AB0207 RECEPTOR EXPRESSION OF ANGIOTENSIN TYPE-1 AND 2 ARE DECREASED IN PATIENTS WITH SYSTEMIC SCLEROSIS AND PULMONARY ARTERIAL HYPERTENSION(PAH) AND CORRELATED WITH SEROLOGICAL LEVELS OF NT-PROBNP
Authors: Sebastian Klapa, Silke Pitann, Gabriela Marschner, Susanne Riepe, Andreas Koch, Antje Müller, Harald Heidecke, Peter Lamprecht, Gabriela Riemekasten
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Previous studies identified functional autoantibodies against the angiotensin receptor type-1 (AT1R) and the endothelin receptor type A (ETAR) in about 85% of the patients with systemic sclerosis (SSc, 1). 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 (2, 3). The levels of the antibodies are associated with clinical findings such as pulmonary arterial hypertension (PAH). Patients with highest antibody levels show worst prognosis and do not respond well to receptor blocker therapy (2-4). Several in vitro effects of the antibodies depend on the antibody levels and on the cell type bearing the receptors. Receptor expression of ETAR and AT1R was highest in early disease (3). <h3>Objectives</h3> To determine predictors of PAH, DU and clinical complications by measuring the antibody levels and the receptor expression on peripheral mononuclear cells in patients with systemic sclerosis. <h3>Methods</h3> The current study analyzed the serological levels of anti-AT1R and anti-ETAR antibodies and the extracellular and intracellular expression of AT1R, AT2R, ETAR and ETBR on circulating CD4pos T cells, CD8pos T cells, CD14pos Macrophages, CD15pos Granulocytes and CD19pos 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 gathering at the time of serum sampling and every three-month up to 27month after baseline. <h3>Results</h3> Patients with PAH demonstrated a lower AT1R MFI and AT1R/AT2R MFI ratio on all PBMC. Levels of NT-proBNP correlated negatively with the AT1R MFI and AT1R/AT2R MFI ratio on all PBMC. The levels of anti-AT1R ab correlated with the NT-proBNP in SSc patients with levels of NT-proBNP &lt;300pg/ml. AT1R MFI on T cells, Granulocytes and Macrophages distinguished between pathological and physiological levels 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%. <h3>Conclusion</h3> 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. <h3>References</h3> [1] Riemekasten G. et al., Involvement of functional autoantibodies against vascular receptors in systemic sclerosis. Ann Rheum Dis. 2011Mar;70(3):530-6. [2] Kill A. et al., Autoantibodies to angiotensin and endothelin receptors in systemic sclerosis induce cellular and systemic events associated with disease pathogenesis. Arthritis Res Ther. 2014Jan28;16(1):R29. [3] Becker MO. Et al., Vascular receptor autoantibodies in pulmonary arterial hypertension associated with systemic sclerosis. Am J Respir Crit Care Med. 2014Oct1;190(7):808-17. [4] Günther J. et al., Angiotensin receptor type 1 and endothelin receptor type A on immune cells mediate migration and the expression of IL-8 and CCL18 when stimulated by autoantibodies from systemic sclerosis patients. Arthritis Res Ther. 2014Mar11;16(2):R65. <h3>Acknowledgement</h3> We thank Actelion Pharmaceutical GmbH for their financial support. <h3>Disclosure of Interests</h3> Sebastian Klapa: None declared, Silke Pitann: None declared, Gabriela Marschner: None declared, Susanne Riepe: None declared, Andreas Koch: None declared, Antje Müller: None declared, Harald Heidecke: None declared, Peter Lamprecht: None declared, Gabriela Riemekasten Consultant for: Chugai, F. Hoffmann-La Roche, Speakers bureau: Chugai, F. Hoffmann-La Roche