Abstract
Genetic deficiency in TLR9 accelerates pathogenesis in the spontaneous polygenic MRL.Faslpr murine model of systemic lupus erythematosus, despite the absence of anti-nucleosome autoantibodies. However, it could be argued that this result was dependent on Fas-deficiency rather than lupus-promoting genes in the MRL genetic background. Here we report the effects of TLR9 deficiency on autoimmune disease independent of the lpr mutation in Fas by characterizing Tlr9-/- and Tlr9+/+ mice on the Fas-intact MRL/+ genetic background. By 30 weeks of age, Tlr9-deficient MRL/+ had more severe renal disease, increased T cell activation, and higher titers of anti-Sm and anti-RNA autoantibodies than Tlr9-intact animals, as had been the case in the MRL.Faslpr model. In addition, Tlr9-deficient MRL/+ mice had increased numbers of germinal center phenotype B cells and an increase in splenic neutrophils and conventional dendritic cell populations. Thus, the disease accelerating effects of Tlr9 deficiency are separable from those mediated by the Fas mutation in the lupus-prone MRL genetic background. Nonetheless, disease acceleration in Tlr9-deficient MRL/+ mice was phenotypically distinct from that in Fas-deficient counterparts, which has important implications.
Highlights
Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by the production of autoantibodies, especially against nucleic acid associated self-antigens
By examining Tlr9 deficiency on the MRL/ + background, we determined that the acceleration of disease observed in the absence of Tlr9 is independent of the Faslpr mutation
MRL.Faslpr mice have lupus-like disease that is polygenically driven, yet the presence of the Fas mutation could have in principle altered the Tlr9-dependency of disease
Summary
Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by the production of autoantibodies, especially against nucleic acid associated self-antigens. Autoreactive B cell receptors are generated at a high frequency as a consequence of V(D)J recombination, and B cells do express TLR7 and TLR9, most individuals do not make significant titers of autoantibodies or progress to end-organ disease due to self-tolerance mechanisms including those that delete, edit or functionally inhibit autoreactive clones prior to entry into the mature B cell repertoire [3,4,5]. SLE in most patients is driven by the additive or synergistic effects of multiple lupus susceptibility alleles that individually confer low disease risk [6]. Animal models of SLE can PLOS ONE | DOI:10.1371/journal.pone.0173471 March 9, 2017
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