A genetic lesion that arrests plasma cell homing to the bone marrow

Erickson, Loren D.; Lin, Ling-Li; Duan, Biyan; Morel, Laurence; Noelle, Randolph J.

doi:10.1073/pnas.2131686100

Cited by 60 publications

(63 citation statements)

References 58 publications

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“…In addition, we have previously shown that both NZM2410 and NZW mice present an accumulation of PC in the spleen. 24 Although we were not able to map the entire phenotype to any single Sle locus, it is also temping to speculate that reduced FcgRIIB expression may contribute to this phenotype, as suggested by our data in Figure 6. Interestingly, close examination of our results in Figures 5 and 6 suggests that Sle1a also impacts the immune response to SRBC immunization, including the number of class-switched PCs.…”

Section: Resultsmentioning

confidence: 83%

“…28 Enzyme-linked immunospot (ELISPOT) assay AFCs were enumerated by ELISPOT as previously described. 24 Serially diluted RBC-depleted spleen and BM cells were added to multiscreen filter plates (Millipore, MA, USA) coated with 5 mg/ml goat antimouse IgG for 6 h at 37 1C. Bound cells were detected with HRP-conjugated-anti-IgG (Southern Biotechnology), and developed by 3-amino-9-ethylcarbazole (AEC, Sigma-Aldrich, St Louis, MO, USA).…”

Section: Immunohistologymentioning

confidence: 99%

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Expression of the autoimmune Fcgr2b NZW allele fails to be upregulated in germinal center B cells and is associated with increased IgG production

et al. 2007

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The inhibitory receptor FcgRIIb regulates B-cell functions. Genetic studies have associated Fcgr2b polymorphisms and lupus susceptibility in both humans and murine models, in which B cells express reduced FcgRIIb levels. Furthermore, FcgRIIb absence results in lupus on the appropriate genetic background, and lentiviral-mediated FcgRIIb overexpression prevents disease in the NZM2410 lupus mouse. The NZM2410/NZW allele Fcgr2b is, however, located in-between Sle1a and Sle1b, two potent susceptibility loci, making it difficult to evaluate Fcr2b NZW independent contribution. By using two congenic strains that each carries only Sle1a (B6.Sle1a(15-353)), or Fcr2b NZW in the absence of Sle1a or Sle1b (B6.Sle1(111-148)), we show that the Fcr2b NZW allele does not upregulate its expression on germinal center B cells and plasma cells, as does the C57BL/6 allele on B6.Sle1a(15-353) B cells. Furthermore, in the absence of the flanking Sle1a and Sle1b, Fcr2b NZW does not produce an autoimmune phenotype, but is associated with an increased number of class-switched plasma cells. These results show that while a lower level of FcgRIIb does not by itself induce the development of autoreactive B cells, it has the potential to amplify the contribution of autoreactive B cells induced by other lupus-susceptibility loci by enhancing the production of class-switched plasma cells.

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Section: Resultsmentioning

confidence: 83%

Section: Immunohistologymentioning

confidence: 99%

Expression of the autoimmune Fcgr2b NZW allele fails to be upregulated in germinal center B cells and is associated with increased IgG production

et al. 2007

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“…Studies are underway to determine whether autoantibodies that arise naturally in autoimmune settings are derived from long-lived or short-lived AFCs. In the New Zealand Black/White and New Zealand M2410 models, the presence of long-lived AFCs has been documented, and interestingly, they have been shown to reside at unique sites (83)(84)(85). Clearly, more studies are warranted to better understand what governs B cell fate decisions in healthy vs autoimmune settings, the outcome of which may have important implications for B cell depletion strategies currently used to treat human autoimmune diseases (86,87).…”

Section: Discussionmentioning

confidence: 99%

The Influence of Effector T Cells and Fas Ligand on Lupus-Associated B Cells

Fields

Nish

Hondowicz

et al. 2005

The Journal of Immunology

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Circulating autoantibodies against dsDNA and chromatin are a characteristic of systemic lupus erythematosus in humans and many mouse models of this disease. B cells expressing these autoantibodies are normally regulated in nonautoimmune-prone mice but are induced to secrete Abs following T cell help. Likewise, anti-chromatin autoantibody production is T cell-dependent in Fas/Fas ligand (FasL)-deficient (lpr/lpr or gld/gld) mice. In this study, we demonstrate that Th2 cells promote anti-chromatin B cell survival and autoantibody production in vivo. FasL influences the ability of Th2 cells to help B cells, as Th2-gld/gld cells support higher titers of anti-chromatin Abs than their FasL-sufficient counterparts and promote anti-chromatin B cell participation in germinal centers. Th1 cells induce anti-chromatin B cell germinal centers regardless of FasL status; however, their ability to stimulate anti-chromatin Ab production positively correlates with their level of IFN-γ production. This distinction is lost if FasL-deficient T cells are used: Th1-gld/gld cells promote significant titers of anti-chromatin Abs regardless of IFN-γ production levels. Thus, FasL from effector T cells plays an important role in determining the fate of anti-chromatin B cells.

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“…GPI-specific IgG1-secreting cells in the spleen, LNs, and bone marrow (BM) were enumerated by GPI-specific ELISPOT assays as previously described, with modifications (22). In brief, 96-well multiscreen plates (Millipore) were coated with rabbit GPI (Sigma-Aldrich) and blocked with RPMI 1640 medium containing 10% FBS.…”

Section: Elisa and Elispot Assaysmentioning

confidence: 99%

A Positive Feedback Loop of IL-21 Signaling Provoked by Homeostatic CD4+CD25− T Cell Expansion Is Essential for the Development of Arthritis in Autoimmune K/BxN Mice

Jang

Cho²,

Park³

et al. 2009

The Journal of Immunology

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Rheumatoid arthritis is a joint-specific autoimmune inflammatory disease of unknown etiology. The K/BxN mouse is a model of rheumatoid arthritis that is thought to be mainly due to autoantibody-mediated inflammatory responses. We showed previously that homeostatic proliferation of autoreactive CD4+ T cells is required for disease initiation in the K/BxN mice. In this study, we show that the homeostatically proliferating CD4+CD25− T cells produce IL-21. We generated IL-21R-deficient (IL-21R−/−) K/BxN mice and found that these mice were completely refractory to the development of spontaneous arthritis. They contained fewer CD4+ T cells with a reduced proportion of homeostatically proliferating cells, fewer follicular Th cells, and, surprisingly, more Th17 cells than their control counterparts. They also failed to develop IgG1+ memory B cells and autoantigen-specific IgG1 Ab-secreting cells. IL-21 induced expression of receptor activator of NF-κB ligand (RANKL) a regulator of osteoclastogenesis, and few RANKL-expressing infiltrates were found in the synovia of IL-21R−/− K/BxN mice. Thus, our results demonstrate that IL-21 forms a positive feedback autocrine loop involving homeostatically activated CD4+ cells and that it plays an essential role in the development of autoimmune arthritis by mechanisms dependent on follicular Th cell development, autoreactive B cell maturation, and RANKL induction but independent of Th17 cell function. Consistent with this, in vivo administration of soluble the IL-21R-Fc fusion protein delayed the onset and progression of arthritis. Our findings suggest that effective targeting of IL-21-mediated processes may be useful in treating autoimmune arthritis.

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A genetic lesion that arrests plasma cell homing to the bone marrow

Cited by 60 publications

References 58 publications

Expression of the autoimmune Fcgr2b NZW allele fails to be upregulated in germinal center B cells and is associated with increased IgG production

Expression of the autoimmune Fcgr2b NZW allele fails to be upregulated in germinal center B cells and is associated with increased IgG production

The Influence of Effector T Cells and Fas Ligand on Lupus-Associated B Cells

A Positive Feedback Loop of IL-21 Signaling Provoked by Homeostatic CD4+CD25− T Cell Expansion Is Essential for the Development of Arthritis in Autoimmune K/BxN Mice

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