T cell-driven B cell hyperactivity plays an essential role in driving autoimmune disease development in systemic lupus erythematosus. IL-21 is a member of the type I cytokine family with pleiotropic activities. It regulates B cell differentiation and function, promotes T follicular helper (T(FH)) cell and Th17 cell differentiation, and downregulates the induction of T regulatory cells. Although IL-21 has been implicated in systemic lupus erythematosus, the relative importance of IL-21R signaling in CD4(+) T cells versus B cells is not clear. To address this question, we took advantage of two induced models of lupus-like chronic graft-versus-host disease by using wild-type or IL-21R(-/-) mice as donors in the parent-into-F1 model and as hosts in the Bm12→B6 model. We show that IL-21R expression on donor CD4(+) T cells is essential for sustaining T(FH) cell number and subsequent help for B cells, resulting in autoantibody production and more severe lupus-like renal disease, but it does not alter the balance of Th17 cells and regulatory T cells. In contrast, IL-21R signaling on B cells is critical for the induction and maintenance of germinal centers, plasma cell differentiation, autoantibody production, and the development of renal disease. These results demonstrate that IL-21 promotes autoimmunity in chronic graft-versus-host disease through both CD4(+) T cell- and B cell-intrinsic mechanisms and suggest that IL-21 blockade may attenuate B cell hyperactivity, as well as the aberrant T(FH) cell pathway that contributes to lupus pathogenesis.
"IL-21 was also initially proposed as an important T cell-derived soluble factor regulating TFH differentiation through engagement of the IL-21R on recently activated CD4+ T cells prior to lineage commitment , , . Subsequent reports ,  including our findings herein demonstrating a reduced (by ∼ 50%) TFH response in the dLN of IAV-infected il-21rα−/− mice (Fig. 1b) further substantiates the contribution of IL21 to TFH differentiation. However, it was unclear whether IL-21 acts directly on naïve/recently activated CD4+ T cells to drive TFH differentiation , , . "
[Show abstract][Hide abstract] ABSTRACT: IL-21 is a type-I cytokine that has pleiotropic immuno-modulatory effects. Primarily produced by activated T cells including NKT and TFH cells, IL-21 plays a pivotal role in promoting TFH differentiation through poorly understood cellular and molecular mechanisms. Here, employing a mouse model of influenza A virus (IAV) infection, we demonstrate that IL-21, initially produced by NKT cells, promotes TFH differentiation by promoting the migration of late activator antigen presenting cell (LAPC), a recently identified TFH inducer, from the infected lungs into the draining lymph nodes (dLN). LAPC migration from IAV-infected lung into the dLN is CXCR3-CXCL9 dependent. IL-21-induced TNF-α production by conventional T cells is critical to stimulate CXCL9 expression by DCs in the dLN, which supports LAPC migration into the dLN and ultimately facilitates TFH differentiation. Our results reveal a previously unappreciated mechanism for IL-21 modulation of TFH responses during respiratory virus infection.
PLoS ONE 09/2014; 9(9):e105872. DOI:10.1371/journal.pone.0105872 · 3.23 Impact Factor
"Further study showed that treatment with an IL-21-neutralizing antibody once per week for 4 weeks could inhibit the expansion of Tfh cells in spleens and reduce the titers of ANA, ds-DNA and renal scores of MRL/lpr mice (Figure S2). These data indicated that IL-21 is a promoting factor in the differentiation/expansion of Tfh cells, germinal center formation, antibody production, and autoimmunity in murine model of lupus , , . "
[Show abstract][Hide abstract] ABSTRACT: T follicular helper (Tfh) cells can mediate humoral immune responses and augment autoimmunity, whereas the role of Tfh cells on regulatory B (B10) cells in autoimmunity diseases is not clear. Here, we investigated the percentages of Tfh cells and B10 cells in lupus-prone MRL/Mp-lpr/lpr (MRL/lpr) mice and examined the effects and mechanism of Tfh cell-derived interleukin-21 (IL-21) on IL-10 production during the differentiation of B10 cells. Both Tfh cells and B10 cells were expanded in spleens of MRL/lpr mice. In addition, a positive correlation between the proportions of Tfh cells and B10 cells was observed. Tfh cell-derived IL-21 from MRL/lpr mice could promote IL-10 production during the differentiation of B10 cells. Importantly, neutralization of IL-21 inhibited IL-10 production and expansion of B10 cells both in vitro and in vivo. IL-21 induced IL-10 production via activation of phosphorylated signal transduction and activator of transcription 3 (p-STAT3). Inhibition of p-STAT3 effectively blocked IL-10 production during the differentiation of B10 cells. Moreover, IL-21-induced IL-10 exerted a regulatory function by inhibiting the proliferation of T cells. These data suggest that Tfh cells not only mediate humoral immune responses and augment autoimmunity but also play a broader role in immune regulatory actions via the induction of IL-10 production.
PLoS ONE 05/2013; 8(4):e62855. DOI:10.1371/journal.pone.0062855 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Lupus nephritis remains one of the most severe manifestations of systemic lupus erythematosus associated with considerable morbidity and mortality. A better understanding of the pathogenesis of lupus nephritis is an important step in identifying more targeted and less toxic therapeutic approaches. Substantial research has helped define the pathogenetic mechanisms of renal manifestations and, in particular, the complex role of type I interferons is increasingly recognized; new insights have been gained into the contribution of immune complexes containing endogenous RNA and DNA in triggering the production of type I interferons by dendritic cells via activation of endosomal toll-like receptors. At the same time, there have been considerable advances in the treatment of lupus nephritis. Corticosteroids have long been the cornerstone of therapy, and the addition of cyclophosphamide has contributed to renal function preservation in patients with severe proliferative glomerulonephritis, though at the cost of serious adverse events. More recently, in an effort to minimize drug toxicity and achieve equal effectiveness, other immunosuppressive agents, including mycophenolate mofetil, have been introduced. Herein, we provide a detailed review of the trials that established the equivalency of these agents in the induction and/or maintenance therapy of lupus nephritis, culminating in the recent publication of new treatment guidelines by the American College of Rheumatology. Although newer biologics have been approved and continue to be a focus of research, they have, for the most part, been relatively disappointing compared to the effectiveness of biologics in other autoimmune diseases. Early diagnosis and treatment are essential for renal preservation.
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