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  • Review Article
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HLA associations in inflammatory arthritis: emerging mechanisms and clinical implications

Nature Reviews Rheumatology volume 15, pages 364–381 (2019)Cite this article

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Abstract

Our understanding of the mechanisms underlying HLA associations with inflammatory arthritis continues to evolve. Disease associations have been refined, and interactions of HLA genotype with other genes and environmental risk factors in determining disease risk have been identified. This Review provides basic information on the genetics and molecular function of HLA molecules, as well as general features of HLA associations with disease. Evidence is discussed regarding the various peptide-dependent and peptide-independent mechanisms by which HLA alleles might contribute to the pathogenesis of three types of inflammatory arthritis: rheumatoid arthritis, spondyloarthritis and systemic juvenile idiopathic arthritis. Also discussed are HLA allelic associations that shed light on the genetic heterogeneity of inflammatory arthritides and on the relationships between adult and paediatric forms of arthritis. Clinical implications range from improved diagnosis and outcome prediction to the possibility of using HLA associations in developing personalized strategies for the treatment and prevention of these diseases.

Key points

  • The HLA gene complex is one of the best-studied regions of the human genome, and technical advances continue to deepen our understanding of its associations with inflammatory arthritis.

  • HLA genotypes corroborate distinct clinical and immunological subtypes between patients with the same clinical diagnosis or within the juvenile idiopathic arthritis umbrella.

  • HLA associations are helping to clarify mechanistic overlap between paediatric and adult forms of arthritis.

  • In some rheumatic conditions, potential mechanisms to explain HLA associations are emerging: shared epitope (SE)-dependent neoantigen presentation in anti-citrullinated protein antibody (ACPA)-positive rheumatoid arthritis and HLA-B27 open conformations stimulating innate immune receptors in spondyloarthritis, among others.

  • HLA associations can provide adjuncts to diagnosis and prognosis of rheumatic conditions, and novel therapeutic and preventive approaches might develop from further mechanistic studies of these associations.

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Fig. 1: Organization of the HLA gene region.
Fig. 2: MHC class I and class II proteins: maturation and function.
Fig. 3: Neoantigen formation and presentation in RA.
Fig. 4: Mechanisms of HLA-B*27 association with spondyloarthritis.

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Acknowledgements

E.D.M. was funded by the US National Institutes of Health (NIH) and the Daylight Foundation. R.B. is a past recipient of a Senior Research Fellowship and a Research Progression Award (18543 and 20648, respectively) from Versus Arthritis.

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Authors and Affiliations

  1. Department of Life Sciences, University of Roehampton, Whitelands College, London, UK

    Robert Busch

  2. School of Medicine, Cardiff University, UHW Main Building, Heath Park, Cardiff, UK

    Simon Kollnberger

  3. Department of Pediatrics, Program in Immunology, Stanford University Medical Center, Stanford, CA, USA

    Elizabeth D. Mellins

Authors
  1. Robert Busch
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  2. Simon Kollnberger
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  3. Elizabeth D. Mellins
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The authors contributed equally to all aspects of the article.

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Related links

Epitope prediction software: www.cbs.dtu.dk/services/NetMHCII-2.3

Epitope prediction software for MHC (including HLA) class I: www.cbs.dtu.dk/services/NetMHCcons/

Epitope prediction software for MHC (including HLA) class II: www.cbs.dtu.dk/services/NetMHCIIpan-3.2

Genome-wide SNP database (humans and other species): https://www.ncbi.nlm.nih.gov/projects/SNP/

George D. Snell’s Nobel Lecture: www.nobelprize.org/prizes/medicine/1980/snell/lecture/

HLA-check tool: https://omictools.com/hla-check-tool

HLA system nomenclature: http://hla.alleles.org/nomenclature/naming.html

Immune Epitope Database and Analysis Resource: www.iedb.org

The IPD-IMGT/HLA database: www.ebi.ac.uk/ipd/imgt/hla/

Supplementary information

Glossary

Epistasis

The ability of one gene to influence the effect of another gene on a phenotype (such as the risk of developing a rheumatological condition); also known as gene–gene interactions.

Polymorphisms

Variability, within a population, of a gene or a group of genes. In the HLA region, several types of polymorphism can be distinguished, including polygeny (the existence of multiple gene loci coding for polypeptides with similar functions), the presence of alternative HLA-DRB genes in some HLA-DRB1 haplotypes, and allelic variation.

Haplotypes

A constellation of allelic variants at closely linked loci, which are preferentially or exclusively inherited together owing to linkage disequilibrium.

Linkage disequilibrium

A lack of recombination within a stretch of DNA (relative to recombination frequencies expected on the basis of the length of DNA involved) such that allelic variants contained within that stretch are systematically co-inherited as a haplotype.

Neoantigen

An antigenic peptide that arises from the post-translational modification of a self-protein, thus making it appear foreign or new; the generation of such peptides is a proposed mechanism for breaking self-tolerance.

Polygenic risk scores

Composite scores based on weighted contributions of a large number of allelic variants across the genome to provide greater stratification of risk, especially at the tail ends of the risk distribution.

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Busch, R., Kollnberger, S. & Mellins, E.D. HLA associations in inflammatory arthritis: emerging mechanisms and clinical implications. Nat Rev Rheumatol 15, 364–381 (2019). https://doi.org/10.1038/s41584-019-0219-5

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