HLA‐D Region genes associated with autoantibody responses to histidyl‐transfer RNA synthetase (Jo‐1) and other translation‐related factors in myositis

Abstract

Myositis has been associated with HLA-B8 and DR3, especially in white patients with polymyositis and serum anti-Jo-1 antibodies. Twenty-eight patients with myositis and serum translation-related autoantibodies anti-Jo-1, anti-PL-7, anti-PL-12, anti-KJ, and anti-SRP were studied for HLA class I1 specificities by Southern blotting with HLA-DRP, DQP, and D Q a probes. The association of HLA-DR3 (DRwl7) with anti-Jo-1 antibodies in white myositis patients was confirmed (P = 0.003, relative risk 8.9). However, HLA-DRw52 haplotypes, regardless of subtype, were present in all of the white and black patients with serum anti-Jo-1 and other translation-related autoantibodies. Moreover, one anti-Jo-1 positive patient had HLADRw8, an HLA-DRw52 haplotype on which the DRp3 gene has been partially deleted. No HLA-DQ specificity or allele was common to all patients. The HLA-DR3, DRS, DRw6, and DRw8 haplotypes, which bear the HLA-DRw52 specificity, share the most homology in the DRPl first hypervariable region at amino acid positions 9-13. Thus, this DRPl region appears to be the most likely candidate "epitope" for translation-related autoimmune responses in inflammatory myositis.Inflammatory myositis, particularly polymyositis in adults and dermatomyositis in children, has been associated with HLA-B8 and DR3 in white individuals (1,2). In an earlier study using serologic HLA typing (3), the specific subset of myositis patients with serum anti-histidyl-transfer RNA (tRNA) synthetase (antiJo-1) autoantibodies (4) had an even higher frequency of HLA-DR3 than myositis patients overall; all 11 patients with serum anti-Jo-1 antibodies had either HLA-DR3 and/or HLA-DRw6. It was hypothesized that this autoimmune response in myositis may be

Recent advances in the immunogenetics of idiopathic inflammatory myopathy

“…The association of anti-Jo-1 antibodies and alleles comprising the 8.1 haplotype has been confirmed in several studies [11,13,29-31]. This strong relationship between HLA and serological subtype is also present for other MSAs/MAAs, in which antibodies other than anti-Jo-1 are associated with other haplotypes.…”

Proinflammatory Histidyl–Transfer RNA Synthetase–Specific CD4+ T Cells in the Blood and Lungs of Patients With Idiopathic Inflammatory Myopathies

“…In our case, the sequence of the first 60 amino acids of HisRS (UniProtKB identifier P12081) was examined to predict peptides that can bind DRB1*03:01; residues 11-23 (HisRS 11-23 ) contained 2 such motifs and therefore had a high probability of containing a bona fide DRB1*03:01 epitope. Thus, HisRS [11][12][13][14][15][16][17][18][19][20][21][22][23] peptide was selected for further functional assays ( Figure 1A). Immunohistochemistry and histopathology.…”

“…To identify the potential presence of antigen-specific T cells against HisRS in the blood of patients with IIM/antisynthetase syndrome, we assessed the up-regulation of CD40L in CD4+ T cells following stimulation with HisRS protein or HisRS [11][12][13][14][15][16][17][18][19][20][21][22][23] After stimulation of PBMCs with HisRS 11-23 , we detected up-regulation of CD40L on CD4+ T cells in 11 of 14 patients with IIM/antisynthetase syndrome, with a median fold change of 3.4 (IQR 1.87-10.9) relative to unstimulated cells (P = 0.0012). The highest response toward HisRS 11-23 (>10-fold change versus unstimulated cells) was observed in 3 of 11 patients with IIM/ antisynthetase syndrome (2 anti-Jo-1+ and 1 anti-Jo-1−), with a median fold change of 12.75 (IQR 10.9-37) ( Figures 1B and C).…”

“…A, A 13-mer peptide within the first 60 amino acids of HisRS was predicted to represent a potential T cell epitope, HisRS [11][12][13][14][15][16][17][18][19][20][21][22][23] . B, Representative plots from fluorescence-activated cell sorter analysis (gated on lymphocytes and CD4+CD3+ T cells, with exclusion of dead cells and monocytes) show up-regulation of CD40L in CD4+ T cells as well as production of interferon-γ (IFNγ), interleukin-2 (IL-2), and IL-17 on peripheral blood mononuclear cells (PBMCs) from an anti-Jo-1+ patient with IIM/antisynthetase syndrome, in unstimulated (un-stim) conditions or after stimulation with full-length HisRS protein or HisRS [11][12][13][14][15][16][17][18][19][20][21][22][23] . C-E, Up-regulation of CD40L expression was examined on CD4+ T cells in PBMCs from anti-Jo-1+ patients with IIM/antisynthetase syndrome (n = 18) (patients P1-P18 in Table 1) (C), patients with sarcoidosis (n = 6) (D), and HLA-DRB1*03-positive healthy controls (HCs) (n = 12) (E).…”

Brief Report: Association of HLA–DRB1*0101/*0405 with susceptibility to anti–melanoma differentiation–associated gene 5 antibody–positive dermatomyositis in the Japanese population

“…In PM/DM, complication with ILD is associated with the anti-aminoacyl-transfer RNA synthetase (anti-aaRS) antibody or anti-MDA-5 antibody. It has been reported that 90% of Caucasian patients with the anti-aaRS antibody are carriers of HLA-DRB1*03 (7). In the Japanese population, HLA-DRB1*0405 is associated with susceptibility to anti-aaRS antibody-positive PM/DM (8).…”