Immune response to dermatomyositis-specific autoantigen, transcriptional intermediary factor 1γ can result in experimental myositis

Objectives To investigate whether autoimmunity to transcriptional intermediary factor 1 (TIF1)gamma, a ubiquitous nuclear autoantigen for myositis-specific autoantibodies detected in patients with dermatomyositis (DM) is pathogenetic for inflammatory myopathy. Methods Wild-type, beta(2)-microglobulin-null, perforin-null, Ig mu-null and interferon alpha/beta receptor (IFNAR)-null mice were immunised with recombinant human TIF1 gamma whole protein. A thymidine incorporation assay was performed using lymph node T cells from TIF1 gamma-immunised mice. Plasma was analysed using immunoprecipitation followed by western blot analysis and enzyme-linked immunosorbent assays. Femoral muscles were histologically and immunohistochemically evaluated. CD8(+) or CD4(+) T cells isolated from lymph node T cells or IgG purified from plasma were adoptively transferred to naive mice. TIF1 gamma-immunised mice were treated with anti-CD8 depleting antibody and a Janus kinase inhibitor, tofacitinib. Results Immunisation with TIF1 gamma-induced experimental myositis presenting with necrosis/atrophy of muscle fibres accompanied by CD8(+) T cell infiltration successfully in wild-type mice, in which TIF1 gamma-specific T cells and antihuman and murine TIF1 gamma IgG antibodies were detected. The incidence and severity of myositis were significantly lower in beta(2)-microglobulin-null, perforin-null, CD8-depleted or IFNAR-null mice, while Ig mu-null mice developed myositis normally. Adoptive transfer of CD8(+) T cells induced myositis in recipients, while transfer of CD4(+) T cells or IgG did not. Treatment with tofacitinib inhibited TIF1 gamma-induced myositis. Conclusions Here we show that TIF1 gamma is immunogenic enough to cause experimental myositis, in which CD8(+) T cells and type I interferons, but not CD4(+) T cells, B cells or antibodies, are required. This murine model would be a tool for understanding the pathologies of DM.

Automated summary

The study investigated the pathogenesis of inflammatory myopathy with autoimmunity to transcriptional intermediary factor 1 (TIF1)gamma, a nuclear autoantigen. Results showed that immunization with TIF1 gamma induced experimental myositis in wild-type mice, while CD8(+) T cells and type I interferons were found to be required for the development of myositis. This murine model could serve as a valuable tool for understanding dermatomyositis pathologies.