Immunogenetic associations of scleroderma‐related antinuclear antibodies

Objective. To compare the specificity of anti-PMScl autoantibodies in serum samples from 43 patients with myositis, scleroderma, or both.Methods. Anti-PM-Scl immunoprecipitates from HeLa cell extract were used as antigen for immunoblot analyses to determine the antigenic components. A series of complementary DNA fragments was expressed in Escheriehiu coli for immunoblot examination of the reaction with the 100-kd protein.Results. The immunoblot against immunoprecipitates was sensitive and specific for detecting reactions with components of the PM-Scl antigen: 42 of 43 sera (97.7%) reacted with the lOO-kd, 27 of 43 (62.8%) with the 70-kd, and 5 of 43 (11.6%) with the 37-kd protein (not previously recognized as antigenic). Forty-one sera reacted with N-terminal protein S1 (amino acids 11-437), 39 with central protein S2 (amino acids 439-749), and 24 with C-terminal protein S3 (amino acids 750-882). Of 42 sera tested, 28 (66.7%) reacted most strongly with S1, and 6 (14.3%) reacted most strongly with S2. Absorption studies implied additional, conformational epitopes not present on the bacterially expressed antigen.Conclusion. There was an overall similarity in reactivity to the PM-Scl antigen, but there were differences in the reactivity to the 70-kd and 37-kd proteins, as well as in the relative strength of the reactivity to the S2 protein.Anti-PM-Scl autoantibody is strongly associated with a clinical picture marked by overlap of

Section: Results Of Immunoblotting With the Immunoprecipitatessupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

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confidence: 98%

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Analysis of the specificity of anti‐pm‐scl autoantibodies

Gě

Trieu

et al. 1994

“…However, a previous study has suggested that the frequency of HLA-DR7 was increased (12). Anti-PM-Scl was associated with the HLA-DR3, DQ2 haplotype in all instances, as reported in several other studies (29,40,41).…”

Section: Discussionsupporting

confidence: 88%

Interrelationship of major histocompatibility complex class II alleles and autoantibodies in four ethnic groups with various forms of myositis

Arnett

Targoff

Mimori

et al. 1996

156

136

Objective. To examine interrelationships among myositis subsets, autoantibodies, and major histocompatibility complex (MHC) class 1 1 alleles across ethnic lines, and to localize genetic susceptibility (presence of HLA-DR versus DQ) to myositis within the MHC class 1 1 region.Methods. MHC class I1 alleles (HLA-DRBZ, DQM, and DQBI, detected by DNA oligotyping) and myositis-specific autoantibodies (MSA) were determined in 224 patients with various myositis syndromes, including 89 whites, 89 African-Americans, 25 MexicanAmericans, and 21 Japanese.Results. Anti-Jo-1 (histidyl-transfer RNA [tRNA] synthetase) and other MSAs (anti-PL-12, anti-PL-7, anti-OJ, anti-EJ, anti-KJ, anti-tRNA, and antisignal recognition particle) were equally distributed among the races, but occurred more often in patients with polymyositis (PM) than in those with dermatomyositis (DM) or other myositis syndromes. MSA frequencies were significantly positively associated with anti-Ro (SS-A) (P = 0.002), and significantly negatively associated with anti-U1 RNP (P = 0.003). Frequencies of the HLA-DRBI *0301 (DR3), DQAZ*0501, and DQBl*O2OISupported by grants from the Muscular Dystrophy Association, the RGK Foundation, NIH grants R-29AR-39325, AR-32214, and AI-27181, and medical research funds from (DQ2) alleles (and haplotype) were each increased in white patients with myositis, especially those with PM, but most strikingly in those with MSAs. However, in the other ethnic groups, except the Japanese group, only frequencies of HLA-DQAI *0501 and the structurally similar DQAI *0402 alleles were significantly increased. The presence of HLA-D@iI*0501 or *040I was most significantly associated with anti-Jo-1, anti-PLU, and other MSAs, compared with myositis patients without MSAs (P = 0.0008,Pc,, = 0.01, odds ratio [OR] = 3.7), and with normal, ethnically matched controls (P = 3 X lo-', P,,, = 1 x OR = 6.5). Among MSApositive patients who were negative for HLADQAl*O501 and *0401, including Japanese patients, the HLA-D&iI *OI02 and *OI03 alleles predominated. In addition, there appeared to be a negative association of the HLA-DR2 alleles (DRBI*I501 and *1503) with PM (P = 0.007, P,,, not significant, OR = 039), but not with DM or myositis overall.Conclusion. By transracial gene mapping, genetic susceptibility to anti-Jo-1 and other MSAs in patients with myositis can be localized within the MHC region to the HLA-DQ4I locus.Polymyositis (PM) and dermatomyositis (DM) are idiopathic inflammatory myopathies that are characterized clinically by proximal muscle weakness, elevations in the level of serum muscle enzymes, especially creatine kinase (CK), and typical abnormal findings on electromyography. Histopathologic analysis has revealed that affected skeletal muscles are infiltrated by inflammatory mononuclear cells, predominantly CDS+ T lymphocytes, and that those muscles show myofibril degeneration, regeneration, and/or necrosis. Similar clinical and histopathologic features of myositis have been observed in association with malignancies, other connective ti...

HLA and clinical associations in systemic sclerosis patients with anti-Th/To antibodies

Falkner

Wilson

Medsger

et al. 1998

Objective. To determine the clinical and immuno-genetic features of systemic sclerosis (SSc) patients with anti-Th/To autoantibodies. Methods. HLA class I1 alleles were determined by DNA oligotyping in a large group of SSc patients with anticentromere antibodies (ACA), anti-topoisomerase I (anti-top0 I), and anti-Th/To autoantibodies. Results. Clinical features of the 28 anti-Th/To-positive SSc patients were similar to those observed in the 56 ACA-positive SSc patients, except for a decreased frequency of gastrointestinal involvement in anti-Th/ To-positive patients. Immunogenetic analysis revealed a significant increase in the frequency of HLA-DRl1 in the anti-Th/To-positive and the anti-top0 I-positive patients. The anti-Th/To-positive patients also had a significant reduction in the frequency of HLA-DR7, similar to that seen in ACA-positive SSc patients. Conclusion. Despite clinical and immunogenetic similarities with both the ACA-and anti-top0 I-positive patients, anti-Th/To-positive SSc patients present a characteristic pattern of clinical and immunogenetic features that may have implications regarding etiology, pathogenesis, and treatment. Systemic sclerosis (SSc) is a multisystem connective tissue disease of unknown etiology that is thought to have an autoimmune origin. This hypothesis is based on the fact that most SSc patients have circulating antibod-ies to self nuclear proteins and that infiltrates of T lymphocytes are observed in early cutaneous lesions (1).