IL‐21 promotes the production of anti‐DNA IgG but is dispensable for kidney damage in lyn −/− mice

The intracellular tyrosine kinase Lyn mediates inhibitory receptor function in B cells and myeloid cells, and Lyn−/− mice spontaneously develop an autoimmune and inflammatory disease that closely resembles human systemic lupus erythematosus. TLR signaling pathways have been implicated in the production of anti-nuclear antibodies in SLE and mouse models of it. We used a conditional allele of Myd88 to determine whether the autoimmunity of Lyn−/− mice is dependent on TLR/MyD88 signaling in B cells and/or in dendritic cells (DCs). The production of IgG anti-nuclear antibodies, as well as the deposition of these antibodies in the glomeruli of the kidneys, leading to glomerulonephritis in Lyn−/− mice were completely abolished by selective deletion of Myd88 in B cells and the autoantibody production and glomerulonepritis were delayed or decreased by deletion of Myd88 in DCs. The reduced autoantibody production in mice lacking MyD88 in B cells or DCs was accompanied by a dramatic decrease of the spontaneous germinal center (GC) response, suggesting that autoantibodies in Lyn−/− mice may depend on GC responses. Consistent with this view, IgG anti-nuclear antibodies were absent if T cells were deleted (TCRβ−/− TCRδ−/− mice) or if T cells were unable to contribute to GC responses due to mutation of the adaptor molecule SAP. Thus, the autoimmunity of Lyn−/− mice was dependent on T cells and on TLR/MyD88 signaling in B cells and in DCs, supporting a model whereby DC hyperactivity combines with defects in tolerance in B cells to lead to a T cell-dependent systemic autoimmunity in Lyn−/− mice.

Section: Discussionsupporting

confidence: 66%

“…4E, 4F). In another recent study the number of Tfh at 4-5 months of age was found to be roughly normal in Lyn −/− mice (38). Importantly, deletion of Myd88 in either DCs or B cells substantially reduced expansion of these cells in Lyn −/− mice (Fig.…”

Section: Resultsmentioning

confidence: 89%

Requirement for MyD88 Signaling in B Cells and Dendritic Cells for Germinal Center Anti-Nuclear Antibody Production in Lyn-Deficient Mice

Hua

Gross

Lamagna

et al. 2014

“…We previously showed that Ets1 levels are low in B cells from Lyn−/− mice as young as one month of age, prior to the production of IgG autoAbs or the development of proinflammatory feedback loops (5). Here, we show that Ets1 levels remain low in Lyn−/−IL-6−/− mice, which do not develop autoreactive IgG, T cell hyperactivation, or kidney damage (23, 45, 54). Consistent with this observation, inflammatory factors such as BAFF and IL-6 that increase with age and drive class switching of autoreactive B cells in Lyn−/− mice (23, 43, 45) do not cause Ets1 downregulation in wild type cells in vitro, while stimuli that induce B cell activation and differentiation, such as BCR and TLRs, do (5).…”

Section: Discussionmentioning

confidence: 66%

Genetic Interaction between Lyn, Ets1, and Btk in the Control of Antibody Levels

Mayeux

Skaug

Luo

et al. 2015

Self Cite

Tight control of B cell differentiation into plasma cells (PCs) is critical for proper immune responses and the prevention of autoimmunity. The Ets1 transcription factor acts in B cells to prevent PC differentiation. Ets1−/− mice accumulate PCs and produce autoantibodies (autoAbs). Ets1 expression is downregulated upon B cell activation through the BCR and TLRs and is maintained by the inhibitory signaling pathway mediated by Lyn, CD22 and SiglecG, and SHP-1. In the absence of these inhibitory components, Ets1 levels are reduced in B cells in a Btk-dependent manner. This leads to increased PCs, autoAbs, and an autoimmune phenotype similar to that of Ets1−/− mice. Defects in inhibitory signaling molecules, including Lyn and Ets1, are associated with human lupus, although the effects are more subtle than the complete deficiency that occurs in knockout mice. Here, we explore the effect of partial disruption of the Lyn/Ets1 pathway on B cell tolerance and find that Lyn+/−Ets1+/− mice demonstrate greater and earlier production of IgM, but not IgG, autoAbs compared to Lyn+/− or Ets1+/− mice. We also show that Btk-dependent downregulation of Ets1 is important for normal PC homeostasis when inhibitory signaling is intact. Ets1-deficiency restores the decrease in steady state PCs and Ab levels observed in Btk−/− mice. Thus, depending on the balance of activating and inhibitory signals to Ets1, there is a continuum of effects on autoAb production and PC maintenance. This ranges from full-blown autoimmunity with complete loss of Ets1-maintaining signals to reduced PC and Ab levels with impaired Ets1 downregulation.

“…Although all of these subsets can influence B cell activation and/or differentiation, IL-21-producing T FH cells are critically required for GC formation and plasma cell (PC) differentiation (7)(8)(9). Consistent with lupus being a B cell-dependent, autoantibodymediated disease, T FH cells and IL-21 have been found to be involved in at least some aspects of lupus-like disease development in several mouse models (10)(11)(12). Importantly, studies have also demonstrated dysregulated T FH cells in SLE patients (13)(14)(15).…”

Section: S Ystemic Lupus Erythematosus (Sle)mentioning

confidence: 99%

Gr1+ Cells Suppress T-Dependent Antibody Responses in (NZB × NZW)F1 Male Mice through Inhibition of T Follicular Helper Cells and Germinal Center Formation

Der

Dimo

Trigunaite

et al. 2014

Systemic lupus erythematosus is an autoimmune disease characterized by elevated production of autoreactive Abs. The disease has a much higher prevalence in women than in men. Although testosterone has been shown to be protective in the disease, and estrogens exacerbating, the discrepancy in prevalence between men and women is still not well understood and the mechanism behind it is unknown. We have recently described that male (New Zealand black [NZB] × New Zealand white [NZW])F1 mice have higher levels of Gr1+CD11b+ cells, and that these cells suppress autoantibody production in vivo. In this article, we extend our findings to show that similarly to humans, female lupus-prone (NZB × NZW)F1 mice also respond with stronger Ab responses to thymus-dependent Ag immunization than male littermates. Furthermore, the presence or absence of Gr1-expressing cells not only control Ag-specific Ab responses in male, but not female, (NZB × NZW)F1 mice, but also significantly alter the activation and differentiation of CD4+ T cells in vitro and in vivo. In particular, we found that Gr1+ cells from male (NZB × NZW)F1 mice suppress the differentiation and effector function of CXCR5+PD-1+ T follicular helper cells, thereby controlling germinal center formation and plasma cell differentiation. This new finding strongly supports efforts to develop new drugs that target myeloid cell subsets in a number of T and B cell–mediated diseases with a female predominance.