RESUMEN
The development of B cells into antibody-secreting plasma cells is central to the adaptive immune system as they induce protective and specific antibody responses against invading pathogens. Various studies have shown that, during this process, hormones can play important roles in the lymphopoiesis, activation, proliferation, and differentiation of B cells, and depending on the signal given by the receptor of each hormone, they can have a positive or negative effect. In autoimmune diseases, hormonal deregulation has been reported to be related to the survival, activation and/or differentiation of autoreactive clones of B cells, thus promoting the development of autoimmunity. Clinical manifestations of autoimmune diseases have been associated with estrogens, prolactin (PRL), and growth hormone (GH) levels. However, androgens, such as testosterone and progesterone (P4), could have a protective effect. The objective of this review is to highlight the links between different hormones and the immune response mediated by B cells in the etiopathogenesis of systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and multiple sclerosis (MS). The data collected provide insights into the role of hormones in the cellular, molecular and/or epigenetic mechanisms that modulate the B-cell response in health and disease.
Asunto(s)
Autoinmunidad , Linfocitos B , Humanos , Linfocitos B/inmunología , Animales , Hormonas/metabolismo , Hormonas/inmunología , Enfermedades Autoinmunes/inmunología , Diferenciación Celular/inmunología , Lupus Eritematoso Sistémico/inmunologíaRESUMEN
Systemic lupus erythematosus (SLE) mainly affects females at reproductive age, which has been associated with hormones, such as prolactin (PRL). Different studies suggest that PRL exacerbates the clinical manifestations of SLE both in patients and in mouse models (e.g., the MRL/lpr strain), increasing the production of autoantibodies, which can be deposited as immune complexes and trigger inflammation and damage to different tissues. The objective of this work was to explore the potential mechanisms by which PRL increases the concentration of self-reactive antibodies in the MRL/lpr SLE model. To this end, we determined the role of PRL on the activation and proliferation of germinal center B cells (B-GCs) and their differentiation into antibody-secreting cells (ASCs). We show that the absolute number and percentage of B-GCs were significantly increased by PRL in vivo or upon in vitro treatment with anti-IgM and anti-CD40 antibodies and PRL. The augmented B-GC numbers correlated with enhanced proliferation, but we did not observe enhanced expression of CD80 and CD86 activation markers or the BCL6 transcription factor, arguing against a more effective differentiation. Nevertheless, we observed enhanced phosphorylation of STAT1, secretion of IL-6, expression of IRF4, numbers of ASCs, and levels of IgG3 antibodies directed against dsDNA. Altogether, these results support the hypothesis that a PRL-mediated expansion of B-GCs yields more self-reactive ASCs, potentially explaining the pathogenic immune complexes that steadily lead to tissue damage during SLE.
Asunto(s)
Autoanticuerpos , Lupus Eritematoso Sistémico , Animales , Femenino , Ratones , Complejo Antígeno-Anticuerpo , Proliferación Celular , Centro Germinal , Inmunoglobulina G , Ratones Endogámicos MRL lpr , Células Plasmáticas , Prolactina/metabolismo , Linfocitos BRESUMEN
The higher frequency of autoimmune diseases in the female population compared to males suggests that certain hormones, such as prolactin (PRL), play a role in determining the prevalence of autoimmunity in women, particularly during childbearing age. PRL can act not only as a hormone but also as a cytokine, being able to modulate immune responses. Hyperprolactinemia has been implicated in the pathogenesis of various autoimmune diseases where it may affect disease activity. One of the conditions where PRL has such a role is systemic lupus erythematosus (SLE). PRL regulates the proliferation and survival of both lymphoid and myeloid cells. It also affects the selection of T-cell repertoires by influencing the thymic microenvironment. In autoimmune conditions, PRL interferes with the activity of regulatory T cells. It also influences B cell tolerance by lowering the activation threshold of anergic B cells. The production of CD40L and cytokines, such as interleukin IL-6, are also promoted by PRL. This, in turn, leads to the production of autoantibodies, one of the hallmarks of SLE. PRL increases the cytotoxic activity of T lymphocytes and the secretion of proinflammatory cytokines. The production of proinflammatory cytokines, particularly those belonging to the type 1 interferon (IFN) family, is part of the SLE characteristic genetic signature. PRL also participates in the maturation and differentiation of dendritic cells, promoting the presentation of autoantigens and high IFNα secretion. It also affects neutrophil function and the production of neutrophil traps. Macrophages and dendritic cells can also be affected by PRL, linking this molecule to the abnormal behavior of both innate and adaptive immune responses.This review aimed to highlight the importance of PRL and its actions on the cells of innate and adaptive immune responses. Additionally, by elucidating the role of PRL in SLE etiopathogenesis, this work will contribute to a better understanding of the factors involved in SLE development and regulation.
Asunto(s)
Enfermedades Autoinmunes , Hiperprolactinemia , Lupus Eritematoso Sistémico , Masculino , Femenino , Humanos , Prolactina/metabolismo , CitocinasRESUMEN
UNLABELLED: Toll-like receptor (TLR)2, TLR4 and CD36 are central in inflammation and the development of atherosclerosis. Oxidized low-density lipoprotein (oxLDL) plays a critical role in this disease through its involvement in the formation of foam cells and the activation of leukocytes. The aim of this research was to analyze the role of TLR2, TLR4 and CD36 in foam cell differentiation and macrophage activation. METHODS: Human macrophages were incubated with monoclonal antibodies specific for TLR2, TLR4 and CD36 prior to stimulation with oxLDL. Subsequently, we analyzed foam cell formation, cytokine secretion, histocompatibility complex (MHC) class II molecules and CD86 expression and T cell proliferation. RESULTS: The stimulation of macrophages with oxLDL induced foam cell formation, cytokine secretion, HLA-DR and CD86 expression and T cell proliferation. The blockage of TLR2, TLR4 and CD36 reduced the secretion of IL-1ß, IL-6 and IL-8, the expression of HLA-DR and CD86, T cell proliferation and foam cell formation. However, the blockage of TLR2 did not affect the formation of foam cells. CONCLUSION: Our study demonstrates that TLR2, TLR4 and CD36 participate in the immune response to oxLDL by inducing an increase in pro-inflammatory cytokines, the expression HLA-DR and CD86 and the proliferation of T cells. However, TLR2 does not participate in the formation of foam cells, while TLR4 and CD36 play a relevant role in this process. These findings suggest that the activation of these receptors by oxLDL contributes to the pathogenesis of atherosclerosis.
Asunto(s)
Antígenos CD36/metabolismo , Células Espumosas , Macrófagos/inmunología , Macrófagos/metabolismo , Receptor Toll-Like 2/metabolismo , Receptor Toll-Like 4/metabolismo , Adulto , Anticuerpos Monoclonales/farmacología , Antígeno B7-2/metabolismo , Antígenos CD36/antagonistas & inhibidores , Células Cultivadas , Citocinas/biosíntesis , Antígenos HLA-DR/inmunología , Antígenos HLA-DR/metabolismo , Voluntarios Sanos , Humanos , Lipoproteínas LDL/farmacología , Activación de Macrófagos/efectos de los fármacos , Activación de Macrófagos/inmunología , Macrófagos/efectos de los fármacos , Masculino , Subgrupos de Linfocitos T/efectos de los fármacos , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Receptor Toll-Like 2/antagonistas & inhibidores , Receptor Toll-Like 4/antagonistas & inhibidores , Adulto JovenRESUMEN
Prolactin (PRL) plays an important role in modulating the immune response. In B cells, PRL enhances antibody production, including antibodies with self-specificity. In this study, our aims were to determine the level of PRL receptor expression during bone-marrow B-cell development and to assess whether the presence of high PRL serum concentrations influences absolute numbers of developing populations and disease outcome in lupus-prone murine models. We observed that the PRL-receptor is expressed in early bone-marrow B-cell; the expression in lupus-prone mice, which had the highest level of expression in pro-B cells and immature cells, differed from that in wild-type mice. These expression levels did not significantly change in response to hyperprolactinemia; however, populations of pro-B and immature cells from lupus-prone strains showed a decrease in the absolute numbers of cells with high PRL-receptor expression in response to PRL. Because immature self-reactive B cells are constantly being eliminated, we assessed the expression of survival factor BIRC5, which is more highly expressed in both pro-B and immature B-cells in response to PRL and correlates with the onset of disease. These results identify an important role of PRL in the early stages of the B-cell maturation process: PRL may promote the survival of self-reactive clones.
Asunto(s)
Linfocitos B/inmunología , Lupus Eritematoso Sistémico/inmunología , Lupus Eritematoso Sistémico/metabolismo , Prolactina/metabolismo , Animales , Anticuerpos Antinucleares/inmunología , Linfocitos B/metabolismo , Modelos Animales de Enfermedad , Femenino , Hiperprolactinemia/genética , Hiperprolactinemia/inmunología , Hiperprolactinemia/metabolismo , Inmunofenotipificación , Proteínas Inhibidoras de la Apoptosis/genética , Proteínas Inhibidoras de la Apoptosis/metabolismo , Lupus Eritematoso Sistémico/genética , Recuento de Linfocitos , Ratones , Ratones Endogámicos MRL lpr , Prolactina/sangre , Receptores de Prolactina/metabolismo , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , SurvivinRESUMEN
Existen evidencias de la relación entre el sistema inmune y el endocrino vía múltiples factores de comunicación, como citocinas, neuropéptidos, neurotransmisores y hormonas. Se ha demostrado la participación de la hormona prolactina en la respuesta inmune innata y adaptativa. Además de ser producida por la glándula pituitaria, también es producida y secretada por las células del sistema inmunológico. El objetivo de esta revisión fue puntualizar acerca de la participación de la prolactina secretada por estas células en la respuesta inmune.
Evidence exists about the relationship between the immune and the endocrine systems through communication of multiple factors such as cytokines, neuropeptides, neurotransmitters and hormones. Among the hormones, prolactin (PRL) has been shown to participate in the innate and adaptive immune response. In addition to being produced by the pituitary gland, PRL is also produced and secreted by cells of the immune system. The aim of this review is to update information about the involvement of PRL secreted by immune system cells in the immune response.
RESUMEN
BACKGROUND: Most infections with human papillomavirus (HPV) are resolved without clinical intervention, but a minority evolves into chronic lesions of distinct grades, including cervical-uterine cancer. It is known that in most cases the immune system mediates elimination of HPV infection. However, the mechanism of immune evasion leading to HPV persistence and development of early cervical lesions is not fully understood. The aim of the present work was to evaluate the potential of peripheral blood leukocytes (PBL) from low-grade squamous intraepithelial lesions (LSIL) patients to be activated ex-vivo by vaccine antigens, the participation of cytotoxic lymphocytes and regulatory T cells, and to determine the secretion of Th1 and Th2 cytokines mediated by stimulation of T cell receptors. RESULTS: We found that PBL from LSIL patients showed a significantly lower proliferation rate to vaccine antigens as compared to that of healthy donors, even though there was not a difference in the presence of antibodies to those antigens in sera from both groups. We did not find differences in either the frequency of CD4 + CD25 + FoxP3+ in PBL, or the levels of IL-4, IL-5 and IL-10 in plasma or conditioned media from PBL incubated with TcR agonists in vitro, between the two groups. However, we detected a lower production of IL-2 and a higher proportion of CD8 + IFNγ + cells in PBL from LSIL patients as compared with PBL from normal donors. We also observed that PBL from patients infected by HPV-16 and -18 were not able to proliferate in the presence of soluble HPV antigens added to the culture; however, a high level of proliferation was attained when these antigens were presented by activated dendritic cells. CONCLUSIONS: Our results suggest that the immunodeficiency reported in LSIL patients could be due to the inability of specific cytotoxic T lymphocytes that for some unknown reason are present but unable to mount a response when challenged with their antigens, probably related to an in situ IL-2 production deficiency.