ImmunologyTier 1Medical Sciences concept

HLA-disease associations (autoimmune and inflammatory conditions)

Core concept

Class I (A, B, C) - on all nucleated cells, present endogenous peptide to CD8
Class II (DR, DQ, DP) - on APCs, present exogenous peptide to CD4
Association arises because a particular groove binds and presents a specific self- or drug-modified peptide

HLA	Disease
B27	Ankylosing spondylitis (~90%), reactive arthritis, acute anterior uveitis, psoriatic and IBD-related spondyloarthritis
B51	Behcet's disease
B47 / DR3	Congenital adrenal hyperplasia (21-OH)
DR3 (DQ2) and DR4 (DQ8)	Type 1 diabetes - highest risk in the DR3/DR4 heterozygote
DR4 (DRB1 shared epitope)	Rheumatoid arthritis
DQ2 / DQ8	Coeliac disease - necessary but not sufficient
*DR2 (DRB115:01)**	Multiple sclerosis, Goodpasture (anti-GBM)
DR3	SLE, Sjogren's, Graves', myasthenia gravis, autoimmune hepatitis type 1, membranous nephropathy
DR15 / DR4	Idiopathic membranous nephropathy (with PLA2R)
*DQ6 (DQB106:02)**	Narcolepsy type 1 (with hypocretin loss)
A3	Haemochromatosis (linkage disequilibrium with HFE, not causal)

Drug hypersensitivity - where HLA testing changes prescribing

HLA	Drug	Reaction
B57:01*	Abacavir	Hypersensitivity syndrome - testing is mandatory before prescribing; NPV essentially 100%
B15:02*	Carbamazepine (and phenytoin, oxcarbazepine)	SJS/TEN in Han Chinese, Thai, Malay, South Asian populations - test before starting
A31:01*	Carbamazepine	DRESS/hypersensitivity in Europeans and Japanese
B58:01*	Allopurinol	SJS/TEN/DRESS - Han Chinese, Thai, Korean; risk also rises with CKD and starting dose
B57:01*	Flucloxacillin	Drug-induced liver injury
*DRB115:01 / DQA101:02*	Co-amoxiclav, lumiracoxib	DILI
B13:01*	Dapsone	Hypersensitivity syndrome

Three mechanisms of HLA-drug interaction: hapten (covalent binding), p-i concept (direct non-covalent binding to TCR/HLA - abacavir), and altered peptide repertoire (abacavir fills the B*57:01 groove and changes which self-peptides are presented)
Population specificity is central: B15:02 testing is worthwhile in South-East Asian ancestry and pointless in Europeans, where A31:01 is the relevant allele

HLA associations are almost never diagnostic on their own - they shift probability
- B27 is present in 6-8% of white Australians and most are healthy -> a positive result in undifferentiated back pain is weak evidence
- The value is negative: DQ2/DQ8-negative essentially excludes coeliac disease (NPV >99%) - useful when the patient is already gluten-free
*Test B57:01 before abacavir** - Australian standard of care
Allopurinol: start at 50-100 mg/day and titrate regardless of genotype; *consider B58:01 testing in Han Chinese, Thai and Korean patients**
Transplant matching uses HLA-A, -B, -C, -DRB1 (+/- DQB1); donor-specific antibodies cause antibody-mediated rejection
Class I loss is a tumour immune-escape mechanism -> a route to checkpoint inhibitor resistance

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