IL-21 Has a Pathogenic Role in a Lupus-Prone Mouse Model and Its Blockade with IL-21R.Fc Reduces Disease Progression

Herber, Deborah; Brown, Thomas; Liang, Spencer; Young, Deborah; Collins, Mary; Dunussi-Joannopoulos, Kyri

doi:10.4049/jimmunol.178.6.3822

Cited by 269 publications

(243 citation statements)

References 53 publications

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“…Finally, given the role of IL‐21 in regulating Tfh cells and germinal centre reactions, a monoclonal antibody against IL‐21 (NNC0114‐0006) is currently in clinical trials for rheumatoid arthritis and systemic lupus erythematosus. These trials follow encouraging evidence for amelioration of disease following blockade of IL‐21 signalling in experimental inflammatory arthritis, systemic lupus erythematosus and graft‐versus‐host disease 133, 134, 135…”

Section: Concluding Remarks and Future Perspectives On The Therapeutimentioning

confidence: 81%

Ectopic lymphoid follicles: inducible centres for generating antigen‐specific immune responses within tissues

2015

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SummaryLymphoid neogenesis is traditionally viewed as a pre‐programmed process that promotes the formation of lymphoid organs during development. Here, the spatial organization of T and B cells in lymph nodes and spleen into discrete structures regulates antigen‐specific responses and adaptive immunity following immune challenge. However, lymphoid neogenesis is also triggered by chronic or persistent inflammation. Here, ectopic (or tertiary) lymphoid organs frequently develop in inflamed tissues as a response to infection, auto‐immunity, transplantation, cancer or environmental irritants. Although these structures affect local immune responses, the contribution of these lymphoid aggregates to the underlining pathology are highly context dependent and can elicit either protective or deleterious outcomes. Here we review the cellular and molecular mechanisms responsible for ectopic lymphoid neogenesis and consider the relevance of these structures in human disease.

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Section: Concluding Remarks and Future Perspectives On The Therapeutimentioning

confidence: 81%

Ectopic lymphoid follicles: inducible centres for generating antigen‐specific immune responses within tissues

2015

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“…Additionally, blocking IL-21 in the lupus-prone MRL lpr mice led to reduced lupus pathologies, such as pathogenic autoantibodies, lymphadenopathy and deposition of immune complexes in the kidney. 42 Consistently, when MLR lpr mice were made deficient in IL-21R, they showed reduced splenomegaly, lymphadenopathy and autoantibody production, and lacked spontaneous GC formation and plasmacell accumulation. 43 Moreover, the role of IL-21 is also shown in another model of murine lupus, NZB/W F1 mice, which exhibit clinical features that resemble those of human SLE, including autoantibody production and immune complex-mediated nephritis.…”

Section: T Fh Cells In Murine Models Of Autoimmune Diseasesmentioning

confidence: 86%

The darker side of follicular helper T cells: from autoimmunity to immunodeficiency

Shekhar

Yang

2012

Cell Mol Immunol

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Follicular helper T (T FH ) cells represent a distinct subset of CD4 1 helper T (T H ) cells specialized in providing help to B cells. They are characterized by their unique transcriptional profile (Bcl6), surface marker expression (CXCR5, PD-1, ICOS and CD40L) and cytokine production pattern (IL-21 and IL-6). T FH cells provide help to B cells both to form germinal centers (GCs) and to differentiate into memory B cells and plasma cells for generation of humoral responses. However, there is emerging evidence that implicates T FH cells in the development of various human pathologies, such as autoimmune diseases, immunodeficiency and lymphoma. This review focuses on the current progress in this area including mouse and human studies. A clearer understanding of the mechanisms of T FH cell-mediated immunity and pathology may be exploited for rational development of therapeutic strategies.

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“…3). In mouse lupus models, elevated IL-21 expression drives pathologic autoantibody production (26,105). The alterations in BAFF, IL-2, and IL-21 in SLE indicate a dysregulation of these factors.…”

Section: Discussionmentioning

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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IL-21 Has a Pathogenic Role in a Lupus-Prone Mouse Model and Its Blockade with IL-21R.Fc Reduces Disease Progression

Cited by 269 publications

References 53 publications

Ectopic lymphoid follicles: inducible centres for generating antigen‐specific immune responses within tissues

Ectopic lymphoid follicles: inducible centres for generating antigen‐specific immune responses within tissues

The darker side of follicular helper T cells: from autoimmunity to immunodeficiency

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

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