SN5 SHORT NOTE 5M ★ High-yield

Describe the MHC (HLA) system and transplantation immunology including graft rejection.

Microbiology · 2nd Professional — Para-Clinical

The Major Histocompatibility Complex

The major histocompatibility complex (MHC), called HLA (human leucocyte antigen) in man, is a cluster of genes on the short arm of chromosome 6 encoding cell-surface molecules that present peptide to T lymphocytes.

Feature	Class I	Class II
Loci	HLA-A, HLA-B, HLA-C	HLA-DP, HLA-DQ, HLA-DR
Distribution	All nucleated cells	Antigen-presenting cells only
Presents to	CD8 cytotoxic T cells	CD4 helper T cells
Peptide origin	Endogenous (viral, tumour), via the proteasome	Exogenous, via lysosomes
Structure	One alpha chain with beta2-microglobulin	Alpha and beta chains
Class III region	Encodes complement C2, C4 and factor B, and TNF — not antigen-presenting molecules	—

HLA genes are the most polymorphic in the human genome, with thousands of alleles, which is why finding a matched unrelated donor is difficult
Inherited as a haplotype — a block of closely linked genes inherited together from each parent. Therefore siblings have a 25% chance of being HLA-identical, 50% haploidentical and 25% completely mismatched, which is why siblings are sought first as donors
Co-dominant expression — both parental haplotypes are expressed

CLINICAL PEARL

The polymorphism that makes transplantation difficult is exactly what protects the species. Each HLA molecule binds only certain peptide shapes, so a population with many different alleles will always contain individuals able to present peptides from any new pathogen. Uniform HLA would mean a single organism could evade everyone at once. Graft rejection is the incidental cost of a system that exists to ensure no epidemic can find the whole population defenceless.

Graft Rejection

Type	Timing	Mechanism	Prevention
Hyperacute	Minutes to hours	Pre-formed antibody (from previous transfusion, pregnancy or transplant) against donor ABO or HLA antigens; complement activation and vascular thrombosis. Type II hypersensitivity	ABO matching and cross-matching — entirely preventable, and the graft is lost on the table if it occurs
Acute	Days to months (commonest in the first 6 months)	Chiefly T-cell mediated (type IV) with a cellular infiltrate; may also be antibody-mediated	Immunosuppression; usually reversible with high-dose steroids or antithymocyte globulin
Chronic	Months to years	Progressive fibrosis and obliterative vasculopathy; both immune and non-immune factors	Poorly responsive to treatment — the main cause of late graft loss
Graft-versus-host disease	After bone marrow or stem cell transplant	The graft's immunocompetent T cells attack the immunosuppressed host — the reverse of ordinary rejection; affects skin, gut and liver	Matching, immunosuppression, and irradiation of blood products for at-risk patients

Types of Graft and Investigations

Types of graft — autograft (self to self) and isograft (identical twin) are accepted; allograft (same species) is rejected without immunosuppression and is the usual clinical situation; xenograft (different species) is vigorously rejected. Pre-transplant investigations — ABO grouping (the first and most important), HLA typing by molecular methods, lymphocytotoxicity cross-match between donor cells and recipient serum (a positive result is an absolute contraindication), panel-reactive antibody screening, and mixed lymphocyte reaction (largely historical)
Privileged sites — the cornea, brain, testis and anterior chamber; corneal grafts survive without matching or systemic immunosuppression

Hla and Disease Association

HLA type	Associated disease
HLA-B27	Ankylosing spondylitis (the strongest known association), reactive arthritis, psoriatic arthropathy, acute anterior uveitis
HLA-DR3, DR4	Type 1 diabetes mellitus
HLA-DQ2, DQ8	Coeliac disease
HLA-DR2, DR4	Multiple sclerosis, Goodpasture syndrome, narcolepsy; rheumatoid arthritis
HLA-B*57:01	Abacavir hypersensitivity — testing is mandatory before prescribing
HLA-B*15:02	Carbamazepine-induced Stevens-Johnson syndrome, strongly associated in Indian and South-East Asian populations
HLA-B*58:01	Allopurinol hypersensitivity. Note that association is not causation — most HLA-B27 carriers never develop ankylosing spondylitis

Applied Aspects

ABO compatibility and cross-matching prevent hyperacute rejection, and are non-negotiable; HLA matching improves long-term survival but is not absolutely required for all organs
Test for HLA-B*57:01 before abacavir and HLA-B*15:02 before carbamazepine where available; both predict severe and potentially fatal reactions, and the second is particularly relevant in India
Corneal grafting requires no HLA matching or systemic immunosuppression in most cases, which makes eye donation and corneal transplantation feasible on a large scale — important in India, where corneal blindness is common
The limiting factor in transplantation in India is organ availability rather than immunology; the Transplantation of Human Organs Act governs consent and prohibits commercial dealing, and deceased donation rates remain low
Lifelong immunosuppression carries its own burden — infection, malignancy, nephrotoxicity and diabetes — so the balance between rejection and toxicity is a permanent clinical problem

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