Host barriers such as the skin, the lung mucosa, the intestinal mucosa and the oral cavity are crucial at preventing contact with potential threats and are populated by a diverse population of innate and adaptive immune cells. Alterations in antigen recognition driven by genetic and environmental factors can lead to autoimmune systemic diseases such rheumatoid arthritis, systemic lupus erythematosus and food allergy. Here we review how different immune cells residing at epithelial barriers, host-derived signals and environmental signals are involved in the initiation and progression of autoimmune responses in these diseases. We discuss how regulation of innate responses at these barriers and the influence of environmental factors such as the microbiota can affect the susceptibility to develop local and systemic autoimmune responses particularly in the cases of food allergy, systemic lupus erythematosus and rheumatoid arthritis. Induction of pathogenic autoreactive immune responses at host barriers in these diseases can contribute to the initiation and progression of their pathogenesis.