TDP-43 pathology links innate and adaptive immunity in amyotrophic lateral sclerosis
Evangelista, B. A.; Ragusa, J. V.; Pellegrino, K.; Wu, Y.; Quiroga-Barber, I.; Cahalan, S. R.; Arooji, O. K.; Madren, J. A.; Schroeter, S.; Cozzarin, J.; Xie, L.; Chen, X.; White, K. K.; Ezzell, J. A.; Iannone, M. A.; Cohen, S.; Traub, R. E.; Li, X.; Bedlack, R.; Phanstiel, D. H.; Meeker, R.; Stanley, N.; Cohen, T. J.
Show abstract
Amyotrophic lateral sclerosis is the most common fatal motor neuron disease. Approximately 90% of ALS patients exhibit pathology of the master RNA regulator, Transactive Response DNA Binding protein (TDP-43). Despite the prevalence TDP-43 pathology in ALS motor neurons, recent findings suggest immune dysfunction is a determinant of disease progression in patients. Whether TDP-43 pathology elicits disease-modifying immune responses in ALS remains underexplored. In this study, we demonstrate that TDP-43 pathology is internalized by antigen presenting cells, causes vesicle rupture, and leads to innate and adaptive immune cell activation. Using a multiplex imaging platform, we observed interactions between innate and adaptive immune cells near TDP-43 pathological lesions in ALS brain. We used a mass cytometry-based whole-blood stimulation assay to provide evidence that ALS patient peripheral immune cells exhibit responses to TDP-43 aggregates. Taken together, this study provides a novel link between TDP-43 pathology and ALS immune dysfunction, and further highlights the translational and diagnostic implications of monitoring and manipulating the ALS immune response.
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