Genetic association of interleukin-21 polymorphisms with systemic lupus erythematosus

Sawalha, Amr H.; Kaufman, Kenneth M.; Kelly, Jennifer A.; Adler, Adam J.; Aberle, Teresa; Kilpatrick, Jeff; Wakeland, Edward K.; Li, Quan-Zhen; Wandstrat, Amy E.; Karp, David; James, Judith A.; Merrill, Joan T.; Lipsky, Peter E.; Harley, John B.

doi:10.1136/ard.2007.075424

Cited by 170 publications

(141 citation statements)

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“…IL-2 is predominately a T cell-derived cytokine that promotes B cell proliferation and enhances the effects of IL-21 in inducing plasmablast by CD40L stimulation (19,28,29). The levels of both cytokines are altered in SLE and thought to play a role in pathogenesis (30)(31)(32)(33).…”

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confidence: 99%

Aiolos Overexpression in Systemic Lupus Erythematosus B Cell Subtypes and BAFF-Induced Memory B Cell Differentiation Are Reduced by CC-220 Modulation of Cereblon Activity

Nakayama¹,

Kosek²,

Capone³

et al. 2017

The Journal of Immunology

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BAFF is a B cell survival and maturation factor implicated in the pathogenesis of systemic lupus erythematosus (SLE). In this in vitro study, we describe that soluble BAFF in combination with IL-2 and IL-21 is a T cell contact-independent inducer of human B cell proliferation, plasmablast differentiation, and IgG secretion from circulating CD27+ memory and memory-like CD27−IgD− double-negative (DN) B cells, but not CD27−IgD+ naive B cells. In contrast, soluble CD40L in combination with IL-2 and IL-21 induces these activities in both memory and naive B cells. Blood from healthy donors and SLE patients have similar circulating levels of IL-2, whereas SLE patients exhibit elevated BAFF and DN B cells and reduced IL-21. B cell differentiation transcription factors in memory, DN, and naive B cells in SLE show elevated levels of Aiolos, whereas Ikaros levels are unchanged. Treatment with CC-220, a modulator of the cullin ring ligase 4-cereblon E3 ubiquitin ligase complex, reduces Aiolos and Ikaros protein levels and BAFF- and CD40L-induced proliferation, plasmablast differentiation, and IgG secretion. The observation that the soluble factors BAFF, IL-2, and IL-21 induce memory and DN B cell activation and differentiation has implications for extrafollicular plasmablast development within inflamed tissue. Inhibition of B cell plasmablast differentiation by reduction of Aiolos and Ikaros may have utility in the treatment of SLE, where elevated levels of BAFF and Aiolos may prime CD27+ memory and DN memory-like B cells to become Ab-producing plasmablasts in the presence of BAFF and proinflammatory cytokines.

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confidence: 99%

Aiolos Overexpression in Systemic Lupus Erythematosus B Cell Subtypes and BAFF-Induced Memory B Cell Differentiation Are Reduced by CC-220 Modulation of Cereblon Activity

Nakayama¹,

Kosek²,

Capone³

et al. 2017

The Journal of Immunology

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“…In B cells, the effect of IL-21 is dependent on their stage of differentiation, such that engagement with naïve B cells confers an apoptotic signal while it promotes T cell-dependent maturation of antigen-experienced B cells to plasma cells (12,13) and is essential for germinal center (GC) formation (6). Recent studies in humans suggest that allelic variation in the IL-21 gene is a risk factor for SLE (14). Previous work showed that BXSB-Yaa mice have elevated IL-21 at the transcriptional and serum protein levels (12).…”

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confidence: 99%

A critical role for IL-21 receptor signaling in the pathogenesis of systemic lupus erythematosus in BXSB-Yaamice

Bubier

Sproule

Foreman

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

269

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Interleukin 21 (IL-21) is a pleiotropic cytokine produced by CD4 T cells that affects the differentiation and function of T, B, and NK cells by binding to a receptor consisting of the common cytokine receptor ␥ chain and the IL-21 receptor (IL-21R). IL-21, a product associated with IL-17-producing CD4 T cells (T H17) and follicular CD4 T helper cells (T FH), has been implicated in autoimmune disorders including the severe systemic lupus erythematosus (SLE)-like disease characteristic of BXSB-Yaa mice. To determine whether IL-21 plays a significant role in this disease, we compared IL-21R-deficient and -competent BXSB-Yaa mice for multiple parameters of SLE. The deficient mice showed none of the abnormalities characteristic of SLE in IL-21R-competent Yaa mice, including hypergammaglobulinemia, autoantibody production, reduced frequencies of marginal zone B cells and monocytosis, renal disease, and premature morbidity. IL-21 production associated with this autoimmune disease was not a product of T H17 cells and was not limited to conventional CXCR5 ؉ TFH but instead was produced broadly by ICOS ؉ CD4 ؉ splenic T cells. IL-21 arising from an abnormal population of CD4 T cells is thus central to the development of this lethal disease, and, more generally, could play an important role in human SLE and related autoimmune disorders.autoimmune disease ͉ autoantibodies ͉ B cells ͉ T cells S ystemic lupus erythematosus (SLE) in humans is a chronic, multigenic autoimmune disease characterized by a wide spectrum of clinical abnormalities, the production of multiple autoantibodies, and the generation of immune complexes that often lead to severe renal disease. The production of autoantibodies is indicative of a profound breakdown in humoral tolerance mechanisms and B cell hyperactivity caused either by B cell-intrinsic abnormalities or immunoregulatory defects of other cell types. Mouse models genetically programmed to develop characteristics of SLE have proven useful for characterizing this disease process and for identifying potential therapeutic targets. Among the most interesting models of SLE are the BXSB mice bearing the Y chromosome-linked autoimmune acceleration (Yaa) mutation (1). Affected animals develop a remarkably severe disease characterized by lymphoid hyperplasia, monocytosis, hypergammaglobulinemia, and severe immune complex-mediated glomerulonephritis. In contrast to the female prevalence of SLE in humans, this disease is male-biased because of the epistatic effects of BXSB-background autosomal alleles in combination with Yaa. This mutant locus is the result of the duplication of at least 17 genes in the X chromosome, including Toll-like receptor 7 (Tlr7), and their placement in the Y chromosome (2, 3). Remarkably, severe autoimmune disease results from the presence of an extra copy of these X-chromosome genes in Yaa mice in combination with BXSB-background autosomal alleles.IL-21 is a pleiotropic member of the ␥-chain family of cytokines, which engages the IL-21 receptor (IL-21R) and the common cytokine re...

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Section: Il-21/il-21r and Slementioning

confidence: 99%

“…50,69 In humans, higher serum IL-21 and IL-21 mRNA levels were observed in SLE patients, 87,88 and population-based case-control association analyses suggest that allelic variation in the IL-21 gene was a risk factor for SLE. 87 In a study evaluating SLE patient autologous mixed CD3 1 T-and CD19 1 B-lymphocyte cultures, the exogenous addition of IL-21 and/or CpG-ODN2006 caused a significant increase in secreted IgG and the PC proportion reduced following IL-21R.Fc treatment. 4 In SLE murine models, the lupus BXSB-Yaa mouse showed increased IL-21 at the transcriptional and serum protein levels compared to wild-type mice 69 and the genetic deletion of IL-21R in these mice led to the disappearance of abnormal SLE characteristics, including hypergammaglobulinemia, autoantibody production and renal disease.…”

Section: Il-21/il-21r and Slementioning

confidence: 99%

IL-21 acts as a promising therapeutic target in systemic lupus erythematosus by regulating plasma cell differentiation

Deng

Wei

2014

Cell Mol Immunol

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Plasma cells, which secrete auto-antibodies, are considered to be the arch-criminal of autoimmune diseases such as systemic lupus erythematosus, but there are many cytokines involved in inducing the differentiation of B-cell subsets into plasma cells. Here, we emphasize IL-21, which has emerged as the most potent inducer of plasma cell differentiation. In this review, we focused on the promoting effects of IL-21 on plasma cell differentiation and discuss how these effects contribute to B cell-mediated autoimmune disease.

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Genetic association of interleukin-21 polymorphisms with systemic lupus erythematosus

Cited by 170 publications

References 19 publications

Aiolos Overexpression in Systemic Lupus Erythematosus B Cell Subtypes and BAFF-Induced Memory B Cell Differentiation Are Reduced by CC-220 Modulation of Cereblon Activity

Aiolos Overexpression in Systemic Lupus Erythematosus B Cell Subtypes and BAFF-Induced Memory B Cell Differentiation Are Reduced by CC-220 Modulation of Cereblon Activity

A critical role for IL-21 receptor signaling in the pathogenesis of systemic lupus erythematosus in BXSB-Yaamice

IL-21 acts as a promising therapeutic target in systemic lupus erythematosus by regulating plasma cell differentiation

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