RESUMO
Autoimmune diseases affect more than 23.5million Americans. Traditional therapies for autoimmune diseases involve immunosuppressive drugs that globally dampen immune responses or target and kill large populations of normal immune cells. Both approaches lead to severe dysfunction of the immune system increasing the risk of infections and cancer. Therefore, a more targeted approach, modulating only the pathogenic autoimmune response, would be tremendously beneficial for autoimmune patients. However, only some novel targets involved in pathogenic autoimmune response have been discovered and it is likely that more remain, currently unknown. Here we review the data that have recently been described about T-bet+ B cells (also known as ABCs). Some data suggest that this B cell subset includes cells that are pathogenic in autoimmune responses. Therefore procedures that target these cells might be useful in autoimmune therapies.
Assuntos
Doenças Autoimunes/imunologia , Doenças Autoimunes/terapia , Linfócitos B/imunologia , Proteínas com Domínio T/imunologia , Animais , Subpopulações de Linfócitos B/imunologia , Subpopulações de Linfócitos B/metabolismo , Linfócitos B/metabolismo , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/terapia , Humanos , Modelos Imunológicos , Terapia de Alvo Molecular/métodos , Terapia de Alvo Molecular/tendências , Proteínas com Domínio T/genética , Proteínas com Domínio T/metabolismoRESUMO
A newly discovered B cell subset, age-associated B cells, expresses the transcription factor T-bet, has a unique surface phenotype, and accumulates progressively with age. Moreover, B cells with these general features are associated with viral infections and autoimmunity in both mice and humans. In this article, we review current understanding of the characteristics, origins, and functions of these cells. We also suggest that the protective versus pathogenic actions of these cells reflect appropriate versus aberrant engagement of regulatory mechanisms that control the Ab responses to nucleic acid-containing Ags.
Assuntos
Envelhecimento/imunologia , Autoimunidade/imunologia , Subpopulações de Linfócitos B/imunologia , Inflamação/imunologia , Proteínas com Domínio T/imunologia , Animais , Subpopulações de Linfócitos B/metabolismo , Humanos , Inflamação/metabolismo , Camundongos , Modelos Imunológicos , Transdução de Sinais/imunologia , Proteínas com Domínio T/metabolismoRESUMO
In addition to the secretion of Ag-specific Abs, B cells may play an important role in the generation of immune responses by efficiently presenting Ag to T cells. We and other investigators recently described a subpopulation of CD11c(+) B cells (Age/autoimmune-associated B cells [ABCs]) that appear with age, during virus infections, and at the onset of some autoimmune diseases and participate in autoimmune responses by secreting autoantibodies. In this study, we assessed the ability of these cells to present Ag and activate Ag-specific T cells. We demonstrated that ABCs present Ag to T cells, in vitro and in vivo, better than do follicular B cells (FO cells). Our data indicate that ABCs express higher levels of the chemokine receptor CCR7, have higher responsiveness to CCL21 and CCL19 than do FO cells, and are localized at the T/B cell border in spleen. Using multiphoton microscopy, we show that, in vivo, CD11c(+) B cells form significantly more stable interactions with T cells than do FO cells. Together, these data identify a previously undescribed role for ABCs as potent APCs and suggest another potential mechanism by which these cells can influence immune responses and/or the development of autoimmunity.
Assuntos
Envelhecimento/imunologia , Células Apresentadoras de Antígenos/imunologia , Autoimunidade , Linfócitos B/imunologia , Antígeno CD11c/imunologia , Baço/imunologia , Envelhecimento/genética , Animais , Células Apresentadoras de Antígenos/citologia , Autoanticorpos/biossíntese , Linfócitos B/citologia , Antígeno CD11c/genética , Quimiocina CCL19/genética , Quimiocina CCL19/imunologia , Quimiocina CCL21/genética , Quimiocina CCL21/imunologia , Feminino , Regulação da Expressão Gênica , Camundongos , Camundongos Endogâmicos C57BL , Receptores CCR7/genética , Receptores CCR7/imunologia , Transdução de Sinais , Baço/citologia , Linfócitos T/citologia , Linfócitos T/imunologiaRESUMO
IgG2a is known to be the most efficient antibody isotype for viral clearance. Here, we demonstrate a unique pathway of B-cell activation, leading to IgG2a production, and involving synergistic stimulation via B-cell antigen receptors, toll-like receptor 7 (TLR7), and IFNγ receptors on B cells. This synergistic stimulation leads to induction of T-box transcription factor T-bet expression in B cells, which, in turn, drives expression of CD11b and CD11c on B cells. T-bet/CD11b/CD11c positive B cells appear during antiviral responses and produce high titers of antiviral IgG2a antibodies that are critical for efficient viral clearance. The results thus demonstrate a previously unknown role for T-bet expression in B cells during viral infections. Moreover, the appearance of T-bet(+) B cells during antiviral responses and during autoimmunity suggests a possible link between these two processes.
Assuntos
Autoimunidade/imunologia , Linfócitos B/imunologia , Gammaherpesvirinae/imunologia , Infecções por Herpesviridae/imunologia , Imunoglobulina G/imunologia , Ativação Linfocitária/imunologia , Proteínas com Domínio T/imunologia , Animais , Primers do DNA/genética , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Glicoproteínas de Membrana/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Reação em Cadeia da Polimerase em Tempo Real , Receptores de Interferon/genética , Receptores de Interferon/imunologia , Proteínas com Domínio T/genética , Receptor 7 Toll-Like/imunologia , Receptor de Interferon gamaRESUMO
The majority of autoimmune diseases have a strong gender bias, affecting mostly females. Gender-specific factors like sex-hormones, the presence or absence of a second X chromosome, and gender-specific gut microbiota may contribute to this bias. In this review we will discuss the role of the X chromosome encoded toll-like receptor 7 (TLR7) and interferon gamma (IFNγ) in the development of autoimmunity. We will also review recent data indicating how these factors may affect an immune response in a gender-dependent manner.
Assuntos
Doenças Autoimunes/genética , Subpopulações de Linfócitos B/imunologia , Interferon gama/genética , Proteínas com Domínio T/genética , Receptor 7 Toll-Like/genética , Animais , Doenças Autoimunes/imunologia , Antígeno CD11c/biossíntese , Feminino , Dosagem de Genes/imunologia , Humanos , Camundongos , Caracteres SexuaisRESUMO
Gammaherpesvirus infections, such as those caused by EBV, have been suggested to promote the development of autoimmunity. To test this idea, we infected healthy WT and lupus-prone B6.Sle123 mice with an EBV-related and rodent-specific gammaherpesvirus, γHV68. Although acute γHV68 infection increased autoantibody levels for 4 to 6 wk, latent infection inhibited these responses for 1 y. The inhibition of autoantibody expression was only observed in B6.Sle123 females and not in males, which already displayed lower autoantibody titers. Contrary to the initial hypothesis, infection of young B6.Sle123 mice, both male and female, resulted in suppression of lymphoid activation and expansion and of glomerular inflammation and sclerosis, preserving kidney function. Moreover, γHV68 infection led to reduced autoantibody titers, lymphoid activation, and glomerular inflammation whether lupus-prone females were infected before or during disease manifestation. Finally, γHV68 infection also inhibited autoantibody production in the genetically distinct MRL/lpr lupus-prone mice. Our findings indicate that γHV68 infection strongly inhibits the development and progression of lupus-like disease in mice that spontaneously develop this condition mediating its beneficial effects at the humoral, cellular, and organ levels. The mechanisms by which the virus exerts this down-modulatory action are not yet clear, but appear to operate via reduced activation of dendritic cells, T cells, and B cells. Gammaherpesviruses coevolved with the vertebrate immune systems, establishing lifelong infections in humans and other mammals. Our findings that γHV68 infection prevents rather than exacerbates autoimmunity in mice suggest that infection with gammaherpesviruses may be protective rather than pathological in most individuals.
Assuntos
Autoimunidade , Infecções por Herpesviridae/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Rhadinovirus , Infecções Tumorais por Vírus/imunologia , Animais , Autoanticorpos/sangue , Células Dendríticas/imunologia , Feminino , Infecções por Herpesviridae/complicações , Lúpus Eritematoso Sistêmico/prevenção & controle , Nefrite Lúpica/imunologia , Nefrite Lúpica/prevenção & controle , Ativação Linfocitária , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos MRL lpr , Modelos Imunológicos , Infecções Tumorais por Vírus/complicaçõesRESUMO
Src-like adaptor protein (SLAP) adapts c-Cbl, an E3 ubiquitin ligase, to activated components of the BCR signaling complex regulating BCR levels and signaling in developing B cells. Based on this function, we asked whether SLAP deficiency could decrease the threshold for tolerance and eliminate development of autoreactive B cells in two models of autoantibody production. First, we sensitized mice with a dsDNA mimetope that causes an anti-dsDNA response. Despite equivalent production of anti-peptide antibodies compared to BALB/c controls, SLAP(-/-) mice did not produce anti-dsDNA. Second, we used the 56R tolerance model. SLAP(-/-) 56R mice had decreased levels of dsDNA-reactive antibodies compared to 56R mice due to skewed light chain usage. Thus, SLAP is a critical regulator of B-cell development and function and its deficiency leads to decreased autoreactive B cells that are otherwise maintained by inefficient receptor editing or failed negative selection.
Assuntos
Anticorpos Antinucleares/biossíntese , DNA/imunologia , Proteínas Proto-Oncogênicas pp60(c-src)/deficiência , Animais , Anticorpos Antinucleares/imunologia , Subpopulações de Linfócitos B/imunologia , Subpopulações de Linfócitos B/metabolismo , Feminino , Cadeias Pesadas de Imunoglobulinas/imunologia , Cadeias Pesadas de Imunoglobulinas/metabolismo , Cadeias kappa de Imunoglobulina/imunologia , Cadeias kappa de Imunoglobulina/metabolismo , Cadeias lambda de Imunoglobulina/imunologia , Cadeias lambda de Imunoglobulina/metabolismo , Camundongos , Camundongos Knockout , Proteínas Proto-Oncogênicas pp60(c-src)/genética , Receptores de Antígenos de Linfócitos B/metabolismoRESUMO
Females are more susceptible than males to many autoimmune diseases. The processes causing this phenomenon are incompletely understood. Here, we demonstrate that aged female mice acquire a previously uncharacterized population of B cells that we call age-associated B cells (ABCs) and that these cells express integrin α(X) chain (CD11c). This unexpected population also appears in young lupus-prone mice. On stimulation, CD11c(+) B cells, both from autoimmune-prone and healthy strains of mice, secrete autoantibodies, and depletion of these cells in vivo leads to reduction of autoreactive antibodies, suggesting that the cells might have a direct role in the development of autoimmunity. We have explored factors that contribute to appearance of ABCs and demonstrated that signaling through Toll-like receptor 7 is crucial for development of this B cell population. We were able to detect a similar population of B cells in the peripheral blood of some elderly women with autoimmune disease, suggesting that there may be parallels between the creation of ABC-like cells between mice and humans.
Assuntos
Autoimunidade/imunologia , Linfócitos B/fisiologia , Antígeno CD11c/metabolismo , Proliferação de Células , Receptor 7 Toll-Like/fisiologia , Idoso , Envelhecimento/imunologia , Animais , Doenças Autoimunes/imunologia , Doenças Autoimunes/metabolismo , Doenças Autoimunes/patologia , Autoimunidade/genética , Autoimunidade/fisiologia , Subpopulações de Linfócitos B/citologia , Subpopulações de Linfócitos B/metabolismo , Subpopulações de Linfócitos B/patologia , Subpopulações de Linfócitos B/fisiologia , Linfócitos B/citologia , Linfócitos B/metabolismo , Linfócitos B/patologia , Estudos de Casos e Controles , Células Cultivadas , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Receptor 7 Toll-Like/metabolismoRESUMO
B cells contribute to multiple aspects of autoimmune disorders and may play a role in triggering disease. Thus, targeting B cells may be a promising strategy for treating autoimmune disorders. Better understanding of the B cell subsets that are responsible for the development of autoimmunity will be critical for developing efficient therapies. Here we have reported that B cells expressing the transcription factor T-bet promote the rapid appearance of autoantibodies and germinal centers in spontaneous murine models of systemic lupus erythematosus (SLE). Conditional deletion of T-bet from B cells impaired the formation of germinal centers and mitigated the development of kidney damage and rapid mortality in SLE mice. B cell-specific deletion of T-bet was also associated with lower activation of both B cells and T cells. Taken together, our results suggest that targeting T-bet-expressing B cells may be a potential target for therapy for autoimmune diseases.
Assuntos
Autoimunidade , Linfócitos B/metabolismo , Lúpus Eritematoso Sistêmico/imunologia , Animais , Autoanticorpos/sangue , Células Cultivadas , Feminino , Expressão Gênica , Centro Germinativo/imunologia , Imunoglobulina G/sangue , Rim/patologia , Rim/fisiopatologia , Lúpus Eritematoso Sistêmico/sangue , Ativação Linfocitária , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas com Domínio T/genética , Proteínas com Domínio T/metabolismo , Linfócitos T/metabolismoRESUMO
Knowledge of the processes that underlie IgG subclass switching could inform strategies designed to counteract infections and autoimmunity. Here we show that TLR7 ligands induce subsets of memory CD4 and CD8 T cells to secrete interferon γ (IFNγ) in the absence of antigen receptor stimulation. In turn, TLR ligation and IFNγ cause B cells to express the transcription factor, T-bet, and to switch immunoglobulin production to IgG2a/c. Absence of TLR7 in T cells leads to the impaired T-bet expression in B cells and subsequent inefficient IgG2a isotype switching both in vitro and during the infection with Friend virus in vivo. Our results reveal a surprising mechanism of antiviral IgG subclass switching through T-cell intrinsic TLR7/IL-12 signaling.
Assuntos
Vírus da Leucemia Murina de Friend/fisiologia , Interferon gama/metabolismo , Interleucina-12/farmacologia , Transdução de Sinais/efeitos dos fármacos , Receptor 7 Toll-Like/metabolismo , Animais , Linfócitos B/citologia , Linfócitos B/imunologia , Linfócitos B/virologia , Células da Medula Óssea/citologia , Células Cultivadas , Ensaio de Imunoadsorção Enzimática , Imidazóis/farmacologia , Imunoglobulina G/metabolismo , Interferon gama/análise , Camundongos , Camundongos Endogâmicos C57BL , Fator 88 de Diferenciação Mieloide/metabolismo , Baço/citologia , Baço/efeitos dos fármacos , Baço/metabolismo , Linfócitos T/citologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismo , Receptor 7 Toll-Like/agonistas , Receptor 7 Toll-Like/genéticaRESUMO
Autoimmune diseases occur when the immune system attacks and destroys the organs and tissues of its own host. Autoimmunity is the third most common type of disease in the United States. Because there is no cure for autoimmunity, it is extremely important to study the mechanisms that trigger these diseases. Most autoimmune diseases predominantly affect females, indicating a strong sex bias. Various factors, including sex hormones, the presence or absence of a second X chromosome, and sex-specific gut microbiota can influence gene expression in a sex-specific way. These changes in gene expression may, in turn, lead to susceptibility or protection from autoimmunity, creating a sex bias for autoimmune diseases. In this Review we discuss recent findings in the field of sex-dependent regulation of gene expression and autoimmunity.
Assuntos
Doenças Autoimunes/imunologia , Caracteres Sexuais , Animais , Doenças Autoimunes/epidemiologia , Cromossomos Humanos X/imunologia , Feminino , Regulação da Expressão Gênica/imunologia , Humanos , Masculino , Estados Unidos/epidemiologiaRESUMO
Although autoantibodies are the hallmarks of most autoimmune diseases, the mechanisms by which autoreactive B cells are generated and accumulate are still poorly understood. Overexpression of Toll-like receptor 7 (TLR7) that recognizes single-stranded RNAs has been implicated in systemic lupus erythematosus (SLE), although the cellular mechanism by which this receptor drives the disease is unknown. We recently identified a population of CD11c(+) age-associated B cells (ABCs) which is driven by TLR7 signaling, secretes autoantibodies and appears in autoimmune-prone mice by the time of onset of autoimmunity. Mice lacking the Mer receptor develop autoantibodies and splenomegaly similar to other mouse models of SLE. Here, we show that Mer(-/-) mice that lack TLR7 fail to develop anti-chromatin IgG antibodies, perhaps because they also fail to develop ABCs. Moreover, depletion of CD11c(+) ABCs from Mer(-/-) mice leads to rapid reduction in autoantibodies. Together, these data strongly suggest that ABCs and/or their descendants are the primary source of autoantibodies in Mer(-/-) mice and that TLR7 signaling is crucial for accumulation of ABCs and development of autoantibodies. These data demonstrate for the first time that TLR7, and not TLR9, is responsible for generation of anti-chromatin IgG antibodies in Mer(-/-) mice.
Assuntos
Autoanticorpos/imunologia , Linfócitos B/imunologia , Glicoproteínas de Membrana/imunologia , Receptor 7 Toll-Like/imunologia , Animais , Antígenos de Diferenciação de Linfócitos B/genética , Antígeno CD11c/genética , Toxina Diftérica/farmacologia , Feminino , Proteínas de Fluorescência Verde/genética , Fator de Crescimento Semelhante a EGF de Ligação à Heparina , Imunoglobulina G/sangue , Peptídeos e Proteínas de Sinalização Intercelular/genética , Masculino , Glicoproteínas de Membrana/deficiência , Glicoproteínas de Membrana/genética , Camundongos , Camundongos Transgênicos , Receptores Imunológicos/deficiência , Receptores Imunológicos/genética , Proteínas com Domínio T/imunologia , Receptor 7 Toll-Like/deficiência , Receptor 7 Toll-Like/genéticaRESUMO
Rare dual-reactive B cells expressing two types of Ig light or heavy chains have been shown to participate in immune responses and differentiate into IgG(+) cells in healthy mice. These cells are generated more often in autoreactive mice, leading us to hypothesize they might be relevant in autoimmunity. Using mice bearing Igk allotypic markers and a wild-type Ig repertoire, we demonstrate that the generation of dual-κ B cells increases with age and disease progression in autoimmune-prone MRL and MRL/lpr mice. These dual-reactive cells express markers of activation and are more frequently autoreactive than single-reactive B cells. Moreover, dual-κ B cells represent up to half of plasmablasts and memory B cells in autoimmune mice, whereas they remain infrequent in healthy mice. Differentiation of dual-κ B cells into plasmablasts is driven by MRL genes, whereas the maintenance of IgG(+) cells is partly dependent on Fas inactivation. Furthermore, dual-κ B cells that differentiate into plasmablasts retain the capacity to secrete autoantibodies. Overall, our study indicates that dual-reactive B cells significantly contribute to the plasmablast and memory B cell populations of autoimmune-prone mice suggesting a role in autoimmunity.
Assuntos
Autoimunidade , Linfócitos B/imunologia , Memória Imunológica , Plasmócitos/imunologia , Fatores Etários , Animais , Autoanticorpos/imunologia , Autoanticorpos/metabolismo , Doenças Autoimunes/genética , Doenças Autoimunes/imunologia , Subpopulações de Linfócitos B/imunologia , Linfócitos B/citologia , Linfócitos B/metabolismo , Diferenciação Celular/imunologia , Seleção Clonal Mediada por Antígeno/genética , Seleção Clonal Mediada por Antígeno/imunologia , Feminino , Hibridomas/metabolismo , Imunoglobulina G/imunologia , Imunoglobulinas/genética , Imunoglobulinas/imunologia , Cinética , Ativação Linfocitária/imunologia , Masculino , Camundongos , Camundongos Endogâmicos MRL lpr , Camundongos Transgênicos , Receptor 7 Toll-Like/imunologia , Receptor fas/imunologia , Receptor fas/metabolismoRESUMO
Autoimmunity is controlled both by the environment and by genetic factors. One of the most well defined genetic factors is polymorphisms, with some alleles of particular genes promoting autoimmune diseases, whereas other alleles either not affecting susceptibility to disease or, in some cases actually inhibiting the appearance of such illnesses. Another genetically controlled factor, gender, also plays a profound role in the incidence of autoimmune diseases. For example, Systemic Lupus Erythematosus (SLE) occurs much more frequently in females than in males in both mice and man. The genetic differences that make some individuals susceptible to autoimmunity and protect others could act in many ways and affect many tissues. In this review we will discuss how gender may act on the cells of the immune system and thereby influence the predisposition of the host to autoimmune diseases.
Assuntos
Doenças Autoimunes/genética , Doenças Autoimunes/imunologia , Autoimunidade , Cromossomos Humanos X , Hormônios Esteroides Gonadais/imunologia , Animais , Doenças Autoimunes/epidemiologia , Feminino , Predisposição Genética para Doença , Humanos , Incidência , Masculino , Camundongos , Polimorfismo Genético , Fatores Sexuais , Células Th1/imunologia , Células Th2/imunologiaRESUMO
Although IgM serves as a first barrier to Ag spreading, the cellular and molecular mechanisms following B lymphocyte activation that lead to IgM secretion are not fully understood. By virtue of their anatomical location, marginal zone (MZ) B cells rapidly generate Ag-specific IgM in response to blood-borne pathogens and play an important role in the protection against these potentially harmful Ags. In this study, we have explored the contribution of TLR agonists to MZ B cell activation and mobilization as well as their ability to promote primary IgM responses in a mouse model. We demonstrate that diverse TLR agonists stimulate MZ B cells to become activated and leave the MZ through pathways that are differentially dependent on MyD88 and IFN-alphabeta receptor signaling. Furthermore, in vivo stimulation of MZ B cells with TLR agonists led to a reduction in the expression of the sphingosine-1-phosphate (S1P) receptors expressed by MZ B cells and/or increased CD69 cell surface levels. Importantly, as adjuvants for a T cell-dependent protein Ag, TLR agonists were found to accelerate the kinetics but not magnitude of the Ag-specific IgM response. Together, these data demonstrate that in vivo TLR agonist treatment enhances the early production of Ag-specific IgM and activates MZ B cells to promote their relocation.