HLA associations in inflammatory arthritis: emerging mechanisms and clinical implications

• Published in: Nature reviews. Rheumatology 2019-06, Vol.15 (6), p.364-381
• Main Authors: Busch, Robert, Kollnberger, Simon, Mellins, Elizabeth D.
• Format: Article
• Language: English
• Subjects: 631/250/21; 692/4023/1670/2766; 692/4023/1670/427/1304; 692/4023/1670/498; 692/420/2780; Antigen presentation; Arthritis; Arthritis - etiology; Arthritis - genetics; Care and treatment; Citrulline; Development and progression; Diagnosis; Gene expression; Genetic aspects; Genomes; Genotypes; Health aspects; Histocompatibility antigen HLA; Histocompatibility antigens; HLA Antigens - genetics; HLA Antigens - physiology; HLA histocompatibility antigens; Humans; Inflammation; Inflammation - etiology; Inflammation - genetics; Inflammatory diseases; Medicine; Medicine & Public Health; Peptides; Review Article; Rheumatic diseases; Rheumatoid arthritis; Rheumatology; Risk factors
• ISSN: 1759-4790; 1759-4804
• DOI: 10.1038/s41584-019-0219-5

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. The HLA region is strongly associated with many rheumatic diseases, including inflammatory arthritis. In this Review, potential mechanisms underpinning these associations are discussed, as are the clinical implications of HLA associations for the diagnosis and treatment 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.