RESUMO
FcgammaRIIB is an inhibitory receptor which plays a role in limiting B cell and DC activation. Since FcgammaRIIB is known to dampen the signaling strength of the BCR, we wished to determine the impact of FcgammaRIIB on the regulation of BCRs which differ in their affinity for DNA. For these studies, FcgammaRIIB deficient BALB/c mice were bred with mice expressing the transgene-encoded H chain of the R4A anti-DNA antibody which gives rise to BCRs which express high, low or no affinity for DNA. The deletion of FcgammaRIIB in R4A BALB/c mice led to an alteration in the B cell repertoire, allowing for the expansion and activation of high affinity DNA-reactive B cells. By 6-8 months of age, R4A x FcgammaRIIB-/- BALB/c mice spontaneously developed anti-DNA antibody titers. These mice also displayed an induction of IFN-inducible genes and an elevation in levels of the B cell survival factor, BAFF. These data demonstrate that FcgammaRIIB preferentially limits activation of high affinity autoreactive B cells and can influence the activation of DC through an immune complex-mediated mechanism.
Assuntos
Anticorpos Antinucleares/imunologia , Fator Ativador de Células B/imunologia , Linfócitos B/imunologia , Células Dendríticas/imunologia , Receptores de IgG/metabolismo , Animais , Anticorpos Antinucleares/genética , Anticorpos Antinucleares/metabolismo , Fator Ativador de Células B/metabolismo , Linfócitos B/metabolismo , Células Dendríticas/metabolismo , Regulação da Expressão Gênica/genética , Regulação da Expressão Gênica/imunologia , Interferons/genética , Interferons/imunologia , Interferons/metabolismo , Interleucina-10/imunologia , Interleucina-10/metabolismo , Interleucina-6/imunologia , Interleucina-6/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Receptores de IgG/genética , Receptores de IgG/imunologiaRESUMO
PURPOSE OF REVIEW: For many decades, it has been speculated that sex hormones play a role in systemic lupus erythematosus. Recent data accumulated during the past few years provide striking evidence that hormonal modulation of B cells can have a profound impact on the survival, maturation and repertoire selection of autoreactive B cells and begin to explain the sex bias associated with the condition. RECENT FINDINGS: While there are still insufficient clinical data to define a role for estrogen or prolactin in human systemic lupus erythematosus, recent studies of anti-DNA antibody transgenic mice clearly demonstrate that an elevation in either estrogen or prolactin breaks tolerance of high affinity DNA-reactive B cells and induces a lupus phenotype. B cells with the same antigenic specificities are rescued by either estrogen or prolactin, but estrogen promotes the survival and activation of the T independent marginal zone B cell subset, while prolactin promotes the survival and activation of the T dependent follicular B cell subset. SUMMARY: Elevations in the levels of estrogen or prolactin can promote the survival and activation of high affinity autoreactive B cells. These hormones engage different B cell pathways to interfere with B cell tolerance. The identification of systemic lupus erythematosus patients with either an estrogen-responsive or prolactin-responsive disease will further the development of therapeutics that can specifically modulate hormonal responses.
Assuntos
Estrogênios/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Prolactina/imunologia , Tolerância a Antígenos Próprios/imunologia , Caracteres Sexuais , Transdução de Sinais/imunologia , Animais , Anticorpos Antinucleares/genética , Anticorpos Antinucleares/imunologia , Linfócitos B/imunologia , Linfócitos B/patologia , Sobrevivência Celular/imunologia , Feminino , Humanos , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/patologia , Lúpus Eritematoso Sistêmico/terapia , Ativação Linfocitária/imunologia , Masculino , Camundongos , Camundongos Transgênicos , Tolerância a Antígenos Próprios/genética , Transdução de Sinais/genética , Linfócitos T/imunologia , Linfócitos T/patologiaRESUMO
There are increasing data suggesting that sex hormones, such as estrogen, have immunomodulatory effects and play a role in disease progression and pathogenesis in patients with the autoimmune disorder systemic lupus erythematosus. We have shown previously that treatment with 17beta-estradiol (E2) induces a lupus phenotype in BALB/c mice that express a transgene-encoded H chain of an anti-DNA Ab. Because E2 treatment interferes with normal tolerance of naive DNA-reactive B cells, we elected to study the effects of hormonal modulation on the regulation of autoreactive B cells at early developmental checkpoints. Single-cell PCR was performed to study the repertoire of DNA-reactive B cell subsets. High-affinity DNA-reactive B cells were rescued at both the immature and transitional B cell stage in E2-treated mice. Interestingly, although low-affinity DNA-reactive B cells survive negative selection in control mice, the frequency of these cells was significantly reduced in the mature pool of E2-treated mice, suggesting that the high-affinity DNA-reactive cells that mature to immunocompetence out-compete the low-affinity population for survival as mature B cells. These data provide evidence that an elevation in serum levels of E2 facilitates the maturation of a pathogenic naive autoreactive B cell repertoire and hampers the maturation of a potentially protective autoreactive B cell repertoire. Furthermore, these data show that both positive and negative selection occur within the transitional B cell stage.
Assuntos
Subpopulações de Linfócitos B/citologia , Subpopulações de Linfócitos B/metabolismo , Diferenciação Celular/imunologia , DNA/imunologia , Estradiol/farmacologia , Animais , Subpopulações de Linfócitos B/imunologia , Sítios de Ligação/efeitos dos fármacos , Sítios de Ligação/imunologia , Antígenos CD4/genética , Linfócitos T CD4-Positivos/imunologia , Diferenciação Celular/efeitos dos fármacos , DNA/metabolismo , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Camundongos Transgênicos , Baço/citologia , Baço/efeitos dos fármacos , Baço/imunologiaRESUMO
Systemic lupus erythematosus is an autoimmune disorder characterized by the production of pathogenic autoantibodies, primarily to nuclear antigens. The etiology of SLE is not entirely understood, but it is well-appreciated that multiple factors such as genetics and environment contribute to disease progression and pathogenesis. There is also convincing evidence that gender plays an import role in SLE since the incidence of disease occurs with a female to male ratio of 9:1. While it is plausible that some sex-linked genes may contribute to the genetic predisposition for the disease, other likely culprits for this gender bias are the sex hormones estrogen and prolactin. The data implicating estrogen and prolactin in SLE, until recently, were largely circumstantial. However, within the last few years, data collected from both human and mouse studies have provided compelling evidence that alterations in sex hormone levels can alter tolerance of autoreactive B cells and exacerbate disease. In this review, we will discuss recent data demonstrating a role for estrogen and prolactin in SLE and the effect of these hormones on B cell maturation, selection and activation.
Assuntos
Linfócitos B/imunologia , Estrogênios/imunologia , Lúpus Eritematoso Sistêmico/etiologia , Prolactina/imunologia , Animais , Linfócitos B/efeitos dos fármacos , Diferenciação Celular , Estrogênios/metabolismo , Estrogênios/farmacologia , Humanos , Lúpus Eritematoso Sistêmico/imunologia , Prolactina/metabolismo , Prolactina/farmacologiaRESUMO
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.