Prevalence of auto-antibodies associated to pulmonary arterial hypertension in scleroderma – A review

Nunes, José Pedro L.; Cunha, André Campos da; Meirinhos, T.; Nunes, Alzira; Araújo, Paulo; Godinho, Ana Rita; Vilela, Eduardo; Vaz, Carlos

doi:10.1016/j.autrev.2018.06.009

Cited by 49 publications

(33 citation statements)

References 83 publications

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“…In our study, 19-23% of patients with antibodies to 1 of the 4 components had PH. This finding is similar to the reported prevalence of PH in different SSc cohorts which showed that 33% (63 of 193) of anti-Th/To-positive patients have PH (25).…”

Section: Discussionsupporting

confidence: 91%

Cancer in Systemic Sclerosis: Analysis of Antibodies Against Components of the Th/To Complex

Mecoli

Adler

Yang

et al. 2020

Arthritis & Rheumatology

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Objective The aim of this study is to describe 4 of the most common autoantibodies against components of the Th/To complex: human POP1 (hPOP1), RPP25, RPP30, and RPP40. We report their prevalence and clinical characteristics in a systemic sclerosis (SSc) population, and determine whether these specificities are associated with cancer. Methods A case–control study was performed using data from the Johns Hopkins Scleroderma Center Cohort. A total of 804 adult patients with SSc were included; 401 SSc patients with no history of cancer after at least 5 years of disease were compared to 403 SSc patients who ever had a history of cancer. Antibodies against hPOP1, RPP25, RPP30, and RPP40 were assayed by immunoprecipitation of 35S‐methionine–labeled proteins generated by in vitro transcription/translation. Demographic and clinical characteristics were compared between groups. Results Of 804 patients, 67 (8.3%) had antibodies against any component of the Th/To complex. Patients with antibodies to any component were significantly more likely to have limited cutaneous disease, less likely to have tendon friction rubs, and more likely to have findings consistent with interstitial lung disease or pulmonary hypertension. Patients with antibodies against hPOP1, RPP25, RPP30, and/or RPP40 were significantly less likely to develop cancer within 2 years of SSc onset (0% versus 11% of antibody‐negative patients; P = 0.009). Conclusion SSc patients who produce autoantibodies to components of the Th/To complex have a clinical phenotype characterized by limited cutaneous disease and pulmonary involvement. Our findings show that the presence of any Th/To autoantibody may have a protective effect against contemporaneous cancer.

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Section: Discussionsupporting

confidence: 91%

Cancer in Systemic Sclerosis: Analysis of Antibodies Against Components of the Th/To Complex

Mecoli

Adler

Yang

et al. 2020

Arthritis & Rheumatology

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“…Antigen targets are the most obvious differences. For the patients with IPAH, the antigen targets are exposed in pulmonary vessels, such as Lamin A/C in endothelial cells ( Table 2 ), however, the targets in PAH-CTD are commonly nuclear (identified as antinuclear antibodies) or DNA (identified as anti-double-stranded DNA antibodies) ( 104 ). Then, the inner relationship between auto-antibodies and PAH is different.…”

Section: Discussionmentioning

confidence: 99%

Autoimmunity in Pulmonary Arterial Hypertension: Evidence for Local Immunoglobulin Production

Shu

Xing

Wang

2021

Front. Cardiovasc. Med.

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Pulmonary arterial hypertension (PAH) is a progressive life-threatening disease. The notion that autoimmunity is associated with PAH is widely recognized by the observations that patients with connective tissue diseases or virus infections are more susceptible to PAH. However, growing evidence supports that the patients with idiopathic PAH (IPAH) with no autoimmune diseases also have auto-antibodies. Anti-inflammatory therapy shows less help in decreasing auto-antibodies, therefore, elucidating the process of immunoglobulin production is in great need. Maladaptive immune response in lung tissues is considered implicating in the local auto-antibodies production in patients with IPAH. In this review, we will discuss the specific cell types involved in the lung in situ immune response, the potential auto-antigens, and the contribution of local immunoglobulin production in PAH development, providing a theoretical basis for drug development and precise treatment in patients with PAH.

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“…All these internal organ complications involve the fibroblast as the key effector cell phenotype driving the fibrotic process in SSc [32]: therefore, there must be a direct and/or indirect link between the presence of anti-Cenp-B/anti-Topo-I antibodies and the pro-fibrotic activation of fibroblasts. In literature, there are some hypotheses on how those antibodies could indirectly mediate the fibrotic development in SSc [33, 34]. Among these, the hypothesis that SSc-specific antibodies could trigger the fibrotic development by inducing microvascular alterations and subsequent tissue remodeling is one of the most reliable [35].…”

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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Prevalence of auto-antibodies associated to pulmonary arterial hypertension in scleroderma – A review

Cited by 49 publications

References 83 publications

Cancer in Systemic Sclerosis: Analysis of Antibodies Against Components of the Th/To Complex

Cancer in Systemic Sclerosis: Analysis of Antibodies Against Components of the Th/To Complex

Autoimmunity in Pulmonary Arterial Hypertension: Evidence for Local Immunoglobulin Production

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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