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MHC/HLA and disease association Robbins based md pathology exam answer

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"HLA Antigens"[MeSH Terms] AND "Disease Susceptibility"[MeSH Terms]

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Robbins Basic Pathology HLA disease associations autoimmune disease table HLA

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MHC/HLA and Disease Association

Definition

The major histocompatibility complex (MHC) is a group of genes on the short arm of chromosome 6. In humans it is called the human leukocyte antigen (HLA) complex.
Its main function is to present antigenic peptides to T lymphocytes. Because HLA genes are highly polymorphic, certain alleles can predispose individuals to particular immune-mediated diseases.
  • Class I HLA: HLA-A, HLA-B, HLA-C
    • Present endogenous or cytosolic antigens to CD8+ T cells
    • Present on all nucleated cells
  • Class II HLA: HLA-DP, HLA-DQ, HLA-DR
    • Present extracellularly derived antigens to CD4+ T cells
    • Mainly on antigen-presenting cells
Robbins & Kumar Basic Pathology, pp. 159-160.

Basis of HLA-Disease Association

Most autoimmune diseases are multifactorial and polygenic. HLA alleles are susceptibility genes, not direct causes of disease.
A disease-associated HLA molecule may predispose to autoimmunity by:
  1. Presenting self-peptides efficiently to autoreactive T cells.
  2. Failing to eliminate autoreactive T cells during thymic selection.
  3. Altering immune responses to environmental triggers, especially infections.
  4. Being inherited in linkage disequilibrium with another nearby susceptibility gene.

Important point

  • The presence of an HLA allele does not mean the person will develop disease.
  • Similarly, a person may develop the disease even without that allele.
  • Thus, HLA association indicates increased relative risk, not diagnostic certainty.
For example, HLA-DR4 increases the risk of rheumatoid arthritis about 3-4 fold, whereas HLA-B27 has a very strong association with ankylosing spondylitis, with a relative risk of 100 or more. Robbins & Kumar Basic Pathology, p. 177.

Important HLA-Disease Associations

DiseaseAssociated HLA allele/haplotype
Ankylosing spondylitisHLA-B27
Reactive arthritisHLA-B27
Acute anterior uveitis associated with spondyloarthropathyHLA-B27
Rheumatoid arthritis, especially ACPA-positive RAHLA-DR4
Type 1 diabetes mellitusHLA-DR3, HLA-DR4; HLA-DQ2/DQ8
Systemic lupus erythematosusHLA-DR2, HLA-DR3
Multiple sclerosisHLA-DR2
Celiac diseaseHLA-DQ2, HLA-DQ8
Graves diseaseHLA-DR3
Hashimoto thyroiditisHLA-DR5
Myasthenia gravisHLA-DR3
Goodpasture syndromeHLA-DR2
Pemphigus vulgarisHLA-DR4
PsoriasisHLA-Cw6
Behçet diseaseHLA-B51
NarcolepsyHLA-DQ6

Clinical Significance

  1. Disease susceptibility: HLA typing can indicate genetic predisposition, particularly in ankylosing spondylitis and celiac disease.
  2. Diagnosis support: HLA-B27 supports, but does not establish, a diagnosis of ankylosing spondylitis.
  3. Exclusion value: Absence of HLA-DQ2/DQ8 makes celiac disease very unlikely.
  4. Transplantation: HLA matching reduces graft rejection.
  5. Drug hypersensitivity: Certain HLA alleles predict severe adverse reactions, for example HLA-B*57:01 with abacavir hypersensitivity.

Conclusion

HLA genes influence the nature of antigen presentation and T-cell responses. Their polymorphism explains susceptibility to several autoimmune and inflammatory diseases. However, HLA alleles confer risk only; development of disease also requires other genetic and environmental factors such as infection, inflammation, and breakdown of self-tolerance.
Exam one-liner:
HLA-disease association refers to increased susceptibility to particular autoimmune diseases in individuals carrying specific MHC alleles; the strongest classic association is HLA-B27 with ankylosing spondylitis.
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