Artikel
Receptor expression of angiotensin type 1 and 2 are decreased and correlate with serological titers of NT-proBNP and the FVC/DLCO ratio in patients with systemic sclerosis and pulmonary arterial hypertension
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Veröffentlicht: | 8. Oktober 2019 |
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Background: Previous studies identified functional autoantibodies against the angiotensin receptor type-1 (anti-AT1R aab) and the endothelin receptor type A (anti-ETAR aab) in about 85% of the patients with systemic sclerosis (SSc). The antibodies are cross-reactive, agonistic and functionally active by increasing the effects of the natural ligands as well as by specific activation of the receptors. Antibody titers are associated with clinical findings such as pulmonary arterial hypertension (PAH). Patients with high antibody concentration have a poor prognosis and do not respond well to receptor blocker therapy. In vitro effects of the antibodies are associated with titers and cell types bearing the receptors. Receptor expression of ETAR and AT1R was high in early disease.
Methods: The aim of this study was to determine predictors of PAH and clinical complications by analysing serological titers of anti-AT1R aab and anti-ETAR aab and the extracellular and intracellular expression of AT1R, AT2R, ETAR and ETBR on circulating CD4+
T-cells, CD8+T-cells, CD14+macrophages, CD15+granulocytes and CD19+B-cells in SSc (n=41) using sandwich ELISA and flow cytometry. Clinical data (PAH, history of digital ulcers, digital-ulcers score, mRSS, pulmonary fibrosis, therapy) and serological markers (ESR, CRP, NT-proBNP) were assessed at the time of serum sampling and every 3 months up to 27 months after baseline.
Results: Patients with PAH demonstrated a lower AT1R-MFI and AT1R/AT2R-MFI ratio on all PBMC. AT2R-MFI on T-cells correlated positively with the FVC/DLCO ratio. Levels of NT-proBNP correlated negatively with the AT1R-MFI and AT1R/AT2R-MFI ratio on all PBMC. Anti-AT1R aab titers correlated with the NT-proBNP in SSc patients with NT-proBNP <300pg/ml. AT1R-MFI levels on T-cells, granulocytes and macrophages dissected between groups of patients with pathological and physiological titers of NT-proBNP. Using Log-rank test and Mantel-Cox proportional hazards model, decreased expression of AT1R-MFI on T-cells, granulocytes and macrophages identified trends of deterioration of NT-proBNP over 50%.
Conclusion: Expression of AT1R and AT2R on PBMC could be of diagnostic value identifying clinical progress and/or subgroups in SSc. Their role in the pathophysiology, e.g. their impact of endothelial damage, has to be further investigated in SSc.
Acknowledgment: We thank Actelion Pharmaceutical GmbH for their financial support.