Ab0907 high expression levels of type i interferon and ip-10 in anti-mda5 antibody-positive dermatomyositis and its implication in the pathogenesis

Background Dermatomyositis (DM) patients with anti-melanoma differentiation-associated protein 5 (MDA5) antibodies (Ab) are likely to have rapidly progressing interstitial lung disease and a poor prognosis. Thus, it is important to understand the pathogenesis of the disease. Objectives The aim of this study was to identify humoral factor(s) that characterize anti-MDA5 Ab + DM and to analyze the cells that produce these factors. Methods Twenty-eight cytokines in the serum of patients with anti-MDA5 Ab + DM patients were screened and compared with the results of patients with other collagen vascular diseases. We also performed an immunohistochemical analysis of skin rashes (Gottron’s signs) from two patients. Results Serum levels of interferon gamma-induced protein 10 (IP-10, CXCL10), one of CXCR3 chemokines, were significantly higher in anti-MDA5 + DM patients than in SLE and anti-MDA5 Ab - DM patients. Moreover, serum interferon (IFN) α2 levels were also higher in anti-MDA5 + DM patients. After initiation of immunosuppressive therapy, IP-10 and IFN-α2 levels decreased rapidly, whereas those of IFN-γ and CXCL9, another CXCR3 chemokine, did not substantially decrease. Skin samples revealed that the IP-10 positive cells in the dermis were positive for CD68 antigen, a monocyte/macrophage marker. In contrast, they contained a few CD8 + cells and almost no CD4 + cells. We also stimulated monocytes from healthy controls with type I and II IFNs in vitro and demonstrated that IP-10 was produced in the culture supernatant in a dose-dependent manner. Conclusion Our results indicate that IP-10 is highly produced in DM patients with ant-MDA5 Abs. The levels of type I IFN were also high and even exceeded those of SLE. Several reports have shown that not only type II IFN but also type I IFN induces IP-10. Thus, type I IFN/IP-10 axis may play an important role in the pathogenesis of anti-MDA5 Ab + DM. Our immunohistochemical analysis of the skin also revealed that IP-10 released from macrophages may prompt infiltration of macrophages themselves, constituting a positive feedback loop in the skin inflammation. Further analyses are required to prove the usefulness of IP-10 as a disease activity and/or prognostic marker of DM with anti-MDA5 Abs. Reference [1]Kokuzawa A, et al. Clin Exp Rheumatol. 2023 Jan 9. doi: 10.55563/clinexprheumatol/em67zx. Online ahead of print. PMID: 36622131 Acknowledgements: NIL. Disclosure of Interests Kojiro Sato Grant/research support from: Asahi Kasei Pharma, Boehringer-Ingelheim, Teijin Pharma, Tanabe-Mitsubishi, and Chugai, Ayako Kokuzawa: None declared, Jun Nakamura: None declared, Yasuyuki Kamata: None declared.