Intracellular virus sensor MDA5 mutation develops autoimmune myocarditis and nephritis.

Mutations in IFIH1 gene encoding viral RNA sensor MDA5 have been reported responsible for many interferonopathies, including Aicardi-Goutières syndrome (AGS) and monogenic lupus, however, the pathological link between IFIH1 mutations and various autoimmune symptoms remains unclear. Here, we generated transgenic mice expressing human MDA5 R779H mutant (R779H Tg), reported in AGS and monogenic lupus patient. Mice spontaneously developed myocarditis and nephritis with upregulation of type I IFNs in the major organs. R779H Tg Mavs-/- and R779H Tg Ifnar-/- showed no phenotypes, indicating direct MDA5-signaling pathway involvement. Rag-2 deficiency and bone marrow cells transfer from wild type to adult mice did not prevent myocarditis development, while mice with cardiomyocyte-specific expression of hMDA5 R779H showed cardiomegaly and high expression of inflammatory cytokines. Taken together, our study clarifies that type I IFNs production and chemokines from cardiomyocytes starts in neonatal period and is critical for the development of myocarditis. Activated lymphocytes and auto-antibodies exacerbate the pathogenesis but are dispensable for the onset.

Concurrent Takayasu Arteritis and Vascular Ehlers-Danlos Syndrome: A Case Report.

Takayasu arteritis (TAK) is a rare primary systemic inflammatory vasculopathy. It is classified as a large-vessel vasculitis and is known to cause inflammatory aneurysms and vascular stenosis. Vascular Ehlers-Danlos syndrome (vEDS) is an autosomal dominant condition known to cause multiple aneurysms and arterial dissection at a young age owing to a mutation in the gene for type III collagen, COL3A1. Here, we present a case of TAK associated with vEDS with the development of multi-organ infarction of the brain, kidney, and spleen owing to multiple arterial aneurysms and stenosis of the internal carotid artery. The patient was successfully treated using anti-inflammatory agents, glucocorticoids, and tocilizumab with the addition of interventional radiology. In our case, a high inflammatory response led to vasculitis being the main cause of the disease with concurrent vEDS. When patients develop multiple aneurysms, stenosis, and dissections leading to multiple organ infarctions, a systemic differential diagnosis to consider concurrent vasculitis syndrome and non-inflammatory vasculopathy, including hereditary disorders, is important even with time constraints.