The importance of the innate immune receptor TLR 9 in the activation



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Lupus is a devastating chronic inflammatory disease of the immune system that affects the skin, joints, kidneys, and other organs. In addition to the need for better clinical treatments of lupus, the study of autoimmune disease is extremely important for its potential in illuminating information about basic immune system function and regulation. The role of innate immune receptor Toll-like receptor (TLR) 9 in lupus is controversial. On one hand, TLR9 is critical for the spontaneous generation of DNA autoantibodies in lupus, yet on the other it is observed to inhibit and down-regulate disease. Interestingly, evidence suggests that autoreactive B cells transition through a unique extrafollicular response instead of a typical germinal center response. We hypothesize TLR9 is involved in this unique developmental pathway. Using transgenic TLR9-/- and wild-type mice we are studying the importance of TLR9 in the autoreactive B cell activation pathway in lupus by investigating the in vitro proliferation of autoreactive cells and the differential expression of surface markers indicative of B cell activation at two days after initiation of disease. We find that this earlier time-point is not useful to studying disease as consistent repeatable results were not obtained. Because of these difficulties we transitioned to an in vivo model using TLR9 inhibitors rather than knockout mice, a system not previously tested. Using this model, we found increased ELISpots in TLR9 inhibited mice (versus wild type mice) as predicted based on previous research indicating elimination of TLR9 exacerbates disease. This finding, however, differs with previous studies using knockout mice showing the opposite, and we hypothesize that our result may be because of TLR9 inhibitions influence on dendritic cells, which may serve a regulatory role in lupus.



Autoimmunity, Lupus, Toll like receptors