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• W4283696226 abstract "Background In SSc, autoantibodies (abs) directed against G protein-coupled receptors (GPCR) are prominent and for example induce release of inflammatory and profibrotic proteins by monocytes (1-3). Increased levels of autoantibodies against angiotensin II type 1 receptor (AT1R abs) have been found in patients with renal involvement in systemic sclerosis (SSc) (4-5). The elevated amount of anti-GPCR abs is accompanied by increased secretion of extracellular vesicles (EVs) in SSc (6). The importance of EVs in the pathogenesis is also based on packing and horizontal transfer of AT1R to different tissues and immune cells, exemplary shown by activated cardiomyocytes leading to higher responsiveness to Angiotensin II of recipient cells and vessels (7). Taken together, the relevance of studying anti-GPCR abs together with GPCR-EVs in SSc pathogenesis becomes evident (8). Interestingly, CCL18 is found to be upregulated in SSc patients and suggested to be upregulated by AT1R abs (9), indicating CCL18 and CCR8 cross-talk via EVs plays an essential role in the pathogenesis of SSc. Objectives Unravel the immune response of peripheral blood monocytes mediated by anti-AT1R abs and EVs to gain new insights into the pathomechanism in SSc. Methods Human peripheral blood monocytes of healthy donors were stimulated by the endogenous AT1R ligand angiotensin II as well as by a monoclonal anti-human AT1R ab and, in comparison, by purified IgG from HD (HD IgG) versus those from SSc (SSc IgG). Further, human peripheral blood monocytes of HD were treated with EVs derived from sera of SSc patients versus sera of HD, in the presence or absence of a monoclonal recombinant anti-AT1R ab. Monoclonal AT1R ab has been generated by hybridoma technique, sequenced and recombinantly expressed in HEK cells. The specificity of AT1R abs was tested by using an AT1R blocker (telmisartan, TEL). EVs were isolated from sera by differential centrifugation to exclude large particles and microvesicles and further by one-step polymer precipitation procedure utilising ExoQuick Exosome Precipitation Solution (System Biosciences, Palo Alto, CA) and subsequent purification by size exclusion. Further, primary human peripheral blood monocytes of HD (n=6) were treated with EVs derived from sera of SSc patients (n=6) versus sera of HD (n=6), in the presence or absence of a monoclonal recombinant anti-AT1R ab. The response of the monocytes was measured via CCL18 secretion by ELISA. Results The recombinant monoclonal anti-human AT1R antibody induced secretion of CCL18, a profibrotic cytokine, by primary monocytes derived from HD. Similarly, the purified IgG fractions derived from SSc patients also induced an increased CCL18 release by monocytes compared to IgG fractions derived from HD. Further, complete amelioration of the AT1R ab effect on CCL18 secretion was found, when monocytic AT1R expression was blocked with TEL. In addition, antagonistic effects of Angiotensin II to the monoclonal AT1R ab were observed. In line, enhanced CCL18 secretion of human monocytes stimulated with SSc-EVs alone and together with the monoclonal AT1R ab was induced. Conclusion The secretion of pro-fibrotic CCL18 by human monocytes in response to a monoclonal AT1R antibody as well as to SSc IgG indicates that anti-AT1R abs are involved in the SSc pathogenesis. Further, this effect could also be due to SSc-EVs potentially presenting anti-GPCR abs to their receptors on immune cells. References [1]Cabral-Marques O, et al. Nat Commun. 2018;9(1):5224. [2]Murthy S, et al. Rheumatology (Oxford). 2021;60(6):3012-22. [3]Günther J, et al. Arthritis Res Ther. 2014;16(2):R65. [4]Kill A, Riemekasten G. Curr Rheumatol Rep. 2015;17(5):34. [5]Xia Y, Kellems RE. Circ Res. 2013;113(1):78-87. [6]Guiducci S, et al. Arthritis Rheum. 2008;58(9):2845-53. [7]Pironti G, et al. Circulation. 2015;131(24):2120-30. [8]Kalluri R, LeBleu VS. Science. 2020;367(6478). [9]Prasse A, et al. Arthritis Rheum. 2007;56(5):1685-93. Disclosure of Interests None declared" @default.
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• W4283696226 date "2022-05-23" @default.
• W4283696226 modified "2023-09-26" @default.
• W4283696226 title "AB0137 SERA DERIVED EXTRACELLULAR VESICLES FROM SYTEMIC SCLEROSIS PATIENT AND AUTOANTIBODIES MEDIATE PERIPHAL BLOOD MONOCYTES ACTIVATION" @default.
• W4283696226 doi "https://doi.org/10.1136/annrheumdis-2022-eular.2746" @default.
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