The path ahead for understanding Toll-like receptor-driven systemic autoimmunity

Five mammalian Toll-like receptors (TLR 3, 7, 8, 9, and 13) recognize nucleic acids (NA) and induce signals that control the function of multiple immune cell types and initiate both innate and adaptive immune responses. While these receptors enable recognition of diverse microbial threats, in some instances, they respond inappropriately to self-NA released from host cells and drive the development of autoimmune diseases. Specifically, activation of TLR7 and TLR8 by self-RNA and TLR9 by self-DNA has been linked to development of a collection of systemic autoimmune or autoinflammatory disorders, including systemic lupus erythematosus, systemic juvenile idiopathic arthritis, and macrophage activation syndrome. Here, we discuss recent progress in understanding how these receptors contribute to such diverse clinical phenotypes. We highlight how comparative studies between mice and humans have not only been beneficial in identifying key pathways relevant for disease but also reveal gaps in our understanding of disease mechanisms. We identify several challenges that we hope the field will tackle in the years ahead.