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Determination of an epitope of the diffuse systemic sclerosis marker antigen DNA topoisomerase I: sequence similarity with retroviral p30gag protein suggests a possible cause for autoimmunity in systemic sclerosis.

ABSTRACT: The possibility that viruses play a role in the etiology of various autoimmune diseases has been proposed. One approach to the search for these agents involves identifying potential crossreactive epitopes in viruses that infect cells of the immune system or of the target tissues. Antibodies to DNA topoisomerase I are the marker autoantibodies for diffuse systemic sclerosis. The major epitope of the antigen was therefore sought through cloning and sequencing of the cDNA for human topoisomerase I and eventually by the synthesis of the smallest possible peptide recognized by sera from patients with the diffuse form of systemic sclerosis. The antigenic 11-amino acid sequence contains 6 sequential amino acids that are identical to a sequence present in the group-specific antigen (p30gag) of some mammalian retroviruses. This sequence is separated by only 1 amino acid from the retroviral epitope sequence that crossreacts with autoantibodies against the marker antigen for mixed connective-tissue disease and systemic lupus erythematosus, the 70-kDa polypeptide of U1 ribonucleoprotein particles. These findings suggest that a retroviral agent may be involved in the pathogenesis of systemic sclerosis and other connective tissue diseases and that antibodies to intracellular antigens are not involved in the pathogenesis of autoimmune disease but may be useful as footprints for tracking the potential etiological agent of autoimmune disease.

SUBMITTER: Maul GG

PROVIDER: S-EPMC298308 | biostudies-other | 1989 Nov

REPOSITORIES: biostudies-other

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Determination of an epitope of the diffuse systemic sclerosis marker antigen DNA topoisomerase I: sequence similarity with retroviral p30gag protein suggests a possible cause for autoimmunity in systemic sclerosis.

Maul G G GG Jimenez S A SA Riggs E E Ziemnicka-Kotula D D

Proceedings of the National Academy of Sciences of the United States of America 19891101 21

The possibility that viruses play a role in the etiology of various autoimmune diseases has been proposed. One approach to the search for these agents involves identifying potential crossreactive epitopes in viruses that infect cells of the immune system or of the target tissues. Antibodies to DNA topoisomerase I are the marker autoantibodies for diffuse systemic sclerosis. The major epitope of the antigen was therefore sought through cloning and sequencing of the cDNA for human topoisomerase I ...[more]

PMID: 2479024

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Project description:BackgroundAbnormalities in lymphocyte surface markers and functions have been described in systemic sclerosis (SSc), but conflicting results abound, and these studies often examined patients with heterogeneous disease duration, severity, clinical phenotype, and concurrent immunosuppressive agents. We studied a clinically homogeneous group of early diffuse cutaneous SSc patients not exposed to immunosuppressive drugs who were enrolled in a clinical trial and compared their immune parameters to healthy control subjects.MethodsLymphocyte subsets were enumerated by multi-parameter flow cytometry of peripheral blood mononuclear cells at baseline visit. Production of the cytokines IL-4 and IL-17 was measured by intracellular flow cytometry following T cell activation.ResultsSSc patients had increased percentages of CD4+ T cells but lower percentages of CD8+ T cells versus controls. The CD28-negative population was expanded in SSc, in the CD4 subset. Striking expansion of CD319+ T cells was noted among the CD4+ cells, in which they were barely detectable in healthy subjects. Frequencies of IL-4 producing cells did not differ between SSc and controls, but expansion of IL-17 producing cells was observed in SSc. A higher proportion of CD319+ cells produced cytokines, compared to other CD4+ cells. Numbers of activated T cells, regulatory T cells, and B cells were similar in SSc and control groups. Circulating follicular helper but not peripheral helper T cells were slightly expanded in SSc.ConclusionIn this carefully selected group of early diffuse cutaneous SSc patients, analysis of immune cell parameters has identified abnormalities that likely reflect disease pathogenesis and that are candidate biomarkers for sub-classification and targeted treatment. The CD4+CD319+ (SLAM-F7+) cells are cytotoxic and oligoclonal, were recently shown to be a dominant T cell population in perivascular lymphocytic infiltrates in SSc skin, actively secrete cytokines, and are emerging as a target for novel treatments of SSc.

Project description:SummaryBackgroundSystemic sclerosis (SSc) is an autoimmune connective tissue disease which affects various tissues and organs, including skin, lungs, kidneys, gastrointestinal tract and cardiovascular system. Cardiac involvement is the most commonly recognized problem and a significant cause of morbidity. The brain natriuretic peptide (BNP) is a previously known marker of elevated cardiovascular risk in SSc, but the levels of BNP in various forms of SSc have not been investigated so far.AimThe aim of our study was to evaluate the influence of SSc on the function of the right ventricle and the right atrium using the echocardiographic parameters. Moreover, we examined the levels of BNP in different forms of SSc as well as the association of disease severity with the plasma concentrations of BNP.MethodsWe included 42 patients with newly diagnosed SSc and patients whose disease had been diagnosed earlier. SSc patients and non-SSc control patients were examined by using echocardiography and the concentrations of BNP were determined.ResultsWe analyzed differences in the parameters of right ventricle (RV) function and right atrium (RA) function between SSc patients and healthy controls. The two groups had similar distribution of gender, but SSc patients were significantly older than controls. RV wall thickness was increased in SSc patients (p<0.001), while right ventricular end-systolic area (RVESA; p=0.408) and right ventricular end-diastolic area (RVEDA; p=0.368) did not differ among the examinees. In contrast, RA minor-axis dimension (p=0.001) and the tricuspid annular plane systolic excursion (TAPSE) (p=0.001) were significantly higher in SSc patients. Also, we analyzed differences in brain natriuretic peptide (BNP) concentrations between diffuse cutaneous systemic sclerosis (DSSc) and limited cutaneous systemic sclerosis (LSSc) patients. DSSc patients had significantly higher concentrations of BNP. We found that levels of BNP were in significant positive correlations with age (p=0.007), disease duration (p=0.023), C reactive protein (CRP) (p=0.032), right ventricle fractional area change (FAC) (p=0.022), pulmonary vascular resistance (PVR) and Rodnan score (p=0.019).ConclusionsGiven the obtained results, the laboratory determination of BNP could be useful in differentiating different forms of systemic sclerosis as well as in predicting the severity of the disease and future cardiovascular complications.

Dataset Information

Determination of an epitope of the diffuse systemic sclerosis marker antigen DNA topoisomerase I: sequence similarity with retroviral p30gag protein suggests a possible cause for autoimmunity in systemic sclerosis.

Publications

Determination of an epitope of the diffuse systemic sclerosis marker antigen DNA topoisomerase I: sequence similarity with retroviral p30gag protein suggests a possible cause for autoimmunity in systemic sclerosis.

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