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Abstract Number: 898

B Cell Specific TLR9 Suppresses Disease in Murine Lupus

Jeremy Tilstra1, Rachael Gordon2, Shinu John3, Brady Marburger2, Sheldon Bastacky4, Kevin Nickerson2 and Mark Shlomchik5, 1Rheumatology, Univ of Pittsburgh Medical Center, Pittsburgh, PA, 2University of Pittsburgh, Pittsburgh, PA, 3Moderna Therapeutics, Cambridge, MA, 4Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, 5Immunology, University of Pittsburgh, Pittsburgh, PA

Meeting: 2017 ACR/ARHP Annual Meeting

Date of first publication: September 18, 2017

Keywords: Lupus, nephritis and toll-like receptors

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Session Information

Date: Sunday, November 5, 2017

Title: 2017 Rheumatology Research Foundation Edmond L. Dubois, MD Memorial Lecture

Session Type: ACR Concurrent Abstract Session

Session Time: 4:30PM-6:00PM

Background/Purpose:

Toll-like receptor (TLR) signaling is a central to lupus pathogenesis. GWAS studies have repeatedly identified components of TLR signaling pathway in SLE patients. Furthermore, the endosomal TLRs, 7 and 9, have been implicated in numerous murine models of SLE. Despite being a “pro-inflammatory” innate immune receptor, TLR9 deficiency in lupus prone MRL.Faslpr mice exacerbates clinical manifestations including reduced lifespan and more severe nephritis, despite lacking anti-nucleosome (anti-DNA) antibodies; while TLR7 deficiency dominantly ameliorates disease. Similar regulatory roles for TLR9 have been identified in multiple other lupus models. The mechanisms by which TLR9 suppresses rather than promotes autoimmunity are unclear. We hypothesized that TLR9 has cell-specific functions.

Methods:

We created two novel murine strains: a conditional TLR9 knock-out (Tlr9flox) and a conditional TLR9 overexpression allele (rosa26-flox-stop-Tlr9). These strains were both fully backcrossed onto lupus prone backgrounds MRL.Faslpr (MRL/lpr) and B6.Yaa.FcgR2b-/-. The Tlr9flox allele was crossed several different cre allelles; including CD19-cre (B cell specific), CD11c-cre (DC specific), MRP8-cre (neutrophil specific), and LysM-cre (macrophage and neutrophil targeting) to assess for cell specific roles of TLR9. Cell specific deletion was assessed using cell sorting and qPCR of genomic DNA. These cohorts were analyzed for disease pathology including proteinuria, renal histology, dermatitis, ANA, and immune cell activation.

Results:

Strikingly, of all the strains tested only B-cell specific deletion of TLR9 exacerbated disease, similar to what was observed in the complete knockout, exhibiting increased proteinuria (p<0.05) and nephritis (p<0.05) with loss of anti-DNA antibodies (p<0.001). DC, macrophage and neutrophil cell specific deletion of TLR9 did not result in alteration of pathology. Given the positive results in the B cell specific deletion. We then performed the reciprocal experiment using the TLR9 overexpression allele which results in a 2 fold overexpression of TLR9 in B cells with a concomitant increase in function. When TLR9 was overexpressed only in B cells, we found that disease was ameliorated in two models of SLE, MRL.Faslpr and B6.Fcgr2b-/-.Yaa,. In both models, there was reduced renal disease including proteinuria (p<0.05) and glomerulonephritis (p<0.05); however, there were minimal alterations in tested anti-RNA and anti-DNA autoantibodies.

Conclusion:

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. Additionally we have effectively ruled out a role for TLR9 in numerous other hematopoietic cell types. The data further suggests that anti-DNA antibodies either play no role or are protective in SLE pathogenesis in these murine models, thus going against the conventional wisdom in the field. To our knowledge this is the first data to show that TLR9 overexpression can be protective, and given its significant ameliorative effect, TLR9 overexpression in B cells alone may represent a potential therapeutic strategy.


Disclosure: J. Tilstra, None; R. Gordon, None; S. John, None; B. Marburger, None; S. Bastacky, None; K. Nickerson, None; M. Shlomchik, None.

To cite this abstract in AMA style:

Tilstra J, Gordon R, John S, Marburger B, Bastacky S, Nickerson K, Shlomchik M. B Cell Specific TLR9 Suppresses Disease in Murine Lupus [abstract]. Arthritis Rheumatol. 2017; 69 (suppl 10). https://acrabstracts.org/abstract/b-cell-specific-tlr9-suppresses-disease-in-murine-lupus/. Accessed .
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