B-Cell Tolerance

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Demin Wang - One of the best experts on this subject based on the ideXlab platform.

  • cxcr5 pd 1 follicular helper cd8 t cells control b cell Tolerance
    Nature Communications, 2019
    Co-Authors: Yuhong Chen, Demin Wang, Yongwei Zheng, Robert Burns, Alexander L Dent, Laurent Malherbe, Mei Yu, Guoping Fu, Quan Zhen Li
    Abstract:

    Many autoimmune diseases are characterized by the production of autoantibodies. The current view is that CD4+ T follicular helper (Tfh) cells are the main subset regulating autoreactive B cells. Here we report a CXCR5+PD1+ Tfh subset of CD8+ T cells whose development and function are negatively modulated by Stat5. These CD8+ Tfh cells regulate the germinal center B cell response and control autoantibody production, as deficiency of Stat5 in CD8 T cells leads to an increase of CD8+ Tfh cells, resulting in the breakdown of B cell Tolerance and concomitant autoantibody production. CD8+ Tfh cells share similar gene signatures with CD4+ Tfh, and require CD40L/CD40 and TCR/MHCI interactions to deliver help to B cells. Our study thus highlights the diversity of follicular T cell subsets that contribute to the breakdown of B-Cell Tolerance. B cell response and antibody production are generally facilitated by CD4+ follicular helper (Tfh) cells. Here the authors identify a subset of CXCR5+PD1+CD8+ Tfh cells that is normally suppressed by STAT5 signaling, so that STAT5 deficiency in mice increases the number of these CD8+ Tfh cells and induces concomitant production of autoantibodies.

  • b cell Tolerance regulates production of antibodies causing heparin induced thrombocytopenia
    Blood, 2014
    Co-Authors: Yongwei Zheng, Renren Wen, Alexander W Wang, Anand Padmanabhan, Benjamin E Tourdot, Debra K Newman, Gilbert C White, Richard H Aster, Demin Wang
    Abstract:

    Immune complexes consisting of heparin, platelet factor 4 (PF4), and PF4/heparin-reactive antibodies are central to the pathogenesis of heparin-induced thrombocytopenia (HIT). It is as yet unclear what triggers the initial induction of pathogenic antibodies. We identified B cells in peripheral blood of healthy adults that produce PF4/heparin-specific antibodies following in vitro stimulation with proinflammatory molecules containing deoxycytosine-deoxyguanosine (CpG). Similarly, B cells from unmanipulated wild-type mice produced PF4/heparin-specific antibodies following in vitro or in vivo CpG stimulation. Thus, both healthy humans and mice possess preexisting inactive/tolerant PF4/heparin-specific B cells. The findings suggest that breakdown of Tolerance leads to PF4/heparin-specific B-Cell activation and antibody production in patients developing HIT. Consistent with this concept, mice lacking protein kinase Cδ (PKCδ) that are prone to breakdown of B-Cell Tolerance produced anti-PF4/heparin antibodies spontaneously. Therefore, breakdown of Tolerance can lead to PF4/heparin-specific antibody production, and B-Cell Tolerance may play an important role in HIT pathogenesis.

  • stat5 protein negatively regulates t follicular helper tfh cell generation and function
    Journal of Biological Chemistry, 2012
    Co-Authors: Roza Nurieva, Andrew Podd, Yuhong Chen, Andrei Alekseev, Hua Huang, Renren Wen, Junmei Wang, Stephanie S Watowich, Chen Dong, Demin Wang
    Abstract:

    Recent work has identified a new subset of CD4(+) T cells named as Tfh cells that are localized in germinal centers and critical in germinal center formation. Tfh cell differentiation is regulated by IL-6 and IL-21, possibly via STAT3 factor, and B cell lymphoma 6 (Bcl6) is specifically expressed in Tfh cells and required for their lineage specification. In the current study, we characterized the role of STAT5 in Tfh cell development. We found that a constitutively active form of STAT5 effectively inhibited Tfh differentiation by suppressing the expression of Tfh-associated factors (CXC motif) receptor 5 (CXCR5), musculoaponeurotic fibrosarcoma (c-Maf), Bcl6, basic leucine zipper transcription factor ATF-like (Batf), and IL-21, and STAT5 deficiency greatly enhanced Tfh gene expression. Importantly, STAT5 regulated the expression of Tfh cell suppressor factor B lymphocyte-induced maturation protein 1 (Blimp-1); STAT5 deficiency impaired Blimp-1 expression and resulted in elevated expression of Tfh-specific genes. Similarly, inhibition of IL-2 potentiated Tfh generation, associated with dampened Blimp-1 expression; Blimp-1 overexpression inhibited Tfh gene expression in Stat5-deficient T cells, suggesting that the IL-2/STAT5 axis functions to regulate Blimp-1 expression. In vivo, deletion of STAT5 in CD4(+) T cells resulted in enhanced development of Tfh cells and germinal center B cells and led to an impairment of B cell Tolerance in a well defined mouse Tolerance model. Taken together, this study demonstrates that STAT5 controls Tfh differentiation.

Betty Diamond - One of the best experts on this subject based on the ideXlab platform.

  • prolactin as a modulator of b cell function implications for sle
    Biomedicine & Pharmacotherapy, 2004
    Co-Authors: Elena Peeva, Jeganathan Venkatesh, Daniel Michael, Betty Diamond
    Abstract:

    Prolactin is not only a lactigenic hormone but also an immunomodulator involved in lymphocyte survival, activation and proliferation. There is increasing data implicating prolactin in autoimmunity, and specifically in SLE. Increased serum prolactin levels have been reported in lupus patients of both genders, and have been associated with accelerated disease expression and early mortality in lupus-prone mice. Furthermore, suppression of prolactin secretion with bromocriptine provides beneficial effects in murine lupus, and perhaps in some SLE patients as well. Treatment with prolactin that causes mild to moderate hyperprolactinemia, similar to that present in SLE patients, breaks Tolerance and induces a lupus-like illness in non-spontaneously autoimmune mice with a susceptible genetic background. These immuno stimulatory effects of prolactin are mediated by a decrease in negative selection and the maturation of autoreactive B cells to the follicular subset. Consistent with the fact that follicular B cells are T cell dependent, CD4+ T cells are necessary for the prolactin-mediated break down of B cell Tolerance. In mice, the effects of prolactin on the immune system are genetically determined, suggesting that only a subset of SLE patients are likely to have a prolactin-responsive disease. The manipulation of serum prolactin or, even more specifically, follicular B cells that are susceptible to the immuno stimulatory effects of prolactin, may provide novel therapeutic options for those SLE patients with a prolactin-modulated disease.

  • estrogen alters thresholds for b cell apoptosis and activation
    Journal of Clinical Investigation, 2002
    Co-Authors: Christine M Grimaldi, James Cleary, Selma A Dagtas, Dariush Moussai, Betty Diamond
    Abstract:

    Estrogen is thought to contribute to the increased frequency of autoimmune disorders occurring in females, but a molecular basis for its effects on autoimmunity remains to be elucidated. We have shown previously that estrogen leads to the survival and activation of autoreactive cells in the naive repertoire. To identify the molecular pathways involved in B cell Tolerance, we sought to identify genes that are differentially regulated by estrogen in mouse B cells. Several genes involved in B cell activation and survival, including cd22, shp-1, bcl-2, and vcam-1, were upregulated by estrogen in B cells. We found that overexpression of CD22 and SHP-1 in B cells decreased B cell receptor signaling. Estrogen receptors alpha and beta are expressed on B cells and are functional, since they can directly upregulate expression of CD22, SHP-1, and Bcl-2. Estrogen treatment protected isolated primary B cells from B cell receptor-mediated apoptosis. These results suggest that estrogen induces a genetic program that alters survival and activation of B cells in a B cell-autonomous fashion and thus skews the naive immune system toward autoreactivity.

  • cutting edge expansion and activation of a population of autoreactive marginal zone b cells in a model of estrogen induced lupus
    Journal of Immunology, 2001
    Co-Authors: Christine M Grimaldi, Daniel Michael, Betty Diamond
    Abstract:

    We have demonstrated previously that 17 β-estradiol (E2) treatment of BALB/c mice transgenic for the heavy chain of a pathogenic anti-DNA Ab induces a lupus-like phenotype with expansion of anti-DNA B cells, elevation of anti-DNA Ab titers, and glomerular immunoglobulin deposition. To understand this loss of B cell Tolerance, the effects of E2 on B cell development and activation were examined. A sustained increase in E2 resulted in an altered distribution of B cell subsets, with a diminished transitional population and an increase in marginal zone B cells. Depletion of CD4 + T cells did not abrogate these effects. Furthermore, the B cells that spontaneously secreted anti-DNA Abs displayed a marginal zone phenotype. Thus, a sustained increase in E2 alters B cell development, leading to the survival, expansion, and activation of a population of autoreactive marginal zone B cells implicating this B cell subset in autoimmunity.

  • cutting edge expansion and activation of a population of autoreactive marginal zone b cells in a model of estrogen induced lupus
    Journal of Immunology, 2001
    Co-Authors: Christine M Grimaldi, Daniel Michael, Betty Diamond
    Abstract:

    We have demonstrated previously that 17 beta-estradiol (E2) treatment of BALB/c mice transgenic for the heavy chain of a pathogenic anti-DNA Ab induces a lupus-like phenotype with expansion of anti-DNA B cells, elevation of anti-DNA Ab titers, and glomerular immunoglobulin deposition. To understand this loss of B cell Tolerance, the effects of E2 on B cell development and activation were examined. A sustained increase in E2 resulted in an altered distribution of B cell subsets, with a diminished transitional population and an increase in marginal zone B cells. Depletion of CD4+ T cells did not abrogate these effects. Furthermore, the B cells that spontaneously secreted anti-DNA Abs displayed a marginal zone phenotype. Thus, a sustained increase in E2 alters B cell development, leading to the survival, expansion, and activation of a population of autoreactive marginal zone B cells implicating this B cell subset in autoimmunity.

  • bromocriptine restores Tolerance in estrogen treated mice
    Journal of Clinical Investigation, 2000
    Co-Authors: Elena Peeva, Christine M Grimaldi, Linda Spatz, Betty Diamond
    Abstract:

    Estrogen can modulate autoimmunity in certain models of systemic lupus erythematosus. Recently, we have shown that it can mediate survival and activation of anti-DNA B cells in a mouse transgenic for the heavy chain of a pathogenic anti-DNA antibody. To identify whether estrogen effects reflect increased prolactin secretion, we characterized B-Cell autoreactivity in transgenic mice given both bromocriptine (an inhibitor of prolactin secretion) and estradiol. Treatment of mice with estradiol plus bromocriptine led to reduced titers of anti-DNA antibodies and diminished IgG deposition in kidneys compared with treatment with estradiol alone. However, mice treated with estradiol plus bromocriptine showed an expansion of transgene-expressing B cells and enhanced Bcl-2 expression, similar to those of estradiol-treated mice. We identified anergic high-affinity anti-DNA B cells in mice treated with estradiol plus bromocriptine, and we showed by molecular analysis of anti-DNA hybridomas that their B cells derive from a naive repertoire. Thus, the estradiol-induced breakdown in B-Cell Tolerance can be abrogated by bromocriptine, which induces anergy in the high-affinity DNA-reactive B cells. These studies demonstrate that some of the effects of estrogen on naive autoreactive B cells require the presence of prolactin and, thus, suggest potential therapeutic interventions in lupus.

Eric Meffre - One of the best experts on this subject based on the ideXlab platform.

  • impaired b cell Tolerance checkpoints promote the development of autoimmune diseases and pathogenic autoantibodies
    Immunological Reviews, 2019
    Co-Authors: Eric Meffre, Kevin C Oconnor
    Abstract:

    A role for B cells in autoimmune diseases is now clearly established both in mouse models and humans by successful treatment of multiple sclerosis and rheumatoid arthritis with anti-CD20 monoclonal antibodies that eliminate B cells. However, the underlying mechanisms by which B cells promote the development of autoimmune diseases remain poorly understood. Here, we review evidence that patients with autoimmune disease suffer from defects in early B-Cell Tolerance checkpoints and therefore fail to counterselect developing autoreactive B cells. These B-Cell Tolerance defects are primary to autoimmune diseases and may result from altered B-Cell receptor signaling and dysregulated T-cell/regulatory T-cell compartment. As a consequence, large numbers of autoreactive naive B cells accumulate in the blood of patients with autoimmune diseases and may promote autoimmunity through the presentation of self-antigen to T cells. In addition, new evidence suggests that this reservoir of autoreactive naive B cells contains clones that may develop into CD27- CD21-/lo B cells associated with increased disease severity and plasma cells secreting potentially pathogenic autoantibodies after the acquisition of somatic hypermutations that improve affinity for self-antigens.

  • defective b cell Tolerance in adenosine deaminase deficiency is corrected by gene therapy
    Journal of Clinical Investigation, 2012
    Co-Authors: Aisha V Sauer, Henner Morbach, Immacolata Brigida, Alessandro Aiuti, Eric Meffre
    Abstract:

    Adenosine deaminase (ADA) gene defects are among the most common causes of SCID. Restoration of purine metabolism and immune functions can be achieved by enzyme replacement therapy, or more effectively by bone marrow transplant or HSC gene therapy (HSC-GT). However, autoimmune complications and autoantibody production, including anti-nuclear antibodies (ANAs), frequently occur in ADA-SCID patients after treatment. To assess whether ADA deficiency affects the establishment of B cell Tolerance, we tested the reactivity of recombinant antibodies isolated from single B cells of ADA-SCID patients before and after HSC-GT. We found that before HSC-GT, new emigrant/transitional and mature naive B cells from ADA-SCID patients contained more autoreactive and ANA-expressing clones, indicative of defective central and peripheral B cell Tolerance checkpoints. We further observed impaired B cell receptor (BCR) and TLR functions in B cells after ADA inhibition, which may underlie the defects in B cell Tolerance. Strikingly, after HSC-GT, ADA-SCID patients displayed quasi-normal early B cell Tolerance checkpoints, as evidenced by restored removal of developing autoreactive and ANA-expressing B cells. Hence, ADA plays an essential role in controlling autoreactive B cell counterselection by regulating BCR and TLR functions.

  • response common variable immunodeficiency patients with increased cd21 lo b cells suffer from altered receptor editing and defective central b cell Tolerance
    Blood, 2011
    Co-Authors: Neil Romberg, Charlotte Cunninghamrundles, Eric Meffre
    Abstract:

    The letter by Rakhmanov et al[1][1] suggested that normal κ/λ ratios in CD21+ naive B cells and increased Igλ-chain usage by CD21−/lo B cells in common variable immunodeficiency disease (CVID) patients with expanded CD21−/lo B-Cell populations (CVID group-Ia[2][2]) were evidence of normal or

  • cd40 ligand and mhc class ii expression are essential for human peripheral b cell Tolerance
    Journal of Experimental Medicine, 2007
    Co-Authors: Maxime Herve, Hans D. Ochs, Isabelle Isnardi, James B Bussel, Charlotte Cunninghamrundles, Eric Meffre
    Abstract:

    Hyper-IgM (HIGM) syndromes are primary immunodeficiencies characterized by defects of class switch recombination and somatic hypermutation. HIGM patients who carry mutations in the CD40-ligand (CD40L) gene expressed by CD4+ T cells suffer from recurrent infections and often develop autoimmune disorders. To investigate the impact of CD40L–CD40 interactions on human B cell Tolerance, we tested by ELISA the reactivity of recombinant antibodies isolated from single B cells from three CD40L-deficient patients. Antibody characteristics and reactivity from CD40L-deficient new emigrant B cells were similar to those from healthy donors, suggesting that CD40L–CD40 interactions do not regulate central B cell Tolerance. In contrast, mature naive B cells from CD40L-deficient patients expressed a high proportion of autoreactive antibodies, including antinuclear antibodies. Thus, CD40L–CD40 interactions are essential for peripheral B cell Tolerance. In addition, a patient with the bare lymphocyte syndrome who could not express MHC class II molecules failed to counterselect autoreactive mature naive B cells, suggesting that peripheral B cell Tolerance also depends on major histocompatibility complex (MHC) class II–T cell receptor (TCR) interactions. The decreased frequency of MHC class II–restricted CD4+ regulatory T cells in CD40L-deficient patients suggests that these T cells may mediate peripheral B cell Tolerance through CD40L–CD40 and MHC class II–TCR interactions.

  • defective b cell Tolerance checkpoints in systemic lupus erythematosus
    Journal of Experimental Medicine, 2005
    Co-Authors: Eric Meffre, Sergey Yurasov, Hedda Wardemann, Johanna Hammersen, Makoto Tsuiji, Virginia Pascual, Michel C Nussenzweig
    Abstract:

    A cardinal feature of systemic lupus erythematosus (SLE) is the development of autoantibodies. The first autoantibodies described in patients with SLE were those specific for nuclei and DNA, but subsequent work has shown that individuals with this disease produce a panoply of different autoantibodies. Thus, one of the constant features of SLE is a profound breakdown in Tolerance in the antibody system. The appearance of self-reactive antibodies in SLE precedes clinical disease, but where in the B cell pathway Tolerance is first broken has not been defined. In healthy humans, autoantibodies are removed from the B cell repertoire in two discrete early checkpoints in B cell development. We found these checkpoints to be defective in three adolescent patients with SLE. 25–50% of the mature naive B cells in SLE patients produce self-reactive antibodies even before they participate in immune responses as compared with 5–20% in controls. We conclude that SLE is associated with abnormal early B cell Tolerance.

Yuhong Chen - One of the best experts on this subject based on the ideXlab platform.

  • cxcr5 pd 1 follicular helper cd8 t cells control b cell Tolerance
    Nature Communications, 2019
    Co-Authors: Yuhong Chen, Demin Wang, Yongwei Zheng, Robert Burns, Alexander L Dent, Laurent Malherbe, Mei Yu, Guoping Fu, Quan Zhen Li
    Abstract:

    Many autoimmune diseases are characterized by the production of autoantibodies. The current view is that CD4+ T follicular helper (Tfh) cells are the main subset regulating autoreactive B cells. Here we report a CXCR5+PD1+ Tfh subset of CD8+ T cells whose development and function are negatively modulated by Stat5. These CD8+ Tfh cells regulate the germinal center B cell response and control autoantibody production, as deficiency of Stat5 in CD8 T cells leads to an increase of CD8+ Tfh cells, resulting in the breakdown of B cell Tolerance and concomitant autoantibody production. CD8+ Tfh cells share similar gene signatures with CD4+ Tfh, and require CD40L/CD40 and TCR/MHCI interactions to deliver help to B cells. Our study thus highlights the diversity of follicular T cell subsets that contribute to the breakdown of B-Cell Tolerance. B cell response and antibody production are generally facilitated by CD4+ follicular helper (Tfh) cells. Here the authors identify a subset of CXCR5+PD1+CD8+ Tfh cells that is normally suppressed by STAT5 signaling, so that STAT5 deficiency in mice increases the number of these CD8+ Tfh cells and induces concomitant production of autoantibodies.

  • cxcr5 pd 1 follicular helper cd8 t cells control b cell Tolerance
    PMC, 2019
    Co-Authors: Yuhong Chen, Yongwei Zheng, Gang Xin, Wen Zhu, Lan Luo, Robert Burns, Alexander L Dent, Nan Zhu, Weiguo Cui, Laurent Malherbe
    Abstract:

    Many autoimmune diseases are characterized by the production of autoantibodies. The current view is that CD4+ T follicular helper (Tfh) cells are the main subset regulating autoreactive B cells. Here we report a CXCR5+PD1+ Tfh subset of CD8+ T cells whose development and function are negatively modulated by Stat5. These CD8+ Tfh cells regulate the germinal center B cell response and control autoantibody production, as deficiency of Stat5 in CD8 T cells leads to an increase of CD8+ Tfh cells, resulting in the breakdown of B cell Tolerance and concomitant autoantibody production. CD8+ Tfh cells share similar gene signatures with CD4+ Tfh, and require CD40L/CD40 and TCR/MHCI interactions to deliver help to B cells. Our study thus highlights the diversity of follicular T cell subsets that contribute to the breakdown of B-Cell Tolerance.

  • stat5 protein negatively regulates t follicular helper tfh cell generation and function
    Journal of Biological Chemistry, 2012
    Co-Authors: Roza Nurieva, Andrew Podd, Yuhong Chen, Andrei Alekseev, Hua Huang, Renren Wen, Junmei Wang, Stephanie S Watowich, Chen Dong, Demin Wang
    Abstract:

    Recent work has identified a new subset of CD4(+) T cells named as Tfh cells that are localized in germinal centers and critical in germinal center formation. Tfh cell differentiation is regulated by IL-6 and IL-21, possibly via STAT3 factor, and B cell lymphoma 6 (Bcl6) is specifically expressed in Tfh cells and required for their lineage specification. In the current study, we characterized the role of STAT5 in Tfh cell development. We found that a constitutively active form of STAT5 effectively inhibited Tfh differentiation by suppressing the expression of Tfh-associated factors (CXC motif) receptor 5 (CXCR5), musculoaponeurotic fibrosarcoma (c-Maf), Bcl6, basic leucine zipper transcription factor ATF-like (Batf), and IL-21, and STAT5 deficiency greatly enhanced Tfh gene expression. Importantly, STAT5 regulated the expression of Tfh cell suppressor factor B lymphocyte-induced maturation protein 1 (Blimp-1); STAT5 deficiency impaired Blimp-1 expression and resulted in elevated expression of Tfh-specific genes. Similarly, inhibition of IL-2 potentiated Tfh generation, associated with dampened Blimp-1 expression; Blimp-1 overexpression inhibited Tfh gene expression in Stat5-deficient T cells, suggesting that the IL-2/STAT5 axis functions to regulate Blimp-1 expression. In vivo, deletion of STAT5 in CD4(+) T cells resulted in enhanced development of Tfh cells and germinal center B cells and led to an impairment of B cell Tolerance in a well defined mouse Tolerance model. Taken together, this study demonstrates that STAT5 controls Tfh differentiation.

Elena Peeva - One of the best experts on this subject based on the ideXlab platform.

  • prolactin alters the mechanisms of b cell Tolerance induction
    Arthritis & Rheumatism, 2009
    Co-Authors: Subhrajit Saha, Elena Peeva, Juana Gonzalez, Gabriel Rosenfeld, Harold D Keiser
    Abstract:

    Objective Autoimmune diseases predominantly affect women, suggesting that female sex hormones may play a role in the pathogenesis of such diseases. We have previously shown that persistent mild-to-moderate elevations in serum prolactin levels induce a break in self Tolerance in mice with a BALB/c genetic background. The aim of this study was to evaluate the effects of hyperprolactinemia on the mechanisms of B cell Tolerance induction. Methods Effects of prolactin on splenic B cell subsets were studied in female BALB/c mice. B cell receptor (BCR)–mediated apoptosis and proliferation of transitional B cells were analyzed by flow cytometry. Expression of apoptotic genes was examined by microarrays and real-time polymerase chain reaction analysis. B cells coexpressing κ/λ light chains were assessed by flow cytometry and immunohistochemistry. Activation status of transitional type 3 (T3) B cells was evaluated by BCR-induced calcium influx studies. Results BCR-mediated apoptosis of the T1 B cell subset, a major checkpoint for negative selection of autoreactive specificities, was decreased in prolactin-treated mice. Microarray studies indicated that this event may be mediated by the prolactin-induced up-regulation of the antiapoptotic gene interferon-γ receptor type II and down-regulation of the proapoptotic gene Trp63. Prolactin treatment also altered the amount of receptor editing, as indicated by the increased number of transitional B cells coexpressing κ/λ light chains. Additionally, hyperprolactinemia modified the level of B cell anergy by increasing the degree of BCR-induced calcium influx in the T3 B cells. Conclusion Persistently elevated serum prolactin levels interfere with B cell Tolerance induction by impairing BCR-mediated clonal deletion, deregulating receptor editing, and decreasing the threshold for activation of anergic B cells, thereby promoting autoreactivity.

  • prolactin as a modulator of b cell function implications for sle
    Biomedicine & Pharmacotherapy, 2004
    Co-Authors: Elena Peeva, Jeganathan Venkatesh, Daniel Michael, Betty Diamond
    Abstract:

    Prolactin is not only a lactigenic hormone but also an immunomodulator involved in lymphocyte survival, activation and proliferation. There is increasing data implicating prolactin in autoimmunity, and specifically in SLE. Increased serum prolactin levels have been reported in lupus patients of both genders, and have been associated with accelerated disease expression and early mortality in lupus-prone mice. Furthermore, suppression of prolactin secretion with bromocriptine provides beneficial effects in murine lupus, and perhaps in some SLE patients as well. Treatment with prolactin that causes mild to moderate hyperprolactinemia, similar to that present in SLE patients, breaks Tolerance and induces a lupus-like illness in non-spontaneously autoimmune mice with a susceptible genetic background. These immuno stimulatory effects of prolactin are mediated by a decrease in negative selection and the maturation of autoreactive B cells to the follicular subset. Consistent with the fact that follicular B cells are T cell dependent, CD4+ T cells are necessary for the prolactin-mediated break down of B cell Tolerance. In mice, the effects of prolactin on the immune system are genetically determined, suggesting that only a subset of SLE patients are likely to have a prolactin-responsive disease. The manipulation of serum prolactin or, even more specifically, follicular B cells that are susceptible to the immuno stimulatory effects of prolactin, may provide novel therapeutic options for those SLE patients with a prolactin-modulated disease.

  • bromocriptine restores Tolerance in estrogen treated mice
    Journal of Clinical Investigation, 2000
    Co-Authors: Elena Peeva, Christine M Grimaldi, Linda Spatz, Betty Diamond
    Abstract:

    Estrogen can modulate autoimmunity in certain models of systemic lupus erythematosus. Recently, we have shown that it can mediate survival and activation of anti-DNA B cells in a mouse transgenic for the heavy chain of a pathogenic anti-DNA antibody. To identify whether estrogen effects reflect increased prolactin secretion, we characterized B-Cell autoreactivity in transgenic mice given both bromocriptine (an inhibitor of prolactin secretion) and estradiol. Treatment of mice with estradiol plus bromocriptine led to reduced titers of anti-DNA antibodies and diminished IgG deposition in kidneys compared with treatment with estradiol alone. However, mice treated with estradiol plus bromocriptine showed an expansion of transgene-expressing B cells and enhanced Bcl-2 expression, similar to those of estradiol-treated mice. We identified anergic high-affinity anti-DNA B cells in mice treated with estradiol plus bromocriptine, and we showed by molecular analysis of anti-DNA hybridomas that their B cells derive from a naive repertoire. Thus, the estradiol-induced breakdown in B-Cell Tolerance can be abrogated by bromocriptine, which induces anergy in the high-affinity DNA-reactive B cells. These studies demonstrate that some of the effects of estrogen on naive autoreactive B cells require the presence of prolactin and, thus, suggest potential therapeutic interventions in lupus.