Serum level of IFN-λ is elevated in idiopathic inflammatory myopathies.

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Idiopathic inflammatory myopathies (IIM) are a heterogeneous group of autoimmune disorders with uncertain pathogenesis. Interferon (IFN)-λ has recently been described as an important mediator of immune responses. The main purpose of this study is to find out whether IFN-λ is involved in IIM. The published RNA-seq data of dermatomyositis (DM) muscle and IIM double negative (DN) B cells were analyzed. Serum IFN-λ1, IFN-λ2, and IFN-λ3 levels of 59 IIM patients and 29 healthy persons were determined by enzyme-linked immunosorbent assay (ELISA). The proportion of DN B cells and subsets as well as phosphorylated STAT1 (p-STAT1) levels in peripheral B cells was measured by flow cytometry. Ex vivo induction of double negative 2 (DN2) B cells were performed for validation. Type III IFN signaling pathway was enriched in muscle tissue from DM patients. Serum IFN-λ1, IFN-λ2, and IFN-λ3 levels were significantly higher in the IIM patients, especially patients with interstitial lung disease (ILD) and skin manifestations. Moreover, serum IFN-λ1 level was positively correlated with the disease activity. In addition, IIM patients with positive anti-melanoma differentiation-associated gene 5 (anti-MDA5) antibodies exhibited higher serum IFN-λ1, IFN-λ2, and IFN-λ3 levels. The frequency of DN2 B cells were elevated in IIM patients' blood. Interestingly, the type III IFN signaling pathway was enriched in circulating DN2 B cells from IIM patients, which could induce T-bet+CD19hi DN2 B cell differentiation ex vivo. IFN-λ may participate in the pathogenesis of IIM by acting on DN2 B cells and serve as a disease biomarker for IIM patients. Key Points • Type III IFN signaling pathway is enriched in the involved muscles of DM patients. • Serum IFN-λ in IIM patients is correlated with disease activity and is higher in patients with ILD, skin lesions, and positive anti-MDA5 antibodies. • DN2 B cells with enriched type III IFN signaling pathway are accumulated in the peripheral blood of IIM patients.