The association of interleukin-21 polymorphisms with interleukin-21 serum levels and risk of systemic lupus erythematosus

Yan, Liang; Luo, Baoming; Wang, Junli; Jiang, Yuan-Wen; Wei, Ye‐Sheng

doi:10.1016/j.gene.2014.01.012

Cited by 42 publications

(38 citation statements)

References 31 publications

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“…3). Differing reports on the levels of IL-21 in SLE patients also have been published; IL-21 levels in SLE patients are shown to be elevated in some studies (102,103), but have no change in another study (104). We observed a small decrease in IL-21 in SLE and extensive overlap with HC levels (Supplemental Fig.…”

Section: Discussionmentioning

confidence: 48%

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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Section: Discussionmentioning

confidence: 48%

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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“…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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“…For instance, it has been found that the rs2055979 C/A and rs13143866 A/G polymorphisms of IL-21 and the levels of IL-21 were significantly associated with various immune-mediated diseases. [12][13][14] Foxp3 (transcription factor forkhead box p3) is a member of the forkhead winged-helix transcription-factor family. 15 Foxp3 is expressed primarily in regulatory Tregulatory (Treg) cells: a subset of T-cells that are immunosuppressive.…”

Section: Interleukin (Il)-21 Gene Encodes a Pro-inflammatory Cytokinementioning

confidence: 99%

Association between functional polymorphisms of Foxp3 and Interleukin-21 genes with the occurrence of recurrent pregnancy loss in Gaza strip-Palestine

Jaber

Sharif

2014

Int J Res Med Sci

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The association of interleukin-21 polymorphisms with interleukin-21 serum levels and risk of systemic lupus erythematosus

Cited by 42 publications

References 31 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

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

Association between functional polymorphisms of Foxp3 and Interleukin-21 genes with the occurrence of recurrent pregnancy loss in Gaza strip-Palestine

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