Human Leukocyte Antigen (HLA) and its Role in Disease Associations

Key concept: Human leukocyte antigens (HLA) are the human major histocompatibility complex (MHC) molecules. Their genes are located on the short arm of chromosome 6 (6p21.3).HLA molecules display peptide antigens to T lymphocytes, enabling adaptive immune recognition. Genetic variation influences susceptibility to autoimmune disease, responses to infection, drug hypersensitivity and transplant compatibility.

Remember: Class I → CD8; Class II → CD4.

🧬 1. HLA Structure and Genetics

• The HLA region contains many genes involved in immune function.
• HLA genes are highly polymorphic: different alleles bind different peptide sequences.
• HLA alleles are inherited as maternal and paternal haplotypes.
• Both parental sets of HLA genes are expressed (codominant expression).
• Linked HLA alleles may be inherited together because of linkage disequilibrium.

Example of nomenclature: HLA-B*27 denotes an allele group, whereas HLA-B*27:05 identifies a more specific allele. HLA-DRB1*15:01 identifies a particular allele of the DRB1 gene.

Clinical significance: HLA polymorphism allows populations to present a broad range of microbial peptides, but particular alleles can also increase susceptibility to autoimmunity or drug reactions.

📑 2. HLA Classification

Class III: The class III region contains genes encoding immune mediators, including complement components C2, C4 and factor B, and cytokines such as TNF.

Class III products do not function as conventional peptide-presenting HLA molecules.

🛡️ 3. How Antigen Presentation Works

Class I: Endogenous pathway

1. Intracellular proteins, including viral proteins, are degraded by the proteasome.
2. Peptides enter the endoplasmic reticulum through the TAP transporter.
3. Peptides bind HLA class I molecules.
4. The peptide-HLA complex is transported to the cell surface.
5. CD8+ T cells recognise the complex and may destroy the infected cell.

Memory aid: Class I displays what is happening INSIDE the cell to CD8+ T cells.

Class II: Exogenous pathway

1. Extracellular antigens are taken up by antigen-presenting cells.
2. Proteins are degraded in endosomal and lysosomal compartments.
3. HLA class II molecules are assembled with an invariant chain, which prevents premature peptide binding.
4. After invariant-chain processing, HLA-DM facilitates peptide loading.
5. The peptide-HLA complex is presented to CD4+ T cells.

CD4+ T cells subsequently coordinate immune responses, including macrophage activation, B-cell help and cytokine production.

Important exception: Dendritic cells can cross-present extracellular antigens on class I molecules, allowing activation of CD8+ T cells.

⚖️ 4. HLA and Immune Tolerance

T cells recognise antigen only when peptides are presented by appropriate HLA molecules. This is known as MHC restriction.

• Positive selection: In the thymus, developing T cells must recognise self-MHC sufficiently to survive.
• Negative selection: Strongly self-reactive T cells are eliminated or diverted into regulatory lineages.
• Peripheral tolerance: Regulatory T cells, anergy and other mechanisms control self-reactive lymphocytes that escape central tolerance.

HLA-associated autoimmune disease may arise through altered presentation of self-peptides, molecular mimicry, changes in the peptide repertoire or interactions with innate immune receptors.

Clinical pearl: An HLA allele generally changes disease susceptibility rather than directly causing disease. Environmental exposures and other genetic factors influence whether disease develops.

⚡ 5. HLA Associations with Autoimmune Disease

🦴 6. HLA-B27: Ankylosing Spondylitis

HLA-B27 is a class I molecule strongly associated with axial spondyloarthritis, including ankylosing spondylitis.

• Most HLA-B27-positive individuals never develop ankylosing spondylitis.
• Not all patients with axial spondyloarthritis carry HLA-B27.
• Prevalence and diagnostic performance vary between populations.
• The result must be interpreted alongside inflammatory back pain, clinical features and imaging.

NICE: Do not exclude spondyloarthritis solely because HLA-B27 is negative or inflammatory markers are normal.

HLA-B27 is a susceptibility marker, not a diagnostic test in isolation.

The precise pathogenic mechanism remains uncertain. Proposed mechanisms include presentation of arthritogenic peptides, abnormal HLA-B27 folding and interactions with innate immune receptors.

🌾 7. HLA-DQ2/DQ8: Coeliac Disease

Coeliac disease is strongly associated with HLA-DQ2.5, DQ2.2 and DQ8.

These class II molecules present gluten-derived peptides to CD4+ T cells, initiating an inappropriate immune response that damages the small-intestinal mucosa.

• Almost all patients with coeliac disease carry a relevant HLA-DQ genotype.
• These genotypes are also found in many healthy individuals.
• A positive result does not diagnose coeliac disease.
• Absence of the relevant genotypes makes coeliac disease very unlikely.

Clinical application: HLA testing has a high negative predictive value but poor positive predictive value.

NICE does not recommend HLA-DQ2/DQ8 testing as the initial investigation in non-specialist settings.

Initial investigations usually include total IgA and IgA tissue transglutaminase antibodies, while the patient continues to consume gluten.

🍬 8. HLA and Type 1 Diabetes

The strongest genetic susceptibility region for type 1 diabetes is the HLA class II region.

• DR3-DQ2 and DR4-DQ8 haplotypes confer increased susceptibility.
• Some HLA haplotypes are protective.
• The genetic risk reflects altered presentation of pancreatic beta-cell antigens to CD4+ T cells.
• HLA typing is not routinely required to diagnose type 1 diabetes.

Clinical distinction: HLA typing identifies inherited susceptibility, whereas islet autoantibodies provide evidence of an autoimmune response.

💊 9. HLA and Drug Hypersensitivity

Certain HLA alleles influence how drugs or drug-modified peptides interact with immune receptors. This can trigger severe, T-cell-mediated adverse drug reactions.

High-yield pharmacogenomics:

HLA-B*57:01 testing is required before starting abacavir. A positive result contraindicates abacavir.

HLA-B*15:02 and HLA-A*31:01 influence carbamazepine prescribing decisions.

HLA-B*58:01 is an important predictor of severe allopurinol hypersensitivity.

A negative HLA test does not eliminate all risk of adverse drug reactions.

HLA allele frequencies differ between ancestry groups, so testing policies may vary. Clinical decisions should follow current prescribing guidance, relevant pharmacogenetic recommendations and individual patient factors rather than ancestry alone.

🦠 10. HLA and Infectious Diseases

• HLA-B*53: Associated with protection against severe malaria in some West African populations.
• HLA-B*57 and B*27: Certain alleles are associated with improved spontaneous control of HIV infection.
• HLA-B*35: Certain subtypes have been associated with more rapid HIV disease progression.

HLA associations with infection are often population-dependent. They may influence peptide presentation and pathogen-specific T-cell responses but should not be used as stand-alone clinical prognostic tests.

🫀 11. HLA and Transplantation

HLA matching is central to transplantation because recipient T cells and antibodies can recognise donor HLA molecules as foreign.

• Solid-organ transplantation: HLA compatibility and donor-specific antibodies influence rejection risk. The relative importance of matching varies by organ and clinical circumstances.
• Kidney transplantation: HLA matching, antibody screening and donor-specific antibody assessment are important.
• Haematopoietic stem-cell transplantation: High-resolution HLA matching is particularly important because donor immune cells may attack recipient tissues.

Graft-versus-host disease (GVHD): Donor T lymphocytes recognise recipient antigens and damage tissues, particularly skin, gastrointestinal tract and liver.

Rejection: Recipient immune responses against donor tissue can produce cellular or antibody-mediated graft injury.

Clinical pearl: In solid-organ transplantation, the recipient immune system may attack the graft. In GVHD following stem-cell transplantation, donor immune cells attack the recipient.

📊 12. High-Yield HLA Association Table

🎓 13. MLA / MRCP Examination Pearls

1. HLA genes are located on chromosome 6.
2. Class I (A, B, C) presents predominantly intracellular antigens to CD8+ T cells.
3. Class II (DR, DQ, DP) presents predominantly extracellular antigens to CD4+ T cells.
4. Class III encodes immune proteins but does not conventionally present peptides.
5. HLA-B27 is associated with axial spondyloarthritis but is not diagnostic.
6. Negative HLA-DQ2/DQ8 typing makes coeliac disease very unlikely.
7. HLA-DRB1*15:01 is an important multiple sclerosis susceptibility allele.
8. HLA-B*57:01 must be tested before abacavir treatment.
9. HLA-B*15:02 is associated with carbamazepine-induced SJS/TEN.
10. HLA-B*58:01 is associated with severe allopurinol hypersensitivity.

✅ Conclusion

HLA molecules are the immune system's antigen display platform.

They determine which peptides are presented to T cells, influence immune tolerance, contribute to autoimmune disease susceptibility and affect transplant compatibility.

The key clinical distinction: Most HLA-disease associations indicate genetic susceptibility, whereas certain HLA-drug associations can directly guide prescribing and prevent serious adverse reactions.

📖 References

• NICE NG65: Spondyloarthritis in over 16s.
• NICE NG20: Coeliac disease.
• Clinical Pharmacogenetics Implementation Consortium (CPIC): Pharmacogenetic Guidelines.