HLA associations in inflammatory arthritis: emerging mechanisms and clinical implications

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. We summarise evidence for various peptidedependent 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 pediatric 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. [ED: Some general editorial comments are replied to in the marginal comments. For replies to reviewers, please see the accompanying file.]

Quality control of HLA-DR molecules by the lysosomal aspartyl protease, cathepsin D

“…A possible precedent for the latter mechanism has been found, albeit in the opposite direction: CatD levels were shown to be elevated in the skin of CatL-deficient mice (80). Adaptation to a chronic lack of active CatD might help to explain why previous studies in CatD knockout mice (40) MHCII allelic variation is a major determinant of autoimmune disease risk (22,(81)(82)(83).…”

Immune checkpoint inhibitor–induced inflammatory arthritis as a model of autoimmune arthritis

“…Studies have since shown that, together, SE alleles are associated with more severe RA as well as developing ACPAs . On the other hand, HLA‐DRB1*03, *08 , and other alleles encoding for a DERAA motif in this same position on the HLA‐DRβ chain tend to be associated with seronegative RA . In addition to the MHC locus, SNPs in other genes have also been linked to an increased risk for developing RA in certain ethnic populations.…”

“…The majority of the genetic susceptibility to SpA is attributed to the HLA class I family of HLA‐B27 alleles, especially the HLA‐B*27:02, *27:04, and *27:05 variants . Studies have also found associations with other HLA‐B alleles such as HLA‐B*40:01 and HLA‐B*47:01 , and with the HLA‐A , HLA‐DPB1 , and HLA‐DRB1 loci (reviewed elsewhere ref.…”

“…Studies have also found associations with other HLA‐B alleles such as HLA‐B*40:01 and HLA‐B*47:01 , and with the HLA‐A , HLA‐DPB1 , and HLA‐DRB1 loci (reviewed elsewhere ref. 138). SNPs in genes outside of the MHC locus have also been linked to an increased risk for developing SpA, including those in ERAP1 and IL23R (reviewed elsewhere ref.…”

“…136,137 On the other hand, HLA-DRB1*03, *08, and other alleles encoding for a DERAA motif in this same position on the HLA-DRβ chain tend to be associated with seronegative RA. 138,139 In addition to the MHC locus, SNPs in other genes have also been linked to an increased risk for developing RA in certain ethnic populations. These include PTPN22, IL23R, STAT4, PADI2, and PADI4, among others (reviewed elsewhere ref.…”