How to treat monogenic SLE?

Systemic lupus erythematosus is a rare and life-threatening autoimmune disease characterized by autoantibodies against double-stranded DNA, with an immunopathology that remains partially unclear. New insights into the disease have been provided by the discovery of key mutations leading to the development of monogenic SLE, occurring in the context of early-onset disease, syndromic lupus, or familial clustering. The increased frequency of discovering these mutations in recent years, thanks to the advent of genetic screening, has greatly enhanced our understanding of the immunopathogenesis of SLE. These monogenic defects include defective clearance of apoptotic bodies, abnormalities in nucleic acid sensing, activation of the type-I interferon pathway, and the breakdown of tolerance through B or T cell activation or lymphocyte proliferation due to anomalies in TLR signalling and/or NFκB pathway overactivation. The translation of genetic discoveries into therapeutic strategies is presented here, within the framework of personalized therapy.

IFN-γ: An overlooked cytokine in dermatomyositis with anti-MDA5 antibodies.

Dermatomyositis with anti-melanoma differentiation-associated gene 5 antibody (anti-MDA5 DM) is a rare autoimmune disease, often complicated by life-threatening, rapidly progressive interstitial lung disease. Additional manifestations of the disease include skin lesions, vascular abnormalities, joints and muscles pain. Despite its clinical significance, the pathogenesis of anti-MDA5 DM remains largely unknown. Currently, the disease is perceived as driven by type I interferon (IFN) whose expression is increased in most of the patients. Importantly, the regulation of IFN-γ is also altered in anti-MDA5 DM as evidenced by the presence of IFN-γ positive histiocytes in the lungs of patients, and the identification of autoantibodies that directly stimulate the production of IFN-γ by mononuclear cells. This review critically examines the pathogenesis of the disease, shedding light on recent findings that emphasize a potential role of IFN-γ. A novel conceptual framework is proposed, which integrates the molecular mechanisms altering IFN-γ regulation in anti-MDA5 DM with the known functional effects of IFN-γ on key tissues affected during the disease, such as the lungs, skin, and vessels. Understanding the precise role and relevance of IFN-γ in the pathogenesis of the disease will not only enhance the selection of available therapies for anti-MDA5 DM patients but also pave the way for the development of new therapeutic approaches targeting the altered molecular pathways.