Functional autoantibodies in systemic sclerosis

Günther, J; Rademacher, Judith; Laar, Jakob M. van; Siegert, Elise; Riemekasten, Gabriela

doi:10.1007/s00281-015-0513-5

Cited by 23 publications

(24 citation statements)

References 110 publications

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“…Mechanistically, a hallmark SSc feature is the presence of high serum concentrations of multiple autoantibodies (129). Among these autoantibodies, increased titers of stimulating autoantibodies targeting both angiotensin II type 1 receptor (AT1R) and endothelin-1 type A receptor (ETAR) have been reported to contribute to SSc pathogenesis and suggested as biomarkers for risk assessment of disease progression (130).…”

Section: Autoantibody-induced Stimulation Of Receptorsmentioning

confidence: 99%

Mechanisms of Autoantibody-Induced Pathology

et al. 2017

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Autoantibodies are frequently observed in healthy individuals. In a minority of these individuals, they lead to manifestation of autoimmune diseases, such as rheumatoid arthritis or Graves' disease. Overall, more than 2.5% of the population is affected by autoantibody-driven autoimmune disease. Pathways leading to autoantibody-induced pathology greatly differ among different diseases, and autoantibodies directed against the same antigen, depending on the targeted epitope, can have diverse effects. To foster knowledge in autoantibody-induced pathology and to encourage development of urgently needed novel therapeutic strategies, we here categorized autoantibodies according to their effects. According to our algorithm, autoantibodies can be classified into the following categories: (1) mimic receptor stimulation, (2) blocking of neural transmission, (3) induction of altered signaling, triggering uncontrolled (4) microthrombosis, (5) cell lysis, (6) neutrophil activation, and (7) induction of inflammation. These mechanisms in relation to disease, as well as principles of autoantibody generation and detection, are reviewed herein.

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Section: Autoantibody-induced Stimulation Of Receptorsmentioning

confidence: 99%

Mechanisms of Autoantibody-Induced Pathology

et al. 2017

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“…Since autoantibodies can be detected in the prodromal phase of AID development, they are potentially useful for detecting treatable early disease [1]. Although some autoimmune serologic markers appear transiently after apparently self-limited infections, immunizations, or injuries, in many situations autoantibodies are also clearly pathogenic [2][3][4][5][6][7][8][9].…”

Section: Introductionmentioning

confidence: 99%

Population-based estimates of humoral autoimmunity from the U.S. National Health and Nutrition Examination Surveys, 1960–2014

2020

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ObjectiveBased on US National Health and Nutrition Examination Survey (NHANES) data, we attempted to provide an unbiased, population-based estimate of autoantibody prevalence overall and by age and sex. MethodsUS autoantibody prevalence estimates for detectable rheumatoid factor, anti-thyroglobulin, anti-thyroperoxidase, anti-transglutaminase, anti-endomysial, anti-GAD65, antinuclear autoantibodies, and autoantibodies to extractable nuclear antigens were estimated from the 1960-1962 National Health Examination Survey, NHANES III (1988, and the NHANES 1999-2014 cross-sectional surveys. Survey design variables and sample weights were used to account for differential probabilities of selection within the complex survey design. Data analysis used SAS TM and SUDAAN™ software. US Census Bureau data were used to estimate the absolute numbers of persons with autoantibodies.

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“…This is also the reason why in the past the use of Topo-I inhibitors for the treatment of SSc patients resulted unsuccessful [47]. With the results of the present study, we assume that anti-Cenp-B and anti-Topo-I antibodies could exert a direct pathogenic role, and therefore, they could be considered “functional antibodies.” In fact, an autoantibody is considered “functional” if its direct interaction with an identified target antigen leads to a molecular pathway activation or inhibition that can be replicated in an experimental setting [48]. Therefore, the results of the present study suggest a new interpretation of the role of anti-Cenp-B and anti-Topo-I antibodies in the disease in terms of disease drivers and not only representing an epiphenomenon and/or useful diagnostic and prognostic tools.…”

Section: Discussionmentioning

confidence: 99%

Antibodies against specific extractable nuclear antigens (ENAs) as diagnostic and prognostic tools and inducers of a profibrotic phenotype in cultured human skin fibroblasts: are they functional?

et al. 2019

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Background: The importance of systemic sclerosis (SSc) autoantibodies for diagnosis has become recognized by their incorporation into the 2013 ACR/EULAR classification criteria. Clear prognostic and phenotypic associations with cutaneous subtype and internal organ involvement have been also described. However, little is known about the potential of autoantibodies to exert a direct pathogenic role in SSc. The aim of the study is to assess the pathogenic capacity of anti-DNA-topoisomerase I (anti-Topo-I) and anti-centromeric protein B (anti-Cenp-B) autoantibodies to induce pro-fibrotic markers in dermal fibroblasts. Methods: Dermal fibroblasts were isolated from unaffected and affected skin samples of (n = 10) limited cutaneous SSc (LcSSc) patients, from affected skin samples of diffuse cutaneous (DcSSc) patients (n = 10) and from healthy subjects (n = 20). Fibroblasts were stimulated with anti-Topo-I, anti-Cenp-B IgGs, and control IgGs in ratios 1:100 and 1:200 for 24 h. Cells were also incubated with 10% SSc anti-Topo-I + and anti-Cenp-B + whole serum and with 10% control serum for 24 h. Viability was assessed by MTT test, while apoptosis was assessed by flow cytometry. Activation of pro-fibrotic genes ACTA2, COL1A1, and TAGLN was evaluated by quantitative real-time PCR (qPCR), while the respective protein levels alpha-smooth-muscle actin (α-SMA), type-I-collagen (Col-I), and transgelin (SM22) were assessed by immunocytochemistry (ICC). Results: MTT showed that anti-Cenp-B/anti-Topo-I IgGs and anti-Cenp-B + /anti-Topo-I + sera reduced viability (in a dilutiondependent manner for IgGs) for all the fibroblast populations. Apoptosis is induced in unaffected LcSSc and control fibroblasts, while affected LcSSc/DcSSc fibroblasts showed apoptosis resistance. Basal mRNA (ACTA2, COL1A1, and TAGLN) and protein (α-SMA, Col-1, and SM22) levels were higher in affected LcSSc/DcSSc fibroblasts compared to LcSSc unaffected and to control ones. Stimulation with anti-Cenp-B/anti-Topo-I IgGs and with anti-Cenp-B + /anti-Topo-I + sera showed a better induction in unaffected LcSSc and control fibroblasts. However, a statistically significant increase of all pro-fibrotic markers is reported also in affected LcSSc/DcSSc fibroblasts upon stimulation with both IgGs and sera. Conclusions: This study suggests a pathogenic role of SSc-specific autoantibodies to directly induce pro-fibrotic activation in human dermal fibroblasts. Therefore, besides the diagnostic and prognostic use of those autoantibodies, these data might further justify the importance of immunosuppressive drugs in the early stages of the autoimmune disease, including SSc.

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Functional autoantibodies in systemic sclerosis

Cited by 23 publications

References 110 publications

Mechanisms of Autoantibody-Induced Pathology

Mechanisms of Autoantibody-Induced Pathology

Population-based estimates of humoral autoimmunity from the U.S. National Health and Nutrition Examination Surveys, 1960–2014

Antibodies against specific extractable nuclear antigens (ENAs) as diagnostic and prognostic tools and inducers of a profibrotic phenotype in cultured human skin fibroblasts: are they functional?

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