RESUMEN
Rationale: A subpopulation of B cells (age-associated B cells [ABCs]) is increased in mice and humans with infections or autoimmune diseases. Because depletion of these cells might be valuable in patients with certain lung diseases, the goal was to find out if ABC-like cells were at elevated levels in such patients.Objectives: To measure ABC-like cell percentages in patients with lung granulomatous diseases.Methods: Peripheral blood and BAL cells from patients with sarcoidosis, beryllium sensitivity, or hypersensitivity pneumonitis and healthy subjects were analyzed for the percentage of B cells that were ABC-like, defined by expression of CD11c, low levels of CD21, FcRL 1-5 (Fc receptor-like protein 1-5) expression, and, in some cases, T-bet.Measurements and Main Results: ABC-like cells in blood were at low percentages in healthy subjects and higher percentages in patients with sarcoidosis as well as at high percentages among BAL cells of patients with sarcoidosis, beryllium disease, and hypersensitivity pneumonitis. Treatment of patients with sarcoidosis led to reduced percentages of ABC-like cells in blood.Conclusions: Increased levels of ABC-like cells in patients with sarcoidosis may be useful in diagnosis. The increase in percentage of ABC-like cells in patients with lung granulomatous diseases and decrease in treated patients suggests that depletion of these cells may be valuable.
Asunto(s)
Alveolitis Alérgica Extrínseca/sangre , Subgrupos de Linfocitos B/metabolismo , Beriliosis/sangre , Líquido del Lavado Bronquioalveolar/citología , Sarcoidosis Pulmonar/sangre , Adulto , Anciano , Anciano de 80 o más Años , Alveolitis Alérgica Extrínseca/inmunología , Subgrupos de Linfocitos B/inmunología , Beriliosis/inmunología , Antígeno CD11c/metabolismo , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Proteínas de la Membrana/metabolismo , Persona de Mediana Edad , Receptores de Superficie Celular/metabolismo , Receptores de Complemento 3d/metabolismo , Receptores Fc/metabolismo , Receptores Inmunológicos/metabolismo , Sarcoidosis Pulmonar/inmunología , Proteínas de Dominio T Box/metabolismo , Adulto JovenRESUMEN
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.
Asunto(s)
Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/terapia , Linfocitos B/inmunología , Proteínas de Dominio T Box/inmunología , Animales , Subgrupos de Linfocitos B/inmunología , Subgrupos de Linfocitos B/metabolismo , Linfocitos B/metabolismo , Encefalomielitis Autoinmune Experimental/inmunología , Encefalomielitis Autoinmune Experimental/terapia , Humanos , Modelos Inmunológicos , Terapia Molecular Dirigida/métodos , Terapia Molecular Dirigida/tendencias , Proteínas de Dominio T Box/genética , Proteínas de Dominio T Box/metabolismoRESUMEN
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.
Asunto(s)
Envejecimiento/inmunología , Autoinmunidad/inmunología , Subgrupos de Linfocitos B/inmunología , Inflamación/inmunología , Proteínas de Dominio T Box/inmunología , Animales , Subgrupos de Linfocitos B/metabolismo , Humanos , Inflamación/metabolismo , Ratones , Modelos Inmunológicos , Transducción de Señal/inmunología , Proteínas de Dominio T Box/metabolismoRESUMEN
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.
Asunto(s)
Envejecimiento/inmunología , Células Presentadoras de Antígenos/inmunología , Autoinmunidad , Linfocitos B/inmunología , Antígeno CD11c/inmunología , Bazo/inmunología , Envejecimiento/genética , Animales , Células Presentadoras de Antígenos/citología , Autoanticuerpos/biosíntesis , Linfocitos B/citología , Antígeno CD11c/genética , Quimiocina CCL19/genética , Quimiocina CCL19/inmunología , Quimiocina CCL21/genética , Quimiocina CCL21/inmunología , Femenino , Regulación de la Expresión Génica , Ratones , Ratones Endogámicos C57BL , Receptores CCR7/genética , Receptores CCR7/inmunología , Transducción de Señal , Bazo/citología , Linfocitos T/citología , Linfocitos T/inmunologíaRESUMEN
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.
Asunto(s)
Autoinmunidad/inmunología , Linfocitos B/inmunología , Gammaherpesvirinae/inmunología , Infecciones por Herpesviridae/inmunología , Inmunoglobulina G/inmunología , Activación de Linfocitos/inmunología , Proteínas de Dominio T Box/inmunología , Animales , Cartilla de ADN/genética , Ensayo de Inmunoadsorción Enzimática , Citometría de Flujo , Glicoproteínas de Membrana/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptores de Interferón/genética , Receptores de Interferón/inmunología , Proteínas de Dominio T Box/genética , Receptor Toll-Like 7/inmunología , Receptor de Interferón gammaRESUMEN
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.
Asunto(s)
Enfermedades Autoinmunes/genética , Subgrupos de Linfocitos B/inmunología , Interferón gamma/genética , Proteínas de Dominio T Box/genética , Receptor Toll-Like 7/genética , Animales , Enfermedades Autoinmunes/inmunología , Antígeno CD11c/biosíntesis , Femenino , Dosificación de Gen/inmunología , Humanos , Ratones , Caracteres SexualesRESUMEN
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.
Asunto(s)
Autoinmunidad , Infecciones por Herpesviridae/inmunología , Lupus Eritematoso Sistémico/inmunología , Rhadinovirus , Infecciones Tumorales por Virus/inmunología , Animales , Autoanticuerpos/sangre , Células Dendríticas/inmunología , Femenino , Infecciones por Herpesviridae/complicaciones , Lupus Eritematoso Sistémico/prevención & control , Nefritis Lúpica/inmunología , Nefritis Lúpica/prevención & control , Activación de Linfocitos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos MRL lpr , Modelos Inmunológicos , Infecciones Tumorales por Virus/complicacionesRESUMEN
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.
Asunto(s)
Anticuerpos Antinucleares/biosíntesis , ADN/inmunología , Proteínas Proto-Oncogénicas pp60(c-src)/deficiencia , Animales , Anticuerpos Antinucleares/inmunología , Subgrupos de Linfocitos B/inmunología , Subgrupos de Linfocitos B/metabolismo , Femenino , Cadenas Pesadas de Inmunoglobulina/inmunología , Cadenas Pesadas de Inmunoglobulina/metabolismo , Cadenas kappa de Inmunoglobulina/inmunología , Cadenas kappa de Inmunoglobulina/metabolismo , Cadenas lambda de Inmunoglobulina/inmunología , Cadenas lambda de Inmunoglobulina/metabolismo , Ratones , Ratones Noqueados , Proteínas Proto-Oncogénicas pp60(c-src)/genética , Receptores de Antígenos de Linfocitos B/metabolismoRESUMEN
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.
Asunto(s)
Autoinmunidad/inmunología , Linfocitos B/fisiología , Antígeno CD11c/metabolismo , Proliferación Celular , Receptor Toll-Like 7/fisiología , Anciano , Envejecimiento/inmunología , Animales , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/metabolismo , Enfermedades Autoinmunes/patología , Autoinmunidad/genética , Autoinmunidad/fisiología , Subgrupos de Linfocitos B/citología , Subgrupos de Linfocitos B/metabolismo , Subgrupos de Linfocitos B/patología , Subgrupos de Linfocitos B/fisiología , Linfocitos B/citología , Linfocitos B/metabolismo , Linfocitos B/patología , Estudios de Casos y Controles , Células Cultivadas , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Receptor Toll-Like 7/metabolismoRESUMEN
IgG anti-polysaccharide (PS) responses to both intact Streptococcus pneumoniae (Pn) and PS conjugate vaccines are dependent on CD4(+) T cells, B7-dependent costimulation, and CD40-CD40-ligand interactions. Nevertheless, the former response, in contrast to the latter, is mediated by an ICOS-independent, apoptosis-prone, extrafollicular pathway that fails to generate PS-specific memory. We show that pre-existing PS-specific Igs, the bacterial surface or particulation, selective recruitment of B cell subsets, or activation and recruitment of Pn protein-specific CD4(+) T cells do not account for the failure of Pn to generate PS-specific IgG memory. Rather, the data suggest that the critical factor may be the lack of covalent attachment of PS to protein in intact Pn, highlighting the potential importance of the physicochemical relationship of PS capsule with the underlying bacterial structure for in vivo induction of PS-specific Igs.
Asunto(s)
Bacterias Grampositivas/inmunología , Inmunoglobulina G/inmunología , Polisacáridos Bacterianos/inmunología , Linfocitos T/inmunología , Vacunas Conjugadas/inmunología , Animales , Anticuerpos Antibacterianos/inmunología , Memoria Inmunológica , Ratones , Streptococcus pneumoniae/inmunologíaRESUMEN
Lsc is a hematopoietic-restricted protein that functions as an effector of G alpha(12/13)-associated G-protein coupled receptors that activates RhoA. In the absence of Lsc leukocytes exhibit impaired migration and B lymphocytes inefficiently resolve integrin-mediated adhesion. Here, we demonstrate that Lsc exists physiologically in primary B lymphocytes as a large molecular weight complex resembling a homo-tetramer. Interfering with the assembly of this large molecular weight Lsc oligomer results in the activation of both Lsc functional activities and leads to cell rounding and inhibition of integrin-mediated adhesion. During cell migration on integrin ligands we find Lsc localizes predominantly toward the rear of migrating cells where we suggest it activates RhoA to resolve integin-mediated adhesion. Together these data demonstrate that Lsc regulates integrin-mediated adhesive events at the trailing edge of migrating cells.
Asunto(s)
Factores de Intercambio de Guanina Nucleótido/química , Factores de Intercambio de Guanina Nucleótido/metabolismo , Integrinas/metabolismo , Proteínas Proto-Oncogénicas/química , Proteínas Proto-Oncogénicas/metabolismo , Animales , Linfocitos B/citología , Adhesión Celular , Línea Celular , Estructuras de la Membrana Celular/metabolismo , Polaridad Celular , Humanos , Ratones , Ratones Endogámicos C57BL , Peso Molecular , Estructura Cuaternaria de Proteína , Estructura Terciaria de Proteína , Transporte de Proteínas , Proteínas RGS/metabolismo , Factores de Intercambio de Guanina Nucleótido RhoRESUMEN
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.
Asunto(s)
Autoinmunidad , Linfocitos B/metabolismo , Lupus Eritematoso Sistémico/inmunología , Animales , Autoanticuerpos/sangre , Células Cultivadas , Femenino , Expresión Génica , Centro Germinal/inmunología , Inmunoglobulina G/sangre , Riñón/patología , Riñón/fisiopatología , Lupus Eritematoso Sistémico/sangre , Activación de Linfocitos , Ratones Endogámicos C57BL , Ratones Transgénicos , Proteínas de Dominio T Box/genética , Proteínas de Dominio T Box/metabolismo , Linfocitos T/metabolismoRESUMEN
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.
Asunto(s)
Virus de la Leucemia Murina de Friend/fisiología , Interferón gamma/metabolismo , Interleucina-12/farmacología , Transducción de Señal/efectos de los fármacos , Receptor Toll-Like 7/metabolismo , Animales , Linfocitos B/citología , Linfocitos B/inmunología , Linfocitos B/virología , Células de la Médula Ósea/citología , Células Cultivadas , Ensayo de Inmunoadsorción Enzimática , Imidazoles/farmacología , Inmunoglobulina G/metabolismo , Interferón gamma/análisis , Ratones , Ratones Endogámicos C57BL , Factor 88 de Diferenciación Mieloide/metabolismo , Bazo/citología , Bazo/efectos de los fármacos , Bazo/metabolismo , Linfocitos T/citología , Linfocitos T/efectos de los fármacos , Linfocitos T/metabolismo , Receptor Toll-Like 7/agonistas , Receptor Toll-Like 7/genéticaRESUMEN
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.
Asunto(s)
Enfermedades Autoinmunes/inmunología , Caracteres Sexuales , Animales , Enfermedades Autoinmunes/epidemiología , Cromosomas Humanos X/inmunología , Femenino , Regulación de la Expresión Génica/inmunología , Humanos , Masculino , Estados Unidos/epidemiologíaRESUMEN
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.
Asunto(s)
Autoanticuerpos/inmunología , Linfocitos B/inmunología , Glicoproteínas de Membrana/inmunología , Receptor Toll-Like 7/inmunología , Animales , Antígenos de Diferenciación de Linfocitos B/genética , Antígeno CD11c/genética , Toxina Diftérica/farmacología , Femenino , Proteínas Fluorescentes Verdes/genética , Factor de Crecimiento Similar a EGF de Unión a Heparina , Inmunoglobulina G/sangre , Péptidos y Proteínas de Señalización Intercelular/genética , Masculino , Glicoproteínas de Membrana/deficiencia , Glicoproteínas de Membrana/genética , Ratones , Ratones Transgénicos , Receptores Inmunológicos/deficiencia , Receptores Inmunológicos/genética , Proteínas de Dominio T Box/inmunología , Receptor Toll-Like 7/deficiencia , Receptor Toll-Like 7/genéticaRESUMEN
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.
Asunto(s)
Autoinmunidad , Linfocitos B/inmunología , Memoria Inmunológica , Células Plasmáticas/inmunología , Factores de Edad , Animales , Autoanticuerpos/inmunología , Autoanticuerpos/metabolismo , Enfermedades Autoinmunes/genética , Enfermedades Autoinmunes/inmunología , Subgrupos de Linfocitos B/inmunología , Linfocitos B/citología , Linfocitos B/metabolismo , Diferenciación Celular/inmunología , Selección Clonal Mediada por Antígenos/genética , Selección Clonal Mediada por Antígenos/inmunología , Femenino , Hibridomas/metabolismo , Inmunoglobulina G/inmunología , Inmunoglobulinas/genética , Inmunoglobulinas/inmunología , Cinética , Activación de Linfocitos/inmunología , Masculino , Ratones , Ratones Endogámicos MRL lpr , Ratones Transgénicos , Receptor Toll-Like 7/inmunología , Receptor fas/inmunología , Receptor fas/metabolismoRESUMEN
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.
Asunto(s)
Enfermedades Autoinmunes/genética , Enfermedades Autoinmunes/inmunología , Autoinmunidad , Cromosomas Humanos X , Hormonas Esteroides Gonadales/inmunología , Animales , Enfermedades Autoinmunes/epidemiología , Femenino , Predisposición Genética a la Enfermedad , Humanos , Incidencia , Masculino , Ratones , Polimorfismo Genético , Factores Sexuales , Células TH1/inmunología , Células Th2/inmunologíaRESUMEN
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.
Asunto(s)
Subgrupos de Linfocitos B/inmunología , Subgrupos de Linfocitos B/metabolismo , Inmunoglobulina M/biosíntesis , Activación de Linfocitos/inmunología , Bazo/inmunología , Bazo/metabolismo , Linfocitos T/inmunología , Receptores Toll-Like/agonistas , Adyuvantes Inmunológicos/fisiología , Animales , Subgrupos de Linfocitos B/citología , Movimiento Celular/inmunología , Lipopolisacáridos/farmacología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores de Lisoesfingolípidos/biosíntesis , Receptores de Lisoesfingolípidos/genética , Transducción de Señal/inmunología , Bazo/citología , Receptores Toll-Like/fisiologíaRESUMEN
IgG antipolysaccharide (PS) and antiprotein responses to Streptococcus pneumoniae (Pn) are both CD4(+) T cell dependent. However, the primary IgG anti-PS response terminates more quickly, uses a shorter period of T cell help, fails to generate memory, and is more dependent on membrane Ig (mIg) signaling. We thus determined whether this limited anti-PS response to Pn reflected a greater propensity of PS-specific B cells to undergo apoptosis. We used mice that constitutively expressed the antiapoptotic protein Bcl-x(L) or Bcl-2 as a B cell-specific transgene. Both transgenic (Tg) mice exhibited increased absolute numbers of splenic B-1 and peritoneal B-1b and B-2 cells, subsets implicated in anti-PS responses, but not in marginal zone B (MZB) cells. Both Tg mouse strains elicited, in an apparently Fas-independent manner, a more prolonged and higher peak primary IgM and IgG anti-PS, but not antiprotein, response to Pn, but without PS-specific memory. A similar effect was not observed using purified PS or pneumococcal conjugate vaccine. In vitro, both splenic MZB and follicular Tg B cells synthesized DNA at markedly higher levels than their wild-type counterparts, following mIg cross-linking. This was associated with increased clonal expansion and decreased apoptosis. Using Lsc(-/-) mice, the Pn-induced IgG response specific for the capsular PS was found to be almost entirely dependent on MZB cells. Collectively, these data suggest that apoptosis may limit mIg-dependent clonal expansion of PS-specific B cells during a primary immune response to an intact bacterium, as well as decrease the pool of PS-responding B cell subsets.