MHC and HLA Molecules
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Direct answer
Major histocompatibility complex (MHC) molecules are cell-surface glycoproteins that display peptide fragments to T cells, and in humans they are called human leukocyte antigen (HLA) molecules. Class I molecules present endogenous peptides to CD8 T cells, while class II molecules present exogenous peptides to CD4 T cells. Certain HLA alleles carry strong disease associations, the classic example being HLA-B27 in ankylosing spondylitis.
What you must remember
- Location: The MHC lies on the short arm of chromosome 6 (6p21), and HLA genes are among the most polymorphic in the human genome.
- Class I structure: A heavy alpha chain with beta-2 microglobulin binds peptides of about 8 to 10 residues, and it is expressed on nearly all nucleated cells.
- Class II structure: Alpha and beta chains form a groove that holds longer peptides, typically 13 to 25 residues, and it is expressed mainly on professional antigen-presenting cells.
- Class I pathway: Cytosolic proteins are degraded by the proteasome and loaded into the endoplasmic reticulum through the TAP transporter.
- Class II pathway: Endocytosed antigen is processed in endosomes, and the invariant chain blocks the groove until HLA-DM swaps in a peptide.
- Class III region: Lies between classes I and II and encodes complement components C2, C4 and factor B, along with TNF.
- Disease associations: HLA-B27 with ankylosing spondylitis, HLA-DQ2 or DQ8 with coeliac disease, and HLA-B*57:01 with abacavir hypersensitivity.
Class I and class II side by side
Both classes display peptides, but they sample different compartments and therefore engage different T-cell subsets. The comparison below covers the features most often tested in exams.
| Feature | Class I | Class II |
|---|---|---|
| Encoding loci | HLA-A, HLA-B, HLA-C | HLA-DR, HLA-DQ, HLA-DP |
| Chains | Heavy alpha chain with beta-2 microglobulin | Alpha and beta chains, both membrane-bound |
| Peptide origin | Cytosolic, endogenous proteins | Endocytosed, exogenous proteins |
| Peptide length | About 8 to 10 residues | About 13 to 25 residues |
| Loading machinery | Proteasome, TAP transporter and tapasin | Invariant chain and HLA-DM |
| Co-receptor | CD8 | CD4 |
| Principal cells | Nearly all nucleated cells | Dendritic cells, macrophages and B cells |
A virus-infected cell is visible to cytotoxic T cells because its class I molecules display viral peptides, so defects in class I expression impair killing of infected cells. Class II displays instead report what an antigen-presenting cell has engulfed and digested. Because the peptide length and co-receptor are the quickest discriminators, memorising them removes most of the confusion in a multiple-choice question.
High-yield viva angles
Most HLA questions test which class is involved and which disease is linked with which allele.
- Trap: Assuming HLA-B27 causes ankylosing spondylitis directly. Correct: It is a strong genetic association rather than a sufficient cause, since most carriers never develop the disease.
- Trap: Placing class II on every nucleated cell. Correct: Class II is restricted mainly to professional antigen-presenting cells, whereas class I is found on nearly all nucleated cells.
- Trap: Linking coeliac disease with HLA-DR. Correct: Coeliac disease is associated with HLA-DQ2 and DQ8, and a negative test for these alleles is useful to exclude it.
Frequently asked questions
Why is HLA-B27 important in medical exams?
HLA-B27 is the classic example of an HLA disease association, linked with ankylosing spondylitis, reactive arthritis and acute anterior uveitis. The association is strong but not deterministic, so most HLA-B27 carriers never develop spondyloarthropathy.
Which MHC class presents peptides to CD8 T cells?
MHC class I presents endogenous peptides, typically 8 to 10 amino acids long, to CD8 cytotoxic T cells. This pathway lets the immune system detect virus-infected or malignant cells that display abnormal proteins.
What is the role of the invariant chain in MHC class II?
The invariant chain, also called CD74, occupies the peptide groove of newly made class II molecules and directs them to endosomes. Cathepsins then trim it to CLIP, and HLA-DM exchanges CLIP for a foreign peptide.
Why are HLA genes important in transplant matching?
HLA genes are highly polymorphic, so mismatch at the HLA-A, HLA-B and HLA-DR loci increases the risk of graft rejection. Matching at these loci improves graft survival and is also used when selecting stem cell donors.
Which HLA allele is screened before starting abacavir?
HLA-B*57:01 is strongly associated with hypersensitivity to abacavir, a nucleoside reverse transcriptase inhibitor used in HIV therapy. Screening for this allele before starting the drug is standard practice, and carriers are generally given an alternative regimen.