Arg Deficiency Does not Influence the Course of Myelin Oligodendrocyte Glycoprotein (MOG35-55)-induced Experimental Autoimmune Encephalomyelitis

Abstract

Background: Inhibition of Abl kinases has an ameliorating effect on the rodent model for multiple sclerosis, experimental autoimmune encephalomyelitis, and arrests lymphocyte activation. The family of Abl kinases consists of the Abl1/Abl and Abl2/Arg tyrosine kinases. While the Abl kinase has been extensively studied in immune activation, roles for Arg are incompletely characterized. To investigate the role for Arg in experimental autoimmune encephalomyelitis, we studied disease development in Arg −/− mice. Methods: Arg −/− and Arg +/+ mice were generated from breeding of Arg +/− mice on the C57BL/6 background. Mice were immunized with the myelin oligodendrocyte glycoprotein (MOG)35–55 peptide and disease development recorded. Lymphocyte phenotypes of wild type Arg +/+ and Arg −/− mice were studied by in vitro stimulation assays and flow cytometry. Results: The breeding of Arg +/+ and Arg −/− mice showed skewing in the frequency of born Arg −/− mice. Loss of Arg function did not affect development of experimental autoimmune encephalomyelitis, but reduced the number of splenic B-cells in Arg −/− mice following immunization with MOG peptide. Conclusions: Development of MOG-induced experimental autoimmune encephalomyelitis is not dependent on Arg, but Arg plays a role for the number of B cells in immunized mice. This might suggest a novel role for the Arg kinase in B-cell trafficking or regulation. Furthermore, the results suggest that Arg is important for normal embryonic development.

B-cells and Inflammation in the Absence of the Abelson Related Gene (Arg)

“…Similar to the B-cell response in the Arg deficient mice, the T-cell response in vitro was not affected in the absence of Arg [14]. Taken together, these and previously reported data suggest that any functional consequences due to the absence of the Arg kinase in B-and T -lymphocyte activation, are rescued by the presence of c-Abl.…”

“…The result was somewhat unexpected because of the previously demonstrated role for the Abl kinases in T-cell signaling and function [15], and we hypothesized that T lymphocyte activation, and thereby the autoimmune response, would be affected in the MOG35-55 immunized Arg -/-mice. In line with the EAE data, in vitro stimulation of T cells from the Arg deficient mice did not show an altered response compared to the Arg +/+ littermates [14]. We therefore concluded that the lack of Arg does not influence T cell activation, neither by MOG(35-55) peptide, mycobacteria, or Pertussis Toxin, which are all included in the induction of EAE, nor by activation of T lymphocytes in vitro.…”

“…This might lead to the assumption that lack of Arg in mature B-cells would give an observable effect upon stimulation of Arg-deficient spleen cells ex vivo. As mentioned above, our data, however, showed that the in vitro proliferative response upon stimulation with anti-IgM or LPS was the same in Arg deficient and Arg sufficient mice [14]. This is in contrast to c-Abl knockout mice, where reduced cell activation and response to anti-IgM in stimulated B-cells was reported [18].…”

“…However, when investigating the B cell population in spleen from MOG(35-55) immunized Arg -/-and Arg +/+ mice, we observed a significant decrease in the relative numbers of B cells in the immunized Arg deficient compared to the non-immunized mice [14]. A number of studies have shown that the Abl kinases are important players in the humoral immune system [16][17][18].…”

“…In a recent article [14], we described the role for Arg in development of Myelin Oligodendrocyte Glycoprotein (MOG35-55)-induced, T-cell dependent experimental autoimmune encephalomyelitis (EAE), a widely used experimental model for multiple sclerosis (MS). We showed that lack of Arg does not change the course of disease compared to disease development in Arg sufficient mice.…”