Innate Immune Receptors as Dynamic Modulators of Extrafollicular Autoimmune B Cell Response

The immune system relies on carefully calibrated cellular machineries to enable distinction between endogenous and foreign molecules, with autoimmunity arising when this balance is disrupted. As potent autoantibody factories, B cells are major drivers of many autoimmune diseases. A significant fraction of patients affected by chronic autoimmune diseases such as systemic lupus erythematosus (SLE) exhibit pathogenic accumulation of B-cell subsets that are believed to be derived from the extrafollicular (EF) differentiation pathway. These B-cell subsets, although variously named and exhibiting intrinsic heterogeneity, are all poised producers of autoantibodies that correlate with patient pathophysiology. In addition, they are often characterized by biomarkers known to drive the innate immune response, including toll-like receptors and complement receptors. Although many innate receptors have well-established functions in myeloid cells and other immune cell types, their B cell-specific functions are still under active investigation and are crucial for understanding the molecular pathways that drive B-cell breaks of tolerance. In this review, we summarize studies on innate immune receptors that serve prominent roles in regulating EF B-cell activation in health and autoimmunity. By discussing independent and collaborative functions of these receptors, we hope to provide new perspectives in autoimmune disease signature research.