Increase in IL-21 producing T-cells in patients with systemic lupus erythematosus

Dolff, Sebastian; Abdulahad, Wayel H.; Westra, Johanna; Meer, Berber Doornbos-van der; Limburg, Pieter C.; Kallenberg, Cees G. M.; Bijl, Marc

doi:10.1186/ar3474

Cited by 114 publications

(91 citation statements)

References 27 publications

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“…Recently, it has been demonstrated that the combination of the pro-inflammatory interleukin-21 (IL-21) and B cell receptor (BCR) stimulation enables B cells to produce and secrete the active form of the cytotoxic serine protease granzyme B (GrB), that, even if it is not accompanied by the production of perforin, as in Natural Killer (NK) and Cytotoxic T lymphocytes, plays a critical role in early anti-viral immune responses, in the regulation of autoimmune mechanisms and in cancer immunosurveillance . Moreover, recent studies have revealed an increase of IL-21 levels in the elderly (Agrawal et al, 2012) and in SLE patients (Dolff et al, 2011) in which we and other groups (Colonna-Romano et al, 2009;Sanz et al, 2008;Wei et al, 2007) have shown the increase of DN B cell population. In order to evaluate whether DN B cells are also involved in IL-21-mediated immune response, we tested the capacity of these cells to produce GrB.…”

Section: Discussionmentioning

confidence: 99%

Trafficking phenotype and production of granzyme B by double negative B cells (IgG+IgD−CD27−) in the elderly

Bulati

Buffa

Martorana

et al. 2014

Experimental Gerontology

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The impairment of humoral immune response in elderly humans has been extensively demonstrated. We have reported the increase of memory B cells (IgG, double negative, DN) population in the elderly, in which there is also a typical inflammatory micro-environment. In order to evaluate whether this pro-inflammatory status could influence the trafficking phenotype of naïve/memory B cells, we have assessed the expression of CCR7, CCR6, CXCR3, CXCR4, CXCR5 and CD62L on naïve/memory B cell subpopulations in young and elderly subjects. Moreover, the combination of pro-inflammatory interleukin-21 (IL-21) and B cell receptor (BCR) stimulation enables B cells to produce and secrete granzyme B (GrB), which plays a critical role in early anti-viral immune responses, in the regulation of autoimmune mechanisms and in cancer immunosurveillance. Our data demonstrate that in the elderly, naïve/memory B cell populations present a different expression of the studied receptors that could be discussed in terms of "inflamm-aging". In particular IgGshow a tissue trafficking phenotype and they can be stimulated to produce GrB.

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Section: Discussionmentioning

confidence: 99%

Trafficking phenotype and production of granzyme B by double negative B cells (IgG+IgD−CD27−) in the elderly

Bulati

Buffa

Martorana

et al. 2014

Experimental Gerontology

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“…Elevated IL-21 levels were found in lupus-prone BXSB.Yaa mice, and autoimmune features were attenuated in BXSB.Yaa and MRL-Fas lpr mice following genetic deletion of IL-21R or IL-21 blockade (20)(21)(22)(23). In patients with lupus, an association between polymorphisms in the IL-21 and IL-21R gene and disease susceptibility was reported, along with increased circulating and intracellular levels of IL-21 (24)(25)(26)(27)(28). Thus, IL-21 is an attractive candidate for therapeutic targeting in autoimmune diseases, including SLE.…”

Section: Nterleukin-21 Is a Member Of The Type I Cytokine Family Wimentioning

confidence: 99%

CTL-Promoting Effects of IL-21 Counteract Murine Lupus in the Parent→F1 Graft-versus-Host Disease Model

Nguyen

Rus

Chen

et al. 2016

The Journal of Immunology

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IL-21 promotes B cell and CTL responses in vivo, conferring IL-21 with a role in both humoral and cellular responses. Because CTL can target and eliminate autoreactive B cells, we investigated whether IL-21R signaling in CD8 T cells would alter the expansion of autoreactive B cells in an autoimmune setting. We addressed this question using the parent→F1 murine model of acute and chronic (lupus-like) graft-versus-host disease (GVHD) as models of a CTL-mediated or T-dependent B cell–mediated response, respectively. Induction of acute GVHD using IL-21R–deficient donor T cells resulted in decreased peak donor CD8 T cell numbers and decreased CTL effector function due to impaired granzyme B/perforin and Fas/Fas ligand pathways and a phenotype of low-intensity chronic GVHD with persistent host B cells, autoantibody production, and mild lupus-like renal disease. CTL effector maturation was critically dependent on IL-21R signaling in Ag-specific donor CD8, but not CD4, T cells. Conversely, treatment of DBA/2J→F1 chronic GVHD mice with IL-21 strongly promoted donor CD8 T cell expansion and rescued defective donor anti-host CTLs, resulting in host B cell elimination, decreased autoantibody levels, and attenuated renal disease, despite evidence of concurrently enhanced CD4 help for B cells and heightened B cell activation. These results demonstrate that, in the setting of lupus-like CD4 T cell–driven B cell hyperactivity, IL-21 signaling on Ag-specific donor CD8 T cells is critical for CTL effector maturation, whereas a lack of IL-21R downregulates CTL responses that would otherwise limit B cell hyperactivity and autoantibody production.

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“…In the mouse, autocrine IL-21 signaling has been proposed to promote Th17 differentiation (36,(41)(42)(43), and consistently, human patients with defective IL-21R signaling lack Th17 cells (44). However, although IL-21 can promote autoimmune diseases such as systemic lupus erythematosus (45,46) or type 1 diabetes (47) by its effect on B cells (48) and dendritic cells (DCs) (49), respectively, inconsistent results have been published on the role of IL-21 in Th17 cell differentiation and Th17-driven experimental autoimmune encephalomyelitis (41,50,51). Interest-ingly, the addition of exogenous TGF-b and IL-21 was reported to induce Th17 differentiation of human naive T cells (8).…”

Section: Ytokines Regulate the Differentiation Of Uncommitted Naivementioning

confidence: 99%

IL-21 Is a Central Memory T Cell–Associated Cytokine That Inhibits the Generation of Pathogenic Th1/17 Effector Cells

Kastirr

Maglie

Paroni

et al. 2014

The Journal of Immunology

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IL-21 promotes Th17 differentiation, and Th17 cells that upregulate T-bet, IFN-γ, and GM-CSF drive experimental autoimmune diseases in mice. Anti–IL-21 treatment of autoimmune patients is therefore a therapeutic option, but the role of IL-21 in human T cell differentiation is incompletely understood. IL-21 was produced at high levels by human CD4+ central memory T cells, suggesting that it is associated with early T cell differentiation. Consistently, it was inhibited by forced expression of T-bet or RORC2, the lineage-defining transcription factors of Th1 and Th17 effector cells, respectively. Although IL-21 was efficiently induced by IL-12 in naive CD4+ T cells, it inhibited the generation of Th1 effector cells in a negative feedback loop. IL-21 was also induced by IL-6 and promoted Th17 differentiation, but it was not absolutely required. Importantly, however, IL-21 promoted IL-10 secretion but inhibited IFN-γ and GM-CSF production in developing Th17 cells, and consequently prevented the generation of polyfunctional Th1/17 effector cells. Moreover, in Th17 memory cells, IL-21 selectively inhibited T-bet upregulation and GM-CSF production. In summary, IL-21 is a central memory T cell–associated cytokine that promotes Th17 differentiation and IL-10 production, but inhibits the generation of potentially pathogenic Th1/17 effector cells. These findings shed new light on the role of IL-21 in T cell differentiation, and have relevant implications for anti–IL-21 therapy of autoimmune diseases.

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Increase in IL-21 producing T-cells in patients with systemic lupus erythematosus

Cited by 114 publications

References 27 publications

Trafficking phenotype and production of granzyme B by double negative B cells (IgG+IgD−CD27−) in the elderly

Trafficking phenotype and production of granzyme B by double negative B cells (IgG+IgD−CD27−) in the elderly

CTL-Promoting Effects of IL-21 Counteract Murine Lupus in the Parent→F1 Graft-versus-Host Disease Model

IL-21 Is a Central Memory T Cell–Associated Cytokine That Inhibits the Generation of Pathogenic Th1/17 Effector Cells

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