Inflamed kidneys of NZB / W mice are a major site for the homeostasis of plasma cells

Cassese, Giuliana; Lindenau, Steffi; Boer, Bauke de; Arce, Sergio; Hauser, Anja E.; Riemekasten, Gabriela; Berek, Claudia; Hiepe, Falk; Krenn, Veit; Radbruch, Andreas; Manz, Rudolf A.

doi:10.1002/1521-4141(200109)31:9<2726::aid-immu2726>3.0.co;2-h

Cited by 212 publications

(200 citation statements)

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“…Second, BAFF is expressed locally in the inflamed tissue, as has been reported in the kidney in lupus nephritis (117). Lastly, plasma cell accumulation has been shown to accumulate and enhance the local concentrations of Ab and immunocomplex formation in inflamed kidneys in a mouse lupus model, demonstrating that local inflamed tissue environments can support plasmablast and plasma cell survival and disease-inducing Ab production (17). Taken together, the inflamed kidney environment in SLE contains the components required to induce local plasmablast differentiation and Ab secretion by T cell-independent mechanisms mediated by BAFF.…”

Section: Discussionmentioning

confidence: 75%

“…In SLE, high levels of memory B cells, plasmablasts, and anti-dsDNA Ab reappearance after B cell-depleting therapy are correlated to increased rates of disease relapse (15,16). The ramifications of these increased circulating autoreactive memory B cells and plasmablasts are that they can lead to their appearance in affected disease tissue, where they enhance local concentrations of Ab and immune complexes, such as observed in the inflamed kidney of a lupus nephritis mouse model (17). The observation that plasma cells appear in areas of T cell-B cell interaction in lupus nephritis kidneys suggests that components of a T celldriven B cell activation and differentiation into Ab-secreting cells may take place locally (18).…”

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confidence: 99%

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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: 75%

mentioning

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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“…They can arise spontaneously in the spleen, in the lymph nodes or at ectopic sites in autoimmune disease [20][21][22] , and these spontaneous GCs can be a site of production of autoantibodies such as rheumatoid factor and anti-DNA [20][21][22] . The assembly of the GCs requires regulation of B and T cell migration, including attracting B and T cells into the GCs, organizing them within GCs, and orchestrating their egress from GCs at appropriate developmental stages 18,23 .…”

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confidence: 99%

Interleukin 17–producing T helper cells and interleukin 17 orchestrate autoreactive germinal center development in autoimmune BXD2 mice

et al. 2007

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Interleukin 17 (IL-17) is a cytokine associated with inflammation, autoimmunity and defense against some bacteria. Here we show that IL-17 can promote autoimmune disease through a mechanism distinct from its proinflammatory effects. As compared with wild-type mice, autoimmune BXD2 mice express more IL-17 and show spontaneous development of germinal centers (GCs) before they increase production of pathogenic autoantibodies. We show that blocking IL-17 signaling disrupts CD4 + T cell and B cell interactions required for the formation of GCs and that mice lacking the IL-17 receptor have reduced GC B cell development and humoral responses. Production of IL-17 correlates with upregulated expression of the genes Rgs13 and Rgs16, which encode regulators of G-protein signaling, and results in suppression of the B cell chemotactic response to the chemokine CXCL12. These findings suggest a mechanism by which IL-17 drives autoimmune responses by promoting the formation of spontaneous GCs.

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“…These limited and poorly defined survival niches exist in the BM, the spleen, and the inflamed organs, and involve the interaction of plasma cells with stromal cells that provide survival factors such as BAFF, APRIL, and IL-6, adhesion molecules such as VCAM-1 and chemokines such as CXCL12 [11,[19][20][21]. In murine lupus, the inflammatory environment, extramedullary hematopoiesis in lymphoid organs, and lymphoid neogenesis in inflamed target organs all provide an expanded number of sites where autoantibody-producing plasma cells can survive.…”

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confidence: 99%

Plasma cells in systemic lupus erythematosus: The long and short of it all

2011

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Plasma cells can be classified as long-or short-lived. The lifespan of a plasma cell largely depends on whether it arises from a germinal center or an extrafollicular locus and most importantly whether it can find a survival niche in the spleen or BM. In systemic lupus erythematosus (SLE) patients, long-lived plasma cells are believed to be responsible for the production of anti-RNA and anti-cardiolipin antibodies, whereas short-lived plasma cells, which are more susceptible to anti-proliferation therapies, are the main producers of anti-DNA antibodies. A previous study showed that transient overexpression of interferon-a (IFN-a), a cytokine that plays a pathogenic role in SLE, accelerates disease onset in lupusprone NZB/W mice. In this issue of the European Journal of Immunology, the same group report that IFN-a induces large numbers of short-lived plasma cells, accompanied by high titers of anti-dsDNA antibodies in NZB/W, but not BALB/c, mice. Our commentary discusses this interesting observation in the context of the previous data regarding plasma cell differentiation and conveys our view about the clinical implications with respect to therapies that target plasma cells in SLE patients.Keywords: Interferon-a . Plasma cells . Systemic lupus erythematosus See accompanying article by Mathian et al.Type I IFNs are believed to play a significant role in systemic lupus erythematosus (SLE) pathogenesis. IFN-a facilitates the maturation of myeloid DC that contribute to T-cell activation and follicular T-helper cell differentiation [1], and that produce the B-cell survival factor B-cell activating factor (BAFF) [2]. IFN-a also directly stimulates CD4 T cells to enhance antigen-specific B-cell activation, increases TLR7 expression in B cells, and promotes T-independent B-cell proliferation and differentiation into early plasmablasts [3]. In several lupus-prone mouse strains, type I IFNs accelerate the break in B-cell tolerance to nucleic acids that occurs spontaneously in these mice with age [4][5][6]. Nucleic acid-containing immune complexes, in turn, can activate intracellular TLRs, resulting in further release of type I IFNs and pro-inflammatory cytokines [7].Consistent with the known biologic functions of IFN-a, Mathian et al. [8] show in this issue of the European Journal of Immunology that NZB/W mice treated with a small dose of IFN-aexpressing adenovirus develop increased serum levels of BAFF, IL-6, and TNFa, and high titers of anti-dsDNA antibodies. In contrast, nonautoimmune BALB/c mice maintain tolerance to self-antigens despite IFN-a-induced upregulation of inflammatory mediators. This indicates that a genetic predisposition is required for IFN-a to initiate autoimmunity and may explain the reason why only few patients develop SLE during type I IFN therapy [3].The findings reported by Mathian et al. [8] complement the recent studies by our group, showing that IgG2a autoantibodies in IFN-a-induced NZB/W mice were derived from germinal centers, whereas IgG3 autoantibodies were derived predominantly from extra...

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Inflamed kidneys of NZB / W mice are a major site for the homeostasis of plasma cells

Cited by 212 publications

References 25 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

Interleukin 17–producing T helper cells and interleukin 17 orchestrate autoreactive germinal center development in autoimmune BXD2 mice

Plasma cells in systemic lupus erythematosus: The long and short of it all

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