIP with high-affinity peptides in MHC II molecules.

MHC Class III

1. Encodes immune effector proteins such as complement components (C2, C4), TNF-α, and other regulatory molecules—not directly involved in antigen presentation

Antigen Presentation & Self vs. Non-Self

1. MHC molecules are fundamental to T-cell mediated immunity, presenting peptides derived from pathogens or self-proteins. Class I signals to cytotoxic cells when cells are infected or transformed; class II primes helper T-cells to orchestrate immune responses

Polymorphism & Immune Diversity

1. MHC loci exhibit extreme polymorphism and codominant expression: individuals express alleles from both parents, increasing peptide recognition breadth
2. This diversity underpins immune robustness across populations and contributes to balancing selection pathways like pathogen-driven allele maintenance

Transplantation & Compatibility

1. MHC mismatches are the primary drivers of allograft rejection. Compatibility of HLA alleles between donor and recipient minimizes immune-mediated graft loss

Evolution & Mate Choice

1. Polymorphism in MHC also influences mate selection, potentially via olfactory cues—as seen in humans and mice—to enhance offspring immune fitness

Autoimmunity & Disease Susceptibility

1. Certain HLA alleles have strong associations with autoimmune disorders—for example, HLA-B27 with ankylosing spondylitis—likely due to aberrant antigen presentation.

Vaccine & Epitope Prediction

1. MHC-peptide binding prediction is essential for vaccine design. Tools like EPIMHC help in epitope mapping via HLA alleles.

Genomic Correlations

1. MHC locus variants have been linked to susceptibility in various diseases through genome-wide association studie.

Summary Table

The MHC (HLA) system resides at the core of adaptive immunity, bridging innate recognition with targeted cellular responses. Its polymorphism, expression dynamics, and regulatory function make it central to immunology, transplantation, autoimmunity, and vaccine design. Understanding MHC biology is pivotal for both fundamental immunological research and clinical translation.