Study of the role of BANK1 in antibody production and antibody-independent functions of B cells in SLE

Descripción del proyecto

Regulación de la hiperactivación del sistema inmunitario en pacientes con lupus

En las enfermedades autoinmunitarias, el sistema inmunitario ataca por error a sus propios órganos y tejidos sanos. El lupus eritematoso sistémico (LES) está relacionado con la disfunción de los linfocitos B y la producción de autoanticuerpos, lo cual genera fenotipos clínicos heterogéneos. Sin embargo, se sabe poco sobre los mecanismos reguladores que fomentan la función atípica de los linfocitos B en el LES. A fin de responder a esta pregunta, los investigadores del proyecto financiado con fondos europeos RoBE estudiarán la proteína BANK1 de linfocitos B, la cual supuestamente desempeña un papel en la hiperactivación de los linfocitos B. Utilizarán un modelo murino de LES para examinar la implicación de BANK1 en la función efectora y la activación de linfocitos B. Además de la información esencial sobre la fisiopatología de la autoinmunidad, los resultados allanarán el camino hacia nuevos tratamientos.

Objetivo

Systemic Lupus Erythematosus (SLE, Lupus) is a life-threatening and incurable autoimmune disease that affects primarily women, its pathogenesis is related with an exaggerated B cells activation that results both in the generation of antibodies against self-nuclear acid antigens and in the generation of subsets of B cells that can exert antibody-independent roles in Lupus. However, the mechanisms that regulate aberrant B cell functions are poorly understood. In this project, we propose to investigate the role of the B cell scaffold protein with ankyrin repeats 1 (BANK1) in the B cell activation signaling pathways in a mouse model of Lupus. We have previously reported that the absence of BANK1 signaling in mice susceptible to Lupus resulted in the reduction of the activation of B cells, circulating total IgG2c and IgG autoantibodies, pro-inflammatory cytokines, and transcription factors related with TLR7 activation. Our data suggest that BANK1 is an important mediator of B cell hyperactivation. We hypothesize that BANK1 plays an important role in B cell signaling affecting their activation and effector functions in Lupus, however we do not fully understand yet the mechanism behind the function of BANK1. Our specific aims are: 1) to define how BANK1 signaling drives class switch recombination, 2) to determine the mechanism by which BANK1 regulates the cytokine production in B cells, and 3) to examine the participation of BANK1 signaling in the differentiation of pathogenic B cell subsets. To accomplish our objectives, we will use flow and mass cytometry, RNA-based next-generation sequencing (RNA-seq) analysis, the assay for transposase-accessible chromatin followed by deep sequencing (ATAC-seq), and a chromatin immunoprecipitation (ChIP) assay. We expect that the results of these studies will help to understand the molecular mechanism underlying the pathogenic B cell response in Lupus and will lead to identification of new avenues for therapeutic development.