Toll-like receptor 9 suppresses lupus disease in Fas-sufficient MRL Mice

• Published in: PloS one 2017-03, Vol.12 (3), p.e0173471-e0173471
• Main Authors: Nickerson, Kevin M, Wang, Yujuan, Bastacky, Sheldon, Shlomchik, Mark J
• Format: Article
• Language: English
• Subjects: Animal models; Animals; Antigens; Autoantibodies; Autoantibodies - biosynthesis; Autoimmune diseases; Biology and Life Sciences; Care and treatment; Cell activation; Chronic conditions; Clear cell-type renal cell carcinoma; Dendritic cells; Deoxyribonucleic acid; Disease; DNA; fas Receptor - metabolism; Female; Immunology; Leukocytes (neutrophilic); Lupus; Lupus Erythematosus, Systemic - genetics; Lupus Erythematosus, Systemic - immunology; Lupus Erythematosus, Systemic - metabolism; Lymphocytes; Lymphocytes B; Lymphocytes T; Medicine and Health Sciences; Mice; Mice, Inbred MRL lpr; Mortality; Mutation; Pathogenesis; Research and Analysis Methods; Ribonucleic acid; RNA; Rodents; Spleen; Systemic lupus erythematosus; T cell receptors; TLR9 protein; Toll-Like Receptor 9 - deficiency; Toll-Like Receptor 9 - metabolism; Toll-like receptors
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0173471

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.