RESUMO
Autoreactive B cells that bind self-antigen with high avidity in the bone marrow undergo mechanisms of central tolerance that prevent their entry into the peripheral B cell population. These mechanisms are breached in many autoimmune patients, increasing their risk of B cell-mediated autoimmune diseases. Resolving the molecular pathways that can break central B cell tolerance could therefore provide avenues to diminish autoimmunity. Here, we show that B cell-intrinsic expression of a constitutively active form of PI3K-P110α by high-avidity autoreactive B cells of mice completely abrogates central B cell tolerance and further promotes these cells to escape from the bone marrow, differentiate in peripheral tissue, and undergo activation in response to self-antigen. Upon stimulation with T cell help factors, these B cells secrete antibodies in vitro but remain unable to secrete autoantibodies in vivo. Overall, our data demonstrate that activation of the PI3K pathway leads high-avidity autoreactive B cells to breach central, but not late, stages of peripheral tolerance.
Assuntos
Autoantígenos/imunologia , Autoimunidade/imunologia , Linfócitos B/imunologia , Tolerância Central/imunologia , Classe Ia de Fosfatidilinositol 3-Quinase/metabolismo , Animais , Autoanticorpos/imunologia , Células da Medula Óssea/metabolismo , Diferenciação Celular/imunologia , Feminino , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Modelos Animais , Receptores de Antígenos de Linfócitos B/metabolismo , Receptores de Complemento 3d/metabolismo , Baço/citologia , Linfócitos T/imunologiaRESUMO
Las enfermedades autoinmunes son patologías de gran complejidad clínica, difícil diagnóstico y complejo tratamiento cuya etiología permanece aún desconocida pese a los múltiples avances realizados en los últimos años. En la génesis de estas enfermedades participan múltiples factores que conflyen entre sí para dar origen a cada una de las patologías autoinmunes conocidas, sean estas órgano-específicas o sistémicas. Entre estos elementos se incluyen la pérdida de los mecanismos de tolerancia, factores de susceptibilidad genética (polimorfismos HLA, genes no HLA y mecanismos epigenéticos), factores ambientales (agentes vivos de enfermedad, agentes inorgánicos, hormonas y otros) y factores inmunológicos (linfocitos reguladores, citoquinas y moléculas coestimulatorias, entre otros). La identificación de estos factores permitirá mejorar el conocimiento de los variados mecanismos que median estas complejas enfermedades, facilitando no sólo el entendimiento de su etiología sino también perfeccionar las herramientas terapéuticas para enfrentarlas.
Autoimmune diseases are pathologies of great clinical complexity, difficult diagnosis and treatment complex which etiology still remains unknowns despite the many advances made in recent years. In the genesis of these diseases involves multiple factors that converge together to give rise to each of the autoimmune diseases knows, whether organ specific or systemic. These elements include loss of tolerance mechanisms, genetic susceptibility factors (HLA polymorphisms, genes non-HLA and epigenetic mechanisms), environmental factors (living agents of disease, inorganic agents, hormones, etc.) and immunologic factors (regulators lymphocyte, cytokines, costimulatory molecules and others). Identifying these factors will improve the knowledge of the various mechanisms that mediate these complex diseases facilitating not only the understanding of the etiology but also improve the therapeutic tools to address them.