Distinct HLA associations with autoantibody-defined subgroups in idiopathic inflammatory myopathies

Abstract

Background: In patients with idiopathic inflammatory myopathies (IIM), autoantibodies are associated with specific clinical phenotypes suggesting a pathogenic role of adaptive immunity. We explored if autoantibody profiles are associated with specific HLA genetic variants and clinical manifestations in IIM.

Methods: We included 1348 IIM patients and determined the occurrence of 14 myositis-specific or -associated autoantibodies. We used unsupervised cluster analysis to identify autoantibody-defined subgroups and logistic regression to estimate associations with clinical manifestations, HLA-DRB1, HLA-DQA1, HLA-DQB1 alleles, and amino acids imputed from genetic information of HLA class II and I molecules.

Findings: We identified eight subgroups with the following dominant autoantibodies: anti-Ro52, -U1RNP, -PM/Scl, -Mi2, -Jo1, -Jo1/Ro52, -TIF1γ or negative for all analysed autoantibodies. Associations with HLA-DRB1∗11, HLA-DRB1∗15, HLA-DQA1∗03, and HLA-DQB1∗03 were present in the anti-U1RNP-dominated subgroup. HLA-DRB1∗03, HLA-DQA1∗05, and HLA-DQB1∗02 alleles were overrepresented in the anti-PM/Scl and anti-Jo1/Ro52-dominated subgroups. HLA-DRB1∗16, HLA-DRB1∗07 alleles were most frequent in anti-Mi2 and HLA-DRB1∗01 and HLA-DRB1∗07 alleles in the anti-TIF1γ subgroup. The HLA-DRB1∗13, HLA-DQA1∗01 and HLA-DQB1∗06 alleles were overrepresented in the negative subgroup. Significant signals from variations in class I molecules were detected in the subgroups dominated by anti-Mi2, anti-Jo1/Ro52, anti-TIF1γ, and the negative subgroup.

Interpretation: Distinct HLA class II and I associations were observed for almost all autoantibody-defined subgroups. The associations support autoantibody profiles use for classifying IIM which would likely reflect underlying pathogenic mechanisms better than classifications based on clinical symptoms and/or histopathological features.

Funding: See a detailed list of funding bodies in the Acknowledgements section at the end of the manuscript.

Keywords: Autoantibody; HLA; Idiopathic inflammatory myopathy; Myositis.

Fig. 1

IIM subgroups based on autoantibody profiles, HLA significant associations, and their correspondence to the clinical/pathological subsets. Distribution of the subgroups defined by autoantibody profiles, their HLA associated alleles, amino acids, and clinical/pathological subsets. Clinical/pathological subsets were defined using the EULAR/ACR classification criteria, the Connors et al. definition for ASyS and the presence of another connective tissue disease for OM. In the representation of the HLA amino acids, the first term is the protein, the second is the position, and the third is the amino acid. Only the positive HLA associations are shown. ASyS, anti-synthetase syndrome; IBM, inclusion body myositis; JDM, juvenile dermatomyositis; PM, polymyositis; DM, dermatomyositis; IMNM, Immune-mediated necrotising myositis; OM, overlap myositis. The unspecific clinical subset (UNS) was not included in this figure, given the very low number of patients (n = 4). The JDM subset is included in the DM clinical subset.

Fig. 2

Significant associations of HLA-DQA1, HLA-DQB1, and HLA-DRB1 alleles with autoantibody-defined subgroups. Significant results from the meta-analyses of the different geographical regions (Czech Republic, Scandinavia, UK). Each subgroup was compared to the rest of the cohort. OR, odds ratio; CI, confidence interval; FDR, false discovery rate.

Fig. 3

Significant associations of HLA amino acids with autoantibody-defined IIM subgroups. Manhattan-plot of the meta-analyses of UK and Scandinavia from the imputed amino acids. (a and b) Subgroups in columns and genes in rows. Some amino acids with a FDR<0.01 are labelled, and the red line indicates the significance threshold of 5% FDR (a: Class II; b: Class I). A, alanine; C, cysteine; D, aspartic acid; E, glutamic acid; F, phenylalanine; G, glycine; H, histidine; I, isoleucine; K, lysine; L, leucine; M, methionine; N, asparagine; P, proline; Q, glutamine; S, serine; T, threonine; R, arginine; V, valine; W, tryptophan; Y, tyrosine; OR, odds ratio.

Fig. 4

Representation of suggested mechanisms for autoantibody production in IIM. Different HLA molecules, determined by their genetic variability, influence antigen presentation, T-cell differentiation and proliferation, and B-cells priming, leading to specific autoantibody production in IIM. Based on the expression of particular HLA alleles, distinct autoantibodies are produced. In some cases, this differential expression of MHCII would lead to B-cell priming and production of both myositis-specific autoantibodies (MSA) (ex: anti-Jo1 or anti-MDA5) and myositis-associated autoantibodies (MAA) (ex: anti-Ro52) in the same individual (subgroup 1 or 6). Created with BioRender.com