MHC / HLA & Antigen Presentation
Class I to CD8, class II to CD4 - plus the HLA links Step 1 tests
MHC basics
MHC = HLA. Major histocompatibility complex molecules, called human leukocyte antigens (HLA) in humans, are encoded in a gene cluster on chromosome 6. The genes are highly polymorphic and expressed codominantly, so each person displays both parental sets. Their job is to present peptide antigens to T cells: MHC I to CD8 T cells, MHC II to CD4 T cells.
Rule of thumb. ENDOGENOUS (intracellular) antigens go on MHC I to CD8 cells; EXOGENOUS (extracellular, phagocytosed) antigens go on MHC II to CD4 cells. Cross-presentation by dendritic cells, which load exogenous antigen onto MHC I to prime CD8 cells, is the notable exception.
| Feature | MHC I | MHC II |
|---|---|---|
| Loci | HLA-A, -B, -C | HLA-DP, -DQ, -DR |
| Expressed on | All nucleated cells + platelets (not mature RBCs) | Professional APCs: dendritic cells, macrophages, B cells |
| Antigen source | Endogenous (viral, tumor, self) | Exogenous (phagocytosed) |
| Structure | One heavy chain + β2-microglobulin | α + β chains |
| Peptide length | ~8–10 residues | Longer |
| Loading | Proteasome → TAP → RER | Invariant chain → CLIP → HLA-DM in endosome |
| T-cell partner | CD8 (cytotoxic) | CD4 (helper) |
The MHC I pathway
Presence everywhere. Because MHC I is on every nucleated cell, CD8 T cells can survey any tissue for intracellular (viral) infection or malignant change. Mature RBCs, lacking nuclei, have no MHC I.
- Cytosolic proteinViral, tumor, or self
- ProteasomeChops it into peptides
- TAPPumps peptides into the RER
- Load onto MHC IHeavy chain + β2-microglobulin
- Golgi → surfaceDisplayed to CD8 T cells
TAP deficiency. TAP (transporter associated with antigen processing) defects cause bare lymphocyte syndrome type I: peptides cannot reach the RER, so surface MHC I is very low and patients have recurrent infections.
Missing self. β2-microglobulin stabilizes MHC I on the surface. A cell without MHC I is invisible to CD8 T cells, which REQUIRE MHC I to recognize antigen, but it becomes a target for NK cells, which kill "missing self." Viruses and tumors that shed MHC I to escape CD8 cells thereby expose themselves to NK killing.
The MHC II pathway
Only professional APCs. MHC II is expressed on dendritic cells, macrophages, and B cells, which take up extracellular antigen and present it to CD4 helper cells.
Invariant chain and CLIP. MHC II is assembled in the RER with the invariant chain (Ii) blocking its groove, which keeps endogenous peptides off MHC II until the molecule reaches the endosome. There, acidification degrades Ii to a small remnant, CLIP, and HLA-DM swaps CLIP for the exogenous peptide.
- MHC II + invariant chainAssembled in RER; groove blocked
- Acidified endosomeInvariant chain degraded to CLIP
- Exogenous peptide arrivesFrom phagocytosed, digested protein
- HLA-DM swaps CLIP for peptidePeptide–MHC II complex forms
- SurfaceDisplayed to CD4 T cells
The two pathways use different gatekeepers: TAP brings peptides to MHC I in the RER; the invariant chain keeps MHC II empty until the endosome, where HLA-DM loads it.
HLA associations: disease and drugs
HLA-B27 and PAIR. HLA-B27 is associated with the seronegative spondyloarthropathies: Psoriatic arthritis, Ankylosing spondylitis, Inflammatory bowel disease–associated arthritis, and Reactive arthritis. A young man with inflammatory back pain, sacroiliitis, and anterior uveitis is the classic B27 patient.
Class II links. HLA-DR3 and DR4 are linked to type 1 diabetes. DR3 is also associated with SLE, Graves disease, Hashimoto thyroiditis, and Addison disease; DR4 with rheumatoid arthritis. HLA-DQ2 and DQ8 are linked to celiac disease; their absence makes celiac disease very unlikely.
| HLA | Associated disease |
|---|---|
| A3 | Hereditary hemochromatosis |
| B27 | Psoriatic arthritis, ankylosing spondylitis, IBD-associated arthritis, reactive arthritis |
| B51 | Behçet disease |
| DQ2 / DQ8 | Celiac disease |
| DR2 | Multiple sclerosis, Goodpasture syndrome, SLE |
| DR3 | Type 1 diabetes, SLE, Graves, Hashimoto, Addison |
| DR4 | Type 1 diabetes, rheumatoid arthritis |
Pharmacogenomic screening. Certain HLA-B alleles predict severe drug hypersensitivity, so screening before prescribing prevents life-threatening reactions.
| Allele | Drug | Reaction |
|---|---|---|
| HLA-B*57:01 | Abacavir | Severe hypersensitivity; screen before prescribing |
| HLA-B*15:02 | Carbamazepine | Stevens-Johnson syndrome (Asian ancestry) |
| HLA-B*58:01 | Allopurinol | Stevens-Johnson syndrome |
HLA in transplantation
Matching. Transplant matching focuses on HLA-A, -B, and -DR — two alleles each, six antigens in all. DR matching matters most for kidney grafts, and better-matched grafts survive longer. ABO compatibility is also required.
Crossmatch. Recipient serum is tested against donor cells before transplant to detect preformed anti-donor HLA antibodies (from prior transfusion, pregnancy, or transplant). A positive crossmatch predicts hyperacute rejection — antibody-mediated graft thrombosis within minutes to hours — so it contraindicates that transplant.
Preformed antibodies cause hyperacute rejection; the crossmatch exists to catch them before surgery.