Background Functional autoantibodies against the angiotensin II receptor type 1 (AT1R) and the endothelin receptor type A (ETAR) have been identified in patients suffering from systemic sclerosis (SSc) .
Objectives Aim of the study was to validateAT1R and ETAR expression in peripheral blood mononuclear cells (PBMCs) and to examine pathological effects mediated through these receptors by the corresponding autoantibodies (Aabs).
Methods Protein expression of AT1R and ETAR on PBMCs from healthy individuals and SSc patients was analyzed using flow cytometry, mRNA expression was examined by real-time PCR in PBMCs from healthy donors. In addition, PBMCs from healthy donors were stimulated in vitro with affinity-purified immunoglobulin G (IgG) from SSc patients positive for AT1R- and ETAR-Aabs, and with IgG from healthy donors serving as control. Alterations in chemotactic motility and cytokine secretion were analyzed using chemotaxis assays and ELISA, respectively. Results were correlated with characteristics/clinical findings of the IgG donors.
Results Both AT1R and ETAR were expressed on human peripheral lymphocytes and monocytes. Protein expression of both receptors was decreased in the tested cohort of SSc patients when compared to healthy donors and correlated negatively with disease duration. In addition, purified IgG from SSc patients induced T cell migration in an anti-AT1R and anti-ETAR Aab level-dependent manner. Moreover, IgG from SSc patients was capable of stimulating PBMCs to produce more IL-8 and CCL18 than IgG from healthy donors. All effects could be significantly abrogated by the application of selective AT1R and ETAR antagonists. Statistical analysis revealed a negative correlation between SSc IgG-induced IL-8 concentrations and disease duration, between SSc IgG-induced CCL18 concentrations and time since onset of lung fibrosis as well as an association of CCL18 concentrations with vascular complications of the corresponding SSc IgG donors.
Conclusions We demonstrated the expression of both, AT1R and ETAR, on human PBMCs, and found a decreased receptor expression on cells from SSc patients suggesting downregulation due to chronic activation. The inflammatory and profibrotic effects upon Aab stimulation in vitro, as shown by T cell migration as well as by the induction of IL-8 and CCL18 secretion, and their associations with clinical findings indicate a role for autoantibody-mediated activation of immune cells mediated through the AT1R and ETAR in the pathogenesis or even the onset of the disease.
Riemekasten et al. Involvement of functional autoantibodies against vascular receptors in systemic sclerosis. Ann Rheum Dis. 2011 Mar;70(3):530-6. doi: 10.1136/ard.2010.135772
Disclosure of Interest None declared