IL-21 promotes lupus-like disease in chronic graft-versus-host disease through both CD4 T cell- and B cell-intrinsic mechanisms.
ABSTRACT 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.
Article: Lupus nephritis: A critical review[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.Autoimmunity reviews 09/2012; 12(2). DOI:10.1016/j.autrev.2012.08.018 · 7.10 Impact Factor
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ABSTRACT: To observe the proportion of peripheral T follicular helper (Tfh) cells in patients with systemic lupus erythematosus (SLE) and to assess the role of steroids on Tfh cells from SLE patients. Peripheral blood mononuclear cells (PBMCs) from 42 SLE patients and 22 matched healthy subjects were collected to assess proportions of circulating CXCR5(+)PD1(+)/CD4(+) T cells (Tfh), CD4(+)CCR6(+) T cells (Th17-like) and CD19(+)CD138(+) plasma cells by flow cytometry. 8 of the patients had their blood redrawn within one week after receiving methylprednisolone pulse treatment. Disease activity was evaluated by SLE disease activity index. To test the effect of IL-21 and corticosteroids on Tfh cells in vitro, PBMCs harvested from another 15 SLE patients were cultured with medium, IL-21, or IL-21+ dexamethasone for 24 hours and 72 hours. PBMCs from an independent 23 SLE patients were cultured with different concentrations of dexamethasone for 24 hours. Compared to normal controls, percentages of circulating Tfh cells, but not Th17 cells, were elevated in SLE patients and correlated with disease activity. Proportions of Tfh cells in SLE patients were positively correlated with those of plasma cells and serum levels of antinuclear antibodies. After methylprednisolone pulse treatment, both percentages and absolute numbers of circulating Tfh cells were significantly decreased. In vitro cultures showed an increase of Tfh cell proportion after IL-21 stimulation that was totally abolished by the addition of dexamethasone. Both 0.5 and 1 µM dexamethasone decreased Tfh cells dose dependently (overall p = 0.013). We demonstrated that elevated circulating Tfh cell proportions in SLE patients correlated with their disease activities, and circulating levels of plasma cells and ANA. Corticosteroids treatment down-regulated aberrant circulating Tfh cell proportions both in vivo and in vitro, making Tfh cells a new treatment target for SLE patients.PLoS ONE 12/2012; 7(12):e51982. DOI:10.1371/journal.pone.0051982 · 3.53 Impact Factor
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ABSTRACT: This study aims to investigate the serum IL-21 levels in systemic lupus erythematosus (SLE) and its relations with clinical and laboratory features. Fifty-seven patients with SLE and 30 healthy volunteers were recruited in the current study. Serum IL-21 levels were detected by enzyme-linked immunosorbent assay. Statistical analyses were performed by SPSS 10.01. Results showed that IL-21 levels were significantly decreased in the serum of patients with SLE compared with controls (P = 0.026). There was no significant difference regarding serum IL-21 level between SLE patients with nephritis and those without nephritis (P = 0.066); no significant difference was found between less active SLE and more active SLE (P = 0.588). The presence of anemia was associated with low serum IL-21 levels (P = 0.030) in SLE patients. In summary, decreased serum level of IL-21 and its association with anemia indicate a possible role of IL-21 in human SLE. However, further studies are needed to confirm this preliminary results.Rheumatology International 03/2013; 33(9). DOI:10.1007/s00296-013-2724-1 · 1.63 Impact Factor