Toll‐Like Receptor 9 Deficiency Breaks Tolerance to RNA‐Associated Antigens and Up‐Regulates Toll‐Like Receptor 7 Protein in Sle1 Mice

Abstract

ObjectiveToll‐like receptors (TLRs) 7 and 9 are important innate signaling molecules with opposing roles in the development and progression of systemic lupus erythematosus (SLE). While multiple studies support the notion of a dependency on TLR‐7 for disease development, genetic ablation of TLR‐9 results in severe disease with glomerulonephritis (GN) by a largely unknown mechanism. This study was undertaken to examine the suppressive role of TLR‐9 in the development of severe lupus in a mouse model.MethodsWe crossed Sle1 lupus‐prone mice with TLR‐9–deficient mice to generate Sle1 TLR‐9−/− mice. Mice ages 4.5–6.5 months were evaluated for severe autoimmunity by assessing splenomegaly, GN, immune cell populations, autoantibody and total Ig profiles, kidney dendritic cell (DC) function, and TLR‐7 protein expression. Mice ages 8–10 weeks were used for functional B cell studies, Ig profiling, and determination of TLR‐7 expression.Results Sle1 TLR‐9−/− mice developed severe disease similar to TLR‐9–deficient MRL and Nba2 models. Sle1 TLR‐9−/− mouse B cells produced more class‐switched antibodies, and the autoantibody repertoire was skewed toward RNA‐containing antigens. GN in these mice was associated with DC infiltration, and purified Sle1 TLR‐9−/− mouse renal DCs were more efficient at TLR‐7–dependent antigen presentation and expressed higher levels of TLR‐7 protein. Importantly, this increase in TLR‐7 expression occurred prior to disease development, indicating a role in the initiation stages of tissue destruction.ConclusionThe increase in TLR‐7–reactive immune complexes, and the concomitant enhanced expression of their receptor, promotes inflammation and disease in Sle1 TLR9−/− mice.

The role of toll-like receptor 9 (TLR9) in autoimmunity : an examination into the relationship between gut microbiota and TLR9 in Systemic Lupus Erythematosus (SLE)

“…To determine whether antibiotic (Abx) treatment alters the immunological phenotypes in B6 and TLR9-deficient mice, we examined splenic weight, immunological traits in spleen and immunoglobulin (Ig) production in serum. Previous data from the Fairhurst lab has shown that TLR9 -/mice develop mild splenomegaly compared to B6 mice [49]. However, in this study we did not observe an increase in splenic weight.…”

“…However, the period of Abx administration was shortened by 2 months to avoid complications in the experiment from the mortality, observed at 6mos Sle1TLR9 -/mice. Consistent with our previous findings [49], Sle1TLR9 -/developed an increase in splenomegaly compared to Sle1 controls. However, Abx administration did not reduce splenomegaly, in contrast to the findings by Mu Q and colleague in MRL-lpr mice [112] ( Figure 3.2 A).…”

“…We recently published a paper which has also shown that TLR9 deficiency in lupusprone B6.Sle results in severe autoimmunity [49]. [49]).…”

“…Previous data has shown an expansion in the T follicular helper population (Tfh) across multiple lupus-prone strains [49,109]. Furthermore, germinal centre (GC) B cells are increased and myelopoesis is present in NZW and BXSB derivative strains [35,49,110].…”

The Role of Nucleic Acid Sensing in Controlling Microbial and Autoimmune Disorders

“…However, TLR7 signaling was normal in SLE B cells (Gies et al, 2018). Moreover, when lupus-prone Sle1 mice were crossed with TLR9 −/− mice, SLE pathology was exacerbated, and TLR7 expression was increased, leading to increased antigen presentation on DCs (Celhar et al, 2018). Similar results were also observed in TLR9 −/− mice treated epicutaneously with imiquimod, which induces local inflammation, as compared to wild-type mice (Liu et al, 2018).…”