Role of TLR9 in Anti-Nucleosome and Anti-DNA Antibody Production in lpr Mutation-Induced Murine Lupus

Abstract

Systemic lupus erythematosus is characterized by the production of autoantibodies directed against nuclear Ags, including nucleosome and DNA. TLR9 is thought to play a role in the production of these autoantibodies through the capacity of nuclear immunogenic particles to interact both with BCR and TLR9. To determine the role of TLR9 in SLE, C57BL/6-lpr/lpr-TLR9−/− and TLR9+/+ mice were analyzed. The abrogation of TLR9 totally impaired the production of anti-nucleosome Abs, whereas no difference was observed in the frequency of anti-dsDNA autoantibodies whose titer was strikingly higher in TLR9−/− mice. In addition a higher rate of mesangial proliferation was observed in the kidney of TLR9-deficient animals. These results indicate that in C57BL/6-lpr/lpr mice, TLR9 is absolutely required for the anti-nucleosome Ab response but not for anti-dsDNA Ab production which is involved in mesangial proliferation.

A tolerogenic role for Toll-like receptor 9 is revealed by B-cell interaction with DNA complexes expressed on apoptotic cells

“…Treatment of mice with CpG to stimulate TLR9 has alleviated disease severity in colitis, arthritis, and diabetes (50)(51)(52)(53). In addition, lupus-related renal disease is exacerbated in TLR9-deficient autoimmune prone mice (20)(21)(22)(23), and recent reports suggest that TLR9 is required to prevent pathological responses that result from TLR7-mediated signaling (24,25). Other studies, however, show that TLR9 stimulation has an adjuvant effect driving Th1 responses allied with IgG2a antibodies, thereby potentially exacerbating autoimmune disease (19,(54)(55)(56)(57).…”

“…The BCR can deliver chromatin complexes from the AC to the endosome, allowing Toll-like receptor 9 (TLR9)-mediated signaling (18,19). Despite this, lupus-related renal disease is exacerbated in TLR9-deficient mice (20)(21)(22)(23), suggesting a regulatory role for TLR9-induced activation of self-reactive B cells in health that breaks down when tolerance is lost, leading to autoimmunity (24,25).…”

Critical Role of TLR2 and TLR4 in Autoantibody Production and Glomerulonephritis in lpr Mutation-Induced Mouse Lupus

“…Indeed, the reactivity of sera from B6 lpr/lpr -Tlr4-deficient mice was strongly decreased against both Gram-positive and Gram-negative bacterial extracts. Thus, the absence of a second signal may explain, on the one hand, the decreased production of anti-DNA and anti-CL Abs and, on the other hand, the unchanged anti-nucleosome autoantibody response considered to be dependent on either the presence of T cell clones specific for nucleosome (42) or TLR9 signaling (20,21).…”

“…In lupus, several reports have focused on the role of TLRs which recognize nucleic acids including TLR3, 7, and 9 (19,20) and demonstrated that their engagement participates in the induction of antinuclear autoantibodies. Recently, using the C57BL/6 lpr/lpr model, we demonstrated that TLR9 is basically required for production of anti-nucleosome Abs (21). Significantly, TLR9-deficient mice presented a more severe disease, suggesting that TLR9 engagement may have a protective role, possibly through the induction of autoantibodies participating in the clearance of apoptotic cell products known to initiate and propagate the disease (20).…”

Endosomal TLR signaling is required for anti-nucleic acid and rheumatoid factor autoantibodies in lupus

“…In MRL-Fas lpr mice, lack of TLR9 had different effects on anti-nuclear Ab specificity in different studies, yet overall disease was inexplicably exacerbated (10)(11)(12). TLR9-deficiency also enhanced disease in MRLFas wt (11), B6-Fas lpr (13), and mutant Plcg2 ϩ/Ali5 mice (14). In striking contrast, lupus-prone Fc␥RIIB Ϫ/Ϫ mice expressing a high-affinity anti-DNA transgene had reduced disease (15), although this may be related to dependence on a single transgenic anti-DNA specificity.…”