Autoimmune host–microbiota interactions at barrier sites and beyond

•Human barrier organs are constitutively colonized by trillions of microorganisms.•The microbiota affects innate and adaptive immune responses locally and systemically.•Microbiota-skewed immune responses induce or exacerbate models of autoimmunity.•Mechanisms may include bystander activation, epitope spread, and crossreactivity.

The microbiota is considered to be an important factor influencing the pathogenesis of autoimmunity at both barrier sites and internal organs. Impinging on innate and adaptive immunity, commensals exert protective or detrimental effects on various autoimmune animal models. Human microbiome studies of autoimmunity remain largely descriptive, but suggest a role for dysbiosis in autoimmune disease. Humanized gnotobiotic approaches have advanced our understanding of immune–commensal interactions, but little is known about the mechanisms in autoimmunity. We propose that, similarly to infectious agents, the microbiota mediates autoimmunity via bystander activation, epitope spread, and, particularly under homeostatic conditions, via crossreactivity. This review presents an overview of the current literature concluding with outstanding questions in this field.