Human Th17- and IgG3-associated autoimmunity induced by a translocating gut pathobiont

Abstract

AbstractExtraintestinal autoimmune diseases are multifactorial with translocating gut pathobionts implicated as instigators and perpetuators in mice. However, the microbial contributions to autoimmunity in humans remain largely unclear, including whether specific pathological human adaptive immune responses are triggered by such pathobionts. We show here that the translocating pathobiontEnterococcus gallinaruminduces human IFNγ+Th17 differentiation and IgG3 subclass switch of anti-E. gallinarumRNA and correlating anti-human RNA autoantibody responses in patients with systemic lupus erythematosus and autoimmune hepatitis. Human Th17 induction byE. gallinarumis cell-contact dependent and involves TLR8-mediated human monocyte activation. In murine gnotobiotic lupus models,E. gallinarumtranslocation triggers IgG3 anti-RNA autoantibody titers that correlate with renal autoimmune pathophysiology and with disease activity in patients. Overall, we define cellular mechanisms of how a translocating pathobiont induces human T- and B-cell-dependent autoimmune responses, providing a framework for developing host- and microbiota-derived biomarkers and targeted therapies in extraintestinal autoimmune diseases.One Sentence SummaryTranslocating pathobiontEnterococcus gallinarumpromotes human Th17 and IgG3 autoantibody responses linked to disease activity in autoimmune patients.