The major histocompatibility complex (MHC) is the most polymorphic locus in the human genome: a ~4 Mb stretch on chromosome 6p21.3 encoding cell-surface glycoproteins that present antigen peptides to T cells. The human MHC proteins are called HLA (human leukocyte antigens). HLA matters clinically in three arenas:
- Transplantation: donor-recipient HLA matching governs graft survival and graft-versus-host disease risk.
- Autoimmunity: many autoimmune conditions show strong HLA allele associations, often the largest single genetic risk factor.
- Pharmacogenomics: specific HLA alleles predict severe hypersensitivity reactions to particular drugs; pre-prescription testing is required for several.
| MHC class I | MHC class II | |
|---|---|---|
| Loci | HLA-A, HLA-B, HLA-C (1 letter) | HLA-DP, HLA-DQ, HLA-DR (2 letters) |
| Structure | 1 long α chain + β2-microglobulin (short) | 2 chains of equal length (α + β) |
| Expression | All nucleated cells, platelets (not RBCs) | Antigen-presenting cells (dendritic cells, macrophages, B cells), thymic epithelium |
| Binds | TCR + CD8 (cytotoxic T cells) | TCR + CD4 (helper T cells) |
| Antigen source | Endogenous (viral, cytosolic proteins) | Exogenous (bacterial, extracellular proteins) |
| Antigen loading | In the rough ER, peptide delivered via TAP (transporter associated with antigen processing) | In acidified endosome after release of the invariant chain |
| Associated protein | β2-microglobulin | Invariant chain |
Two arithmetic mnemonics: MHC I loci have 1 letter; MHC II loci have 2 letters. CD8 × MHC I = 8; CD4 × MHC II = 8 (both products are 8).
A handful of HLA-disease associations are worth knowing cold. HLA is typically necessary but not sufficient: most carriers never develop the associated disease.
| HLA allele | Associated diseases | Mnemonic |
|---|---|---|
| HLA-A3 | Hereditary hemochromatosis | "hA3mochromatosis" (British spelling, hae-mochromatosis) |
| HLA-B27 | Psoriatic arthritis, Ankylosing spondylitis, IBD-associated arthritis, Reactive arthritis | PAIR (the seronegative spondyloarthropathies) |
| HLA-DQ2 / HLA-DQ8 | Celiac disease (>95% of patients carry one or both) | "I ate (8) too (2) much at Dairy Queen" |
| HLA-DR2 | Multiple sclerosis (specifically DRB1*15:01), SLE | 2 sticks on the "DRuMS" 🥁; "2,3 S-L-E". |
| HLA-DR3 | Graves disease, Hashimoto thyroiditis, Type 1 diabetes, SLE | "DRiv3 THRu": HLA-DR3, THyRoid disease |
| HLA-DR4 | Rheumatoid arthritis, type 1 diabetes | "4 walls in a rheum"; "3,4, Sugar galore." |
| HLA-DQB1*06:02 | Narcolepsy with cataplexy (~98% concordance, the strongest HLA-disease association known) | "0602: nodding off at 6:02" |
Highest T1D risk: DR3/DR4 heterozygotes. The two haplotypes synergize rather than simply adding.
Pre-prescription testing is required or strongly recommended for these drug-allele pairs. See predictive testing for the broader pharmacogenomics framework.
| Allele | Drug | Reaction | Population enrichment |
|---|---|---|---|
| HLA-B*57:01 | Abacavir | Hypersensitivity (rash, fever, systemic) | FDA black-box; test before prescribing in all ancestries |
| HLA-B*15:02 | Carbamazepine (and other aromatic anticonvulsants) | Stevens-Johnson syndrome / toxic epidermal necrolysis | East and Southeast Asian populations |
| HLA-A*31:01 | Carbamazepine | SJS/TEN | European, Japanese ancestry |
| HLA-B*58:01 | Allopurinol | Severe cutaneous adverse reactions | Han Chinese, Thai, Korean |
The mechanism is the same antigen-presentation pathway misfiring: certain HLA pockets bind drug-modified self-peptides, presenting them as foreign and triggering cytotoxic T-cell responses.
Transplantation matching. For hematopoietic stem cell transplant (HSCT), high-resolution typing of HLA-A, -B, -C, -DRB1, and often -DQB1 is performed; 10/10 or 12/12 allele-level matches give the best outcomes. For solid organ transplant, the importance of HLA matching varies by organ: kidney (matching reduces rejection), liver (less critical), cornea (avascular, minimal HLA need).
Autoimmunity risk modulation. HLA is typically the single largest genetic risk factor for an autoimmune disease, but environmental triggers and other genetic modifiers determine penetrance. This is the canonical multifactorial inheritance example.
Drug hypersensitivity prediction. A positive pre-prescription HLA test converts a rare-but-severe reaction (abacavir hypersensitivity, SJS/TEN) into a preventable one. Counseling implications: a positive result also has predictive value for the patient's first-degree relatives, who may share the allele.
Savior-sibling PGT. Embryos can be selected for HLA compatibility with an existing sick sibling needing HSCT, alongside testing the embryo for the affected condition itself.
- HLA-B27 is the prototype association but is neither necessary nor sufficient: ~90% of ankylosing spondylitis patients are B27-positive, yet only ~5% of B27-positive individuals develop AS. The same logic applies to most HLA-disease associations.
- Celiac DQ2/DQ8 testing is most useful as a rule-out: a negative result has ~99% negative predictive value. A positive result is common in the general population (~30%) and is not diagnostic on its own.
- HLA testing for autoimmunity is rarely useful clinically. Pharmacogenomic and transplant uses are where HLA testing actually changes management.
- The MHC region's extreme linkage disequilibrium creates extended haplotypes (e.g., the "ancestral 8.1 haplotype" carrying HLA-A1-B8-DR3) that explain why multiple autoimmune diseases co-occur in the same family.
- HLA-A3 and hemochromatosis is LD-tagging, not causation. A3 sits on the same ancestral haplotype as the causal HFE C282Y variant (~5 Mb apart on 6p). Modern hemochromatosis testing genotypes HFE directly. This is the textbook example of tag SNPs vs causal variants in GWAS.
- HLA-DQB1*06:02 / narcolepsy with cataplexy is the strongest HLA-disease association known (~98% concordance). The mechanism is loss of hypocretin/orexin-producing neurons in the lateral hypothalamus, likely autoimmune.