The exacerbating role of Ras guanyl-releasing protein 1 in idiopathic inflammatory myopathies.

Idiopathic inflammatory myopathies (IIMs) are autoimmune disorders characterized by muscle injury mediated by both T cells and macrophages. Ras guanyl-releasing protein 1 (RasGRP1) is a guanine exchange factor for a small G protein Ras, expressed in immune cells. In this study, we investigated the role of RasGRP1 in IIMs. RasGRP1 was expressed in either CD8+, CD4+ or CD68+ cells in muscles from IIM patients as well as a murine model of myositis, C protein-induced myositis (CIM). RasGRP1 expression was upregulated in activated CD8+ T cells and macrophages in vitro. Response to MHC Class I-restricted stimulation in Rasgrp1-/- CD8+ T cells was impaired. Furthermore, Rasgrp1-/- mice were resistant to CIM. Differentially expressed genes between Rasgrp1-/- and WT mice with CIM were enriched in both adaptive and innate immune responses. These results suggested that RasGRP1 could exacerbate myositis via both T cells and macrophages. RasGRP1 is a possible therapeutic target for IIMs.