Anti‐chromatin antibodies drive <i>in vivo</i> antigen‐specific activation and somatic hypermutation of rheumatoid factor B cells at extrafollicular sites

Herlands, Robin; William, Jacqueline; Hershberg, Uri; Shlomchik, Mark J.

doi:10.1002/eji.200737752

Cited by 65 publications

(113 citation statements)

References 97 publications

(145 reference statements)

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“…We have been using AM14 B-cell receptor (BCR) transgenic (Tg) mice (AM14), specific for self-IgG2a of the "a" allotype [rheumatoid factor (RF) specificity], to study spontaneous and induced RF responses that both use the EF pathway (5,12). AM14 B cells are activated by IgG2a antichromatin in vitro and in vivo in a TLR-dependent fashion (13,14).…”

mentioning

confidence: 99%

Facultative role for T cells in extrafollicular Toll-like receptor-dependent autoreactive B-cell responses in vivo

Sweet

Ols

Cullen

et al. 2011

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

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Extrafollicular (EF) B-cell responses are increasingly being recognized as an alternative pathway of B-cell activation, particularly in autoimmunity. Critical cellular interactions required for the EF Bcell response are unclear. A key question in autoimmunity, in which Toll-like receptor (TLR) signals are costimulatory and could be sufficient for B-cell activation, is whether T cells are required for the response. This is pivotal, because autoreactive B cells are considered antigen-presenting cells for autoreactive T cells, but where such interactions occur has not been identified. Here, using AM14 site-directed transgenic rheumatoid factor (RF) mice, we report that B cells can be activated, differentiate, and isotypeswitch independent of antigen-specific T-cell help, αβ T cells, CD40L signaling, and IL-21 signaling to B cells. However, T cells do dramatically enhance the response, and this occurs via CD40L and IL-21 signals. Surprisingly, the response is completely inducible T-cell costimulator ligand independent. These results establish that, although not required, T cells substantially amplify EF autoantibody production and thereby implicate T-independent autoreactive B cells as a potential vector for breaking T-cell tolerance. We suggest that these findings explain why autoreactivity first focuses on self-components for which B cells carry TLR ligands, because these will uniquely be able to activate B cells independently of T cells, with subsequent T-B interactions activating autoreactive T cells, resulting in chronic autoimmunity.systemic lupus | autoantibodies

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mentioning

confidence: 99%

Facultative role for T cells in extrafollicular Toll-like receptor-dependent autoreactive B-cell responses in vivo

Sweet

Ols

Cullen

et al. 2011

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

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“…This is particularly relevant to SLE because autoreactive B cells that recognize and internalize DNA activate TLR9 and may also be exposed to excessive CD40-mediated signals and cytokines. Although extrafollicular B cells do not undergo extensive somatic mutation, they may still secrete pathogenic autoantibodies [12,13]. Plasma cells derived from the extrafollicular focus are dependent on BAFF and a proliferationinducing ligand (APRIL) for their immediate survival but they are short-lived, surviving an average of 3-4 days [11,16].…”

mentioning

confidence: 99%

“…It is not clear why, in the same patient, the plasma cells with different specificities differ in their lifespan. One possibility is that TLR9 engagement by DNA preferentially directs DNA-specific B cells to extrafollicular foci [12]. Alternatively, there might be differences in the signals downstream of TLR engagement by DNA versus RNA or in the cytokine microenvironment in which the different specificities arise.…”

mentioning

confidence: 99%

“…B cells with intrinsically higher affinity preferentially migrate to the extrafollicular focus where they rapidly expand and become plasma cells that secrete a first wave of protective antibodies [10,11]. Migration to the extrafollicular focus requires expression of the adhesion molecule Epstein-Barr virus induced molecule-2 (EBI2) and is enhanced by strong costimulatory signals, TLR9 ligation, and exposure to IL-12 [12][13][14][15]. This is particularly relevant to SLE because autoreactive B cells that recognize and internalize DNA activate TLR9 and may also be exposed to excessive CD40-mediated signals and cytokines.…”

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confidence: 99%

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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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“…Histological examination demonstrated that these antibody-secreting cells localize at the red pulp/T cell border (Fig. 3 I), a site previously shown to harbor autoreactive antibody-producing cells (Herlands et al, 2007;Nickerson et al, 2013a). We did not observe YFP + Ars/A1 B cell-containing germinal centers in any time point examined (unpublished data).…”

Section: Res Ults Ship-1 Is Required For the Maintenance Of B Cell Anmentioning

confidence: 54%

Continuous inhibitory signaling by both SHP-1 and SHIP-1 pathways is required to maintain unresponsiveness of anergic B cells

Getahun¹,

Beavers²,

Larson³

et al. 2016

J Cell Biol

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, via SH2 binding, and activation of Lyn. Upon dual phosphorylation, ITAMs become docking sites for the kinase Syk that, in turn, is activated by phosphorylation, leading to phosphorylation of several downstream targets and culminating in B cell activation (Packard and Cambier, 2013). Whereas Lyn plays a role in B cell activation, it also propagates activity of regulatory signaling pathways by, for example, phosphor-

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Anti‐chromatin antibodies drive in vivo antigen‐specific activation and somatic hypermutation of rheumatoid factor B cells at extrafollicular sites

Cited by 65 publications

References 97 publications

Facultative role for T cells in extrafollicular Toll-like receptor-dependent autoreactive B-cell responses in vivo

Facultative role for T cells in extrafollicular Toll-like receptor-dependent autoreactive B-cell responses in vivo

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

Continuous inhibitory signaling by both SHP-1 and SHIP-1 pathways is required to maintain unresponsiveness of anergic B cells

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