ImmunologyTier 1Medical Sciences concept

MHC/HLA function in antigen presentation

Core concept

MHC/HLA presents processed peptide to T cells - a T-cell receptor cannot see free antigen, only peptide + MHC (MHC restriction)
Genes on chromosome 6p21, the most polymorphic locus in the genome; codominant, inherited as a haplotype -> 25% chance two siblings are HLA-identical

	Class I	Class II
Loci	HLA-A, -B, -C	HLA-DR, -DQ, -DP
Structure	Polymorphic heavy chain (alpha1-3) + invariant beta-2 microglobulin	Two chains, alpha + beta, both membrane-anchored
Expressed on	All nucleated cells (+ platelets)	Professional APCs only - dendritic cells, macrophages, B cells; also activated endothelium and thymic epithelium
Presents to	CD8+ cytotoxic T cells	CD4+ helper T cells
Peptide source	Endogenous/intracellular - cytosolic proteins, virus, tumour	Exogenous - phagocytosed/endocytosed material
Peptide length	8-10 aa - closed groove, ends anchored	13-25 aa - open groove, peptide overhangs
"Rule of 8"	Class I x CD8 = 8	Class II x CD4 = 8

*Red cells and most neurones do not express HLA* - the reason blood is matched by ABO/Rh, not HLA, and the basis of CNS immune privilege
Leucocytes express HLA densely; platelets carry class I -> anti-HLA alloimmunisation causes platelet refractoriness -> HLA-matched platelets

Class I processing pathway

Cytosolic protein -> ubiquitinated -> proteasome (immunoproteasome in inflamed cells) -> peptide
-> TAP1/TAP2 transports it into the ER
-> loaded onto the class I heavy chain + beta-2 microglobulin with tapasin, calreticulin, ERp57
-> Golgi -> surface
*Beta-2 microglobulin is obligatory for stable surface expression* - loss -> no class I on the cell surface
Cross-presentation - dendritic cells route exogenous antigen into class I -> primes CD8 responses to viruses that do not infect DCs, and to tumours

Class II processing pathway

Endocytosed protein -> endosome/lysosome, cathepsin cleavage
Class II assembled in the ER with the invariant chain (Ii) occupying the groove (prevents premature loading of endogenous peptide)
Ii degraded to CLIP, exchanged for antigenic peptide by HLA-DM (HLA-DO regulates DM)
-> surface
IFN-gamma upregulates both classes, via CIITA for class II
- CIITA or RFX mutations -> bare lymphocyte syndrome type II - absent class II, no CD4 help, a form of combined immunodeficiency
- TAP mutations -> bare lymphocyte syndrome type I

Beta-2 microglobulin as a lab test

Shed from all nucleated cells -> serum level reflects cell turnover and renal clearance
Prognostic in myeloma (ISS staging), CLL and lymphoma; also raised in renal failure and inflammation
Dialysis-related amyloidosis (Abeta2M) - carpal tunnel, shoulder pain, cystic bone lesions

Transplantation - HLA matching (DR > B > A), calculated PRA, virtual and physical crossmatch, donor-specific antibody surveillance
Immune evasion by downregulating class I - many viruses (CMV, HSV, HIV Nef) and tumours
- But "missing self" activates NK cells - the failsafe; hence viruses also encode MHC decoys
Bortezomib targets the proteasome, the first step of the class I pathway - relevant to plasma cell killing and to reducing HLA antibody production in AMR
HLA disease associations (the exam list)
- HLA-B27 - ankylosing spondylitis, reactive arthritis, acute anterior uveitis, IBD-associated
- *HLA-B57:01 - abacavir hypersensitivity** (mandatory screening)
- *HLA-B58:01 - allopurinol SJS/TEN** (Han Chinese, Thai, Korean)
- *HLA-B15:02 - carbamazepine SJS/TEN** (South-East Asian)
- HLA-DQ2/DQ8 - coeliac disease (high sensitivity, poor specificity - useful to exclude)
- HLA-DR3/DR4 - type 1 diabetes; DR3 - SLE, Sjogren, Graves, myasthenia
- HLA-DR15 - Goodpasture, multiple sclerosis; *DQB106:02 - narcolepsy type 1**
- HLA-DRB1 shared epitope - rheumatoid arthritis (anti-CCP positive)
- *HLA-B51 - Behcet**; HLA-A3 - haemochromatosis (historical marker)
Transfusion-related - anti-HLA in donor plasma causes TRALI; leucodepletion reduces alloimmunisation and febrile reactions

3 more sections, plus exam facts

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