Autoimmune rheumatologic diseases

B Cell Specific TLR9 Modulates Disease in Murine Lupus

Thursday, June 15
3:26 PM - 3:39 PM

The importance of Toll-like receptor (TLR) signaling in lupus is well documented. Despite being a "pro-inflammatory" innate immune receptor, TLR9 deficiency in lupus prone mice exacerbates clinical manifestations including reduced lifespan and more severe nephritis, despite lacking anti-nucleosome (anti-DNA) antibodies; while TLR7 deficiency dominantly ameliorates disease.


The mechanisms by which TLR9 suppresses rather than promotes autoimmunity are unclear. We hypothesized that TLR9 has cell-specific functions. Thus, we created two novel murine strains: a conditional TLR9 knock-out (Tlr9flox)and a conditional TLR9 overexpression allele (rosa26-flox-stop-Tlr9). Both were crossed onto lupus prone backgrounds with a B cell specific (CD19) Cre allele, given the importance of TLR signaling in B cells in lupus, then aged and analyzed for clinical manifestations.


Strikingly, B-cell specific deletion of TLR9 exacerbated disease, similar to the complete knockout, exhibiting increased proteinuria and nephritis (p < 0.05) with loss of anti-nucleosome antibodies (p < 0.001). The B cell specific TLR9 overexpression construct resulted in a 1.8 fold overexpression of TLR9 (p < 0.01) with a concomitant increase in function. This modest TLR9 overexpressed in B cells ameliorated disease in two models of SLE, MRL.Faslpr and B6.Fcgr2b-/-.Yaa,. Both strains exhibited reduced renal disease including proteinuria and nephritis (p < 0.05) without alterations in tested autoantibodies, suggesting that this response may be antibody independent. These data, in which we manipulate TLR9 expression in both directions, indicate B cell expression of TLR9 accounts for a substantial proportion of the known TLR9 regulatory effect. Given its significant ameliorative effect, TLR9 overexpression in B cells alone may represent a potential therapeutic strategy.


Jeremy Tilstra

University of Pittsburgh

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Shinu John

Moderna Therapeutics

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Brady Marburger

University of Pittsburgh

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Sheldon Bastacky

University of Pittsburgh

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Kevin Nickerson

University of Pittsburgh

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Mark Shlomchik

University of Pittsburgh

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