Background/Purpose:

G protein-coupled receptors (GPCRs) are a family of integral membrane proteins mediating cell trafficking and cellular homeostasis. In the last decades, several functional autoantibodies (ab) against GPCR have been described to be involved in the pathogenesis of various diseases including systemic sclerosis. As suggested by our studies for the autoantibodies against angiotensin and endothelin receptors, anti-GPCR ab may also be present in healthy individuals. However; the role of autoantibodies in physiology is under debate.

Methods:

Antibodies against 10 different GPCR were analysed in 198 healthy donors, 249 patients with SLE, 376 patients with SSc, 47 patients with rheumatoid arthritis, and 128 patients with granulomatosis with polyangiitis (GPA) by ELISA. In patients with SSc, we also have analysed the ab levels against 31 targets including GPCR, growth factors, and signalling molecules. Possible functional interactions of the 31 autoantibody target molecules were studied by STRING, DAVID, and enriched Gene Ontology. Migration assays were performed as well as cell culture experiments stimulating PBMC with IgG from healthy donors. C56Bl/6 mice were immunized with ETAR and the cellular homeostasis was studied by flow cytometry, histology, and compared with the ab levels against anti-ETAR ab.

Results: The detection of antibodies against 10 different GPCR revealed either increased or decreased antibody levels in a disease-specific manner when compared to healthy donors. Antibodies against ETAR were increased in patients with SSc and SLE and decreased in patients with GPA. In addition to the disease-specific ab signatures, we identified SSc-specific correlations between the 31 target antibodies. Possible functional interactions of the 31 autoantibody revealed a network of GPCR, growth factors, and signalling molecules with endothelin receptor type A (ETAR) in the centre. Migration and locomotion were suggested to be the most significant functions regulated by an assumed antibody network. Accordingly, IgG from healthy donors induced both IL-8 expression in PBMC as well as, depending on the anti-ETAR ab levels, migration of neutrophils and lymphocytes, which was specifically diminished by the ETAR blocker sitaxentan. In vivo, increased anti-ETAR ab levels were associated with an altered homeostasis of innate and adaptive immune cells in different tissues.

Conclusion: As indicated for anti-ETAR antibodies, anti-GPCR antibodies reveal physiological levels in healthy donors and specific alterations in different autoimmune diseases. The antibodies are involved in the homeostasis of immune cells and could contribute to disease pathogenesis.

« Back to 2017 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/physiological-autoantibodies-against-the-endthelin-receptor-type-a-are-critically-involved-in-the-homeostasis-of-immune-cells/