# Lecture 12: The Major Histocompatibility Complex (MHC)
## Immunology
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## Learning Objectives
By the end of this lecture, students will be able to:
1. Describe the structure of MHC class I and class II molecules
2. Explain the genetic organization and polymorphism of the MHC locus (HLA in humans)
3. Distinguish between MHC class I and class II in terms of structure, expression, and function
4. Explain the concept of MHC restriction and its discovery
5. Discuss the clinical significance of MHC in disease susceptibility and transplantation
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## Lecture Content
### I. Overview of the MHC
The major histocompatibility complex (MHC) is a cluster of highly polymorphic genes encoding cell-surface glycoproteins. In humans, this system is called the **HLA (human leukocyte antigen)** system and is located on chromosome 6p21. The primary function of MHC molecules is to present peptide antigens to T cells: MHC class I presents peptides to CD8+ cytotoxic T cells, while MHC class II presents peptides to CD4+ helper T cells. The MHC is the most polymorphic genetic locus in the human genome, a feature originally discovered through transplant rejection studies, which gave rise to the name "histocompatibility."
### II. MHC Class I Molecules
MHC class I molecules are heterodimers consisting of an α chain (heavy chain, approximately 45 kDa) and β2-microglobulin (β2m, approximately 12 kDa). The α chain is encoded in the MHC locus, while β2m is encoded on chromosome 15. The α chain has three extracellular domains: α1, α2, and α3. The **peptide-binding groove** is formed by the α1 and α2 domains, with closed ends that accommodate short peptides of 8-10 amino acids. The groove has a floor of 8 antiparallel β-strands and walls of 2 α-helices, with anchor residues on the peptide fitting into pockets (A-F) in the groove. The α3 domain has an immunoglobulin-like fold and interacts with the CD8 co-receptor. β2m stabilizes the overall structure and is required for surface expression.
MHC class I is expressed on virtually **all nucleated cells** (but not mature red blood cells). Expression levels vary: lymphocytes, macrophages, and DCs express high levels, while hepatocytes and neurons express lower levels. Expression is upregulated by IFN-α, IFN-β, IFN-γ, and TNF-α. The classical **HLA class I genes** are HLA-A, HLA-B, and HLA-C (class Ia). Non-classical class Ib genes include HLA-E (a ligand for NKG2A/CD94 on NK cells), HLA-F, and HLA-G (expressed on trophoblast cells, where it inhibits NK cell and CTL activity to promote maternal-fetal tolerance).
### III. MHC Class II Molecules
MHC class II molecules are heterodimers consisting of an α chain (approximately 33 kDa) and a β chain (approximately 28 kDa), both encoded in the MHC locus. Each chain has two extracellular domains: α1 and α2, and β1 and β2. The **peptide-binding groove** is formed by the α1 and β1 domains, and unlike class I, it has open ends that accommodate longer peptides of 13-25 amino acids, with the peptide extending out of the groove. The groove structure is similar overall, with α-helical walls and a β-sheet floor. The β2 domain interacts with the CD4 co-receptor.
MHC class II expression is restricted to **professional antigen-presenting cells (APCs)**: dendritic cells (constitutive, high levels), macrophages (constitutive, upregulated by activation), B cells (constitutive), and thymic epithelial cells. Expression can be induced on other cell types by IFN-γ, including endothelial cells, epithelial cells, and fibroblasts. The **HLA class II genes** are HLA-DP, HLA-DQ, and HLA-DR, with the DR locus potentially having additional β chain genes that allow expression of additional DR molecules.
A side-by-side structural comparison of MHC class I and MHC class II molecules. Left panel (MHC Class I): The alpha chain is shown with three domains (alpha-1, alpha-2, alpha-3) anchored in the cell membrane, with beta-2-microglobulin non-covalently associated. The peptide-binding groove formed by alpha-1 and alpha-2 is shown from a top-down view containing a short peptide (8-10 aa) with closed ends. CD8 co-receptor is shown binding the alpha-3 domain. Right panel (MHC Class II): The alpha and beta chains are shown with two domains each (alpha-1, alpha-2; beta-1, beta-2). The peptide-binding groove formed by alpha-1 and beta-1 is shown from a top-down view containing a longer peptide (13-25 aa) with open ends (peptide extends beyond the groove). CD4 co-receptor is shown binding the beta-2 domain. A table below compares: peptide length, groove structure, co-receptor, expression pattern, and source of presented antigens.
### IV. Genetic Organization of the HLA Locus
The HLA locus is located on the short arm of chromosome 6 (6p21.3), spans approximately 4 Mb, and contains more than 200 genes. It is organized into three regions. The **class I region** (telomeric) contains HLA-A, HLA-B, HLA-C, and non-classical genes. The **class II region** (centromeric) contains HLA-DP, HLA-DQ, and HLA-DR, along with genes involved in antigen processing (TAP1, TAP2, tapasin, LMP2, LMP7, DM, and DO). The **class III region** (between class I and II) contains complement genes (C2, C4, Factor B), TNF-α, TNF-β, and HSP70 -- these are not MHC molecules structurally but are functionally important in immunity.
A key feature of HLA expression is **codominance**: both maternal and paternal alleles are expressed, so each individual expresses up to 6 classical class I molecules (2 HLA-A + 2 HLA-B + 2 HLA-C) and 6 or more class II molecules. Codominance maximizes the diversity of peptides that can be presented. A **haplotype** is the set of HLA alleles inherited together on one chromosome 6. Haplotypes are inherited as a block due to low recombination frequency within the HLA region, and two siblings have a 25% chance of being HLA-identical.
### V. MHC Polymorphism
HLA genes are the most polymorphic in the human genome, with HLA-B having over 7,000 identified alleles, HLA-A over 6,000, and HLA-DRB1 over 3,000. Most polymorphisms are concentrated in the peptide-binding groove (α1/α2 for class I; α1/β1 for class II), so different alleles have different peptide-binding specificities. Each MHC molecule can bind approximately 1,000-10,000 different peptides, making binding promiscuous but selective.
The evolutionary significance of this polymorphism is maintained by **balancing selection** and heterozygote advantage: heterozygous individuals can present a wider array of pathogen peptides, conferring a survival advantage. Evidence from epidemiological studies shows that MHC-diverse populations survive epidemics better, and HLA allele frequencies differ by geographic region based on prevalent pathogens, reflecting pathogen-driven selection.
### VI. MHC Restriction
T cells can only recognize antigen when it is presented by MHC molecules, not as free antigen. This principle was established by the landmark discovery of **Zinkernagel and Doherty in 1974** (Nobel Prize 1996), who showed that CD8+ CTLs from LCMV-infected mice killed virus-infected target cells only if the targets shared the same MHC class I haplotype. This "dual recognition" means that the TCR simultaneously recognizes both the peptide and the MHC molecule. CD4+ T cells are MHC class II-restricted, while CD8+ T cells are MHC class I-restricted. MHC restriction is established during thymic selection, specifically during positive selection.
### VII. HLA and Disease Association
Certain HLA alleles are associated with increased susceptibility or resistance to specific diseases. The strongest associations include **HLA-B27** with ankylosing spondylitis (relative risk approximately 90-100), reactive arthritis, anterior uveitis, and psoriatic arthritis; **HLA-DQ2/DQ8** with celiac disease (approximately 95% of patients carry DQ2); **HLA-DR4** with rheumatoid arthritis (the shared epitope hypothesis posits that specific amino acid sequences in the HLA-DRB1 peptide-binding groove predispose to RA); **HLA-DR3/DR4** with type 1 diabetes mellitus; **HLA-DR2** (specifically DRB1*15:01) with multiple sclerosis (while being protective against T1D); **HLA-DRB1*15:01** with narcolepsy; **HLA-B*57:01** with abacavir hypersensitivity, requiring pharmacogenomic testing before prescription; **HLA-B*58:01** with allopurinol hypersensitivity and severe cutaneous reactions; and **HLA-B*57 and HLA-B*27** with slow HIV progression in elite controllers.
The mechanisms underlying these disease associations include presentation of self-peptides that trigger autoimmune T cells, molecular mimicry between pathogen and self-peptides, altered peptide repertoire, and the arthritogenic peptide hypothesis for HLA-B27.
### VIII. MHC in Transplantation
MHC molecules are the primary targets of transplant rejection. Donor MHC molecules are recognized as foreign by recipient T cells through two pathways. **Direct allorecognition** occurs when recipient T cells directly recognize intact donor MHC molecules on donor cells, with an extraordinarily high frequency of alloreactive T cells (approximately 1-10%). **Indirect allorecognition** involves recipient APCs processing shed donor MHC molecules and presenting donor-derived peptides on self-MHC. HLA matching between donor and recipient improves transplant outcomes, with matching being most important for HLA-A, HLA-B, and HLA-DR in kidney transplantation, and close matching (10/10 allele match) being required for bone marrow transplant.
A diagram of the HLA complex on chromosome 6p21. The chromosome is shown with the three regions delineated: Class II region (centromeric side) containing DP, DQ, DR genes along with TAP1, TAP2, LMP2, LMP7, DM, and DO genes. Class III region (middle) containing complement genes (C2, C4A, C4B, Factor B), TNF-alpha, and HSP70. Class I region (telomeric side) containing HLA-B, HLA-C, and HLA-A genes, plus non-classical genes (HLA-E, HLA-F, HLA-G). Below, a family inheritance diagram shows how HLA haplotypes are inherited as blocks: parents with haplotypes a/b and c/d produce four possible offspring (a/c, a/d, b/c, b/d), each with a 25% probability. The probability of two siblings being HLA-identical (sharing both haplotypes) is 25%.
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