Functional Consequences of the Developmental Arrest and Follicular Exclusion of Anti-Double-Stranded DNA B Cells

Mandik-Nayak, Laura; Seo, Su-jean; Eaton-Bassiri, Ashlyn; Allman, David; Hardy, Richard R.; Erikson, Jan

doi:10.4049/jimmunol.164.3.1161

Cited by 52 publications

(54 citation statements)

References 43 publications

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“…Bromodeoxyuridine (BrdU)-incorporation experiments have confirmed increased turnover rates in ssDNA-and dsDNA-specific models 14,24,41 , but not for anergic B cells from the insulin-or Sm-specific models.…”

Section: Decreased Lifespanmentioning

confidence: 97%

“…By contrast, BCR-mediated upregulation of CD86 expression is fully functional in insulin-specific B cells from V h 125×V κ 125 mice 27 , yet these cells are unable to mount T-cell-dependent immune responses 26 . Interestingly, all of these anergic B cells, including those from HEL-, Ars-, ssDNA-, insulin-and dsDNA-specific models, can be stimulated by IL-4 and CD40-specific antibody in vitro, suggesting that they are capable of responding to T-cell-derived signals if they are provided in the correct context 27,33,41,65 (S.B.G. and J.C.C., unpublished observations).…”

Section: Biological Consequences Of Bcr Signalling In Anergic Cellsmentioning

confidence: 99%

“…By contrast, some autoreactive B cells proliferate, yet maintain anergy and fail to secrete immunoglobulin in response to TLR ligation 5,13,14,27,41,55 (S.B.G. and J.C.C., unpublished observations).…”

Section: Effects Of Innate Immune Signalsmentioning

confidence: 99%

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B-cell anergy: from transgenic models to naturally occurring anergic B cells?

et al. 2007

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Anergy, a condition in which cells persist in the periphery but are unresponsive to antigen, is responsible for silencing many self-reactive B cells. Loss of anergy is known to contribute to the development of autoimmune diseases, including systemic lupus erythematosus and type 1 diabetes. Multiple transgenic mouse models have enabled the dissection of mechanisms that underlie anergy, and recently, anergic B cells have been identified in the periphery of wild-type mice. Heterogeneity of mechanistic concepts developed using model systems has complicated our understanding of anergy and its biological features. In this Review, we compare and contrast the salient features of anergic B cells with a view to developing unifying mechanistic hypotheses that explain their lifestyles.The generation of B cells occurs throughout life and proceeds through several distinct stages and checkpoints (FIG. 1). After birth, B-cell generation occurs in the bone marrow, where cells progress through pro-B-cell and pre-B-cell stages of development. At the next stage (as immature B cells), they acquire antigen specificity by virtue of expression of a functional Bcell receptor (BCR); this is also the first key specificity checkpoint in B-cell development. Cells that successfully traverse this phase enter the periphery as transitional B cells.The ability of the adaptive immune system to provide protection against pathogens requires a diverse BCR repertoire that can recognize a broad range of foreign proteins. Diversity is generated early in development by random rearrangement of immunoglobulin genes. This inevitably results in the genesis of receptors that recognize self antigens. It is estimated that 75% of human early immature B cells are self-reactive 1 . About a third of these self-reactive immature B cells are purged from the repertoire by receptor editing, wherein renewed immunoglobulin gene rearrangement generates a new light chain to pair with the existing immunoglobulin heavy chain in an anthropomorphic effort to generate a non-self-reactive © 2007 Nature Publishing Group Correspondence to J.C.C. cambierj@njc.org. Competing interests statementThe authors declare no competing financial interests. DATABASES NIH Public Access Author ManuscriptNat Rev Immunol. Author manuscript; available in PMC 2013 July 17. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript BCR 2,3 . Failing this, these B cells are deleted by apoptosis 4 . Despite these mechanisms of central tolerance, many self-reactive B cells escape to the periphery where they are silenced by an induced state of unresponsiveness known as anergy (BOX 1). Anergy can be viewed as nothing more than the state of lethargy that ensues when B cells mount a normal initial response to antigen but fail to receive secondary signals that sustain their activation. Paradoxically, the maintenance of anergy requires chronic binding of antigen and signal transduction, yet the stimulation of unoccupied receptors fails to trigger signal transduction pathways that are...

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Section: Decreased Lifespanmentioning

confidence: 97%

Section: Biological Consequences Of Bcr Signalling In Anergic Cellsmentioning

confidence: 99%

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B-cell anergy: from transgenic models to naturally occurring anergic B cells?

et al. 2007

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“…The pairing of the VH3H9 IgH with the V 1 L chain generates an anti-dsDNA Ab (27,28). This facilitates tracking of anti-dsDNA B cells in vivo in a diverse repertoire by the use of anti-Ig reagents (17)(18)(19).…”

Section: Altered Localization and Cell Surface Phenotype Of Anti-dsdnmentioning

confidence: 99%

Fas/Fas Ligand Deficiency Results in Altered Localization of Anti-Double-Stranded DNA B Cells and Dendritic Cells

Fields

Sokol

Eaton-Bassiri

et al. 2001

The Journal of Immunology

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Autoantibodies directed against dsDNA are found in patients with systemic lupus erythematosus as well as in mice functionally deficient in either Fas or Fas ligand (FasL) (lpr/lpr or gld/gld mice). Previously, an IgH chain transgene has been used to track anti-dsDNA B cells in both nonautoimmune BALB/c mice, in which autoreactive B cells are held in check, and MRL-lpr/lpr mice, in which autoantibodies are produced. In this study, we have isolated the Fas/FasL mutations away from the autoimmune-prone MRL background, and we show that anti-dsDNA B cells in Fas/FasL-deficient BALB/c mice are no longer follicularly excluded, and they produce autoantibodies. Strikingly, this is accompanied by alterations in the frequency and localization of dendritic cells as well as a global increase in CD4 T cell activation. Notably, as opposed to MRL-lpr/lpr mice, BALB-lpr/lpr mice show no appreciable kidney pathology. Thus, while some aspects of autoimmune pathology (e.g., nephritis) rely on the interaction of the MRL background with the lpr mutation, mutations in Fas/FasL alone are sufficient to alter the fate of anti-dsDNA B cells, dendritic cells, and T cells.

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“…B cells that fail to edit successfully away from their autoreactive specificity undergo apoptosis in the bone marrow, prohibiting further differentiation (4,8). Other autoreactive B cells exit the bone marrow and either developmentally arrest at a transitional stage in the spleen (9,10) or become anergic B-2 cells (5,11,12).…”

mentioning

confidence: 99%

Evidence for a Ligand-Mediated Positive Selection Signal in Differentiation to a Mature B Cell

Wang

Clarke

2003

The Journal of Immunology

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Positive selection is required for B cell differentiation, as indicated by the requirement for expression of the pre-B cell receptor (pre-BCR) and the BCR at the pre-B and immature B cell stages, respectively. Positive selection mediated by a tonic signal from these receptors is sufficient to drive B cell differentiation beyond the pre-B and immature B cell stages, but it is unclear whether additional positive selection signals are required for differentiation to a mature B-2 cell. We have identified a population of Ig transgenic B cells that differentiatively arrest at a transitional B cell stage in the spleen. They exhibit no evidence of Ag encounter or negative selection and can differentiate to mature B-2 cells in vivo upon weak BCR stimulation or adoptive transfer to irradiated hosts. These data are consistent with a requirement for a ligand-mediated BCR signal for differentiation to a mature B-2 cell.

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Functional Consequences of the Developmental Arrest and Follicular Exclusion of Anti-Double-Stranded DNA B Cells

Cited by 52 publications

References 43 publications

B-cell anergy: from transgenic models to naturally occurring anergic B cells?

B-cell anergy: from transgenic models to naturally occurring anergic B cells?

Fas/Fas Ligand Deficiency Results in Altered Localization of Anti-Double-Stranded DNA B Cells and Dendritic Cells

Evidence for a Ligand-Mediated Positive Selection Signal in Differentiation to a Mature B Cell

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