Abstract / Summary
Abstract Mutations in GRN and C9orf72 are common causes of frontotemporal dementia (FTD). While it is well-recognized that GRN or C9orf72 mutations also increase the risk of autoimmune diseases, the intersection of innate and adaptive immunity, neuroinflammation, and neurodegeneration in FTD remains unclear. Here we show that concurrent loss of Grn and C9orf72 breaks immune tolerance by activating the pattern recognition receptor, TLR7, leading to clonal expansion of age-associated B cells and activated B cells. Grn-/-;C9orf72-/- B cells exhibited heightened responses upon TLR7 activation and produced autoantibodies that target the axon guidance receptor Robo3 to promote astroglial pathology. Interestingly, immunization with Robo3 extracellular domain in young Grn-/-;C9orf72-/- mice accelerated astrogliosis. Conversely, TLR7 antagonist M5049 treatment rescued B cell defects, reduced anti-Robo3 autoantibodies, and mitigated astrogliosis and synaptic loss in Grn-/-;C9orf72-/- mice. Together, these results offer critical insights into how TLR7-mediated autoimmune dysfunction targets Robo3 to drive neuroinflammation and neurodegeneration in FTD.