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

Abstract

OBJECTIVES:

To investigate whether autoimmunity to transcriptional intermediary factor 1 (TIF1)γ, a ubiquitous nuclear autoantigen for myositis-specific autoantibodies detected in patients with dermatomyositis (DM) is pathogenetic for inflammatory myopathy.

METHODS:

Wild-type, β2-microglobulin-null, perforin-null, Igμ-null and interferon α/β receptor (IFNAR)-null mice were immunised with recombinant human TIF1γ whole protein. A thymidine incorporation assay was performed using lymph node T cells from TIF1γ-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 naïve mice. TIF1γ-immunised mice were treated with anti-CD8 depleting antibody and a Janus kinase inhibitor, tofacitinib.

RESULTS:

Immunisation with TIF1γ-induced experimental myositis presenting with necrosis/atrophy of muscle fibres accompanied by CD8+ T cell infiltration successfully in wild-type mice, in which TIF1γ-specific T cells and antihuman and murine TIF1γ IgG antibodies were detected. The incidence and severity of myositis were significantly lower in β₂-microglobulin-null, perforin-null, CD8-depleted or IFNAR-null mice, while Igμ-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 TIF1γ-induced myositis.

CONCLUSIONS:

Here we show that TIF1γ 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.

• Authors: Naoko Okiyama, Yuki Ichimura, Miwako Shobo, Ryota Tanaka, Noriko Kubota, Akimasa Saito, Yosuke Ishitsuka, Rei Watanabe, Yasuhiro Fujisawa, Yoshiyuki Nakamura, Akihiro Murakami, Hisako Kayama, Kiyoshi Takeda, Manabu Fujimoto
• Journal: Annals of the rheumatic diseases (Ann Rheum Dis) Vol. 80 Issue 9 Pg. 1201-1208 (09 2021) ISSN: 1468-2060 [Electronic] England
• PMID: 33811031 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.

Chemical References

• Immunoglobulin G
• Immunoglobulin mu-Chains
• Janus Kinase Inhibitors
• Piperidines
• Pyrimidines
• TRIM33 protein, human
• Transcription Factors
• Trim33 protein, mouse
• beta 2-Microglobulin
• Perforin
• Receptor, Interferon alpha-beta
• tofacitinib

Topics

• Adoptive Transfer
• Animals
• CD4-Positive T-Lymphocytes (immunology, transplantation)
• CD8-Positive T-Lymphocytes (immunology, transplantation)
• Dermatomyositis (immunology)
• Disease Models, Animal
• Humans
• Immunization
• Immunoglobulin G (immunology)
• Immunoglobulin mu-Chains (genetics)
• Janus Kinase Inhibitors (pharmacology)
• Mice
• Mice, Knockout
• Nervous System Autoimmune Disease, Experimental (immunology)
• Perforin (genetics)
• Piperidines (pharmacology)
• Pyrimidines (pharmacology)
• Receptor, Interferon alpha-beta (genetics)
• T-Lymphocytes (immunology)
• Transcription Factors (immunology)
• beta 2-Microglobulin (genetics)