The transcription factor Bright plays a role in marginal zone B lymphocyte development and autoantibody production

Abstract

Previous data suggested that constitutive expression of the transcription factor Bright (B cell regulator of immunoglobulin heavy chain transcription), normally tightly regulated during B cell differentiation, was associated with autoantibody production. Here we show that constitutive Bright expression results in skewing of mature B lineage subpopulations toward marginal zone cells at the expense of the follicular subpopulation. C57Bl/6 transgenic mice constitutively expressing Bright in B lineage cells generated autoantibodies that were not the result of global increases in immunoglobulin or of breaches in key tolerance checkpoints typically defective in other autoimmune mouse models. Rather, autoimmunity correlated with increased numbers of marginal zone B cells and alterations in the phenotype and gene expression profiles of lymphocytes within the follicular B cell compartment. These data suggest a novel role for Bright in the normal development of mature B cell subsets and in autoantibody production.

Differential Expression of the Transcription Factor ARID3a in Lupus Patient Hematopoietic Progenitor Cells

“…6) are alternative pre-pro B cells associated with autoreactive immunoglobulin repertoires. However, over-expression of ARID3a in B lineage cells in transgenic mice resulted in autoreactive antibody production (19, 28), and the humanized mouse model data presented herein also suggest that autoantibodies may be preferentially generated in mice reconstituted with ARID3a H versus ARID3a L cells (Table 1). Using a gating strategy characterized by Griffin et al (41, 42), we identified small numbers of putative human B1-like B cells in the spleens of our chimeric mice.…”

“…ARID3a expression in mouse B cells was associated with autoantibody production (19). Therefore, we examined sera from each of the recipient mice for the presence of antinuclear antibodies (ANAs).…”

“…Forced expression of ARID3a/Bright throughout all B lineage cells in mice resulted in the production of anti-nuclear antibodies and immunoglobulin deposition in renal glomeruli (19), common characteristics of patients with systemic lupus erythematosus (SLE). Systemic lupus erythematosus (SLE) is an autoimmune disease manifested by varying degrees of disease severity (reviewed in 20).…”

Whole-exome sequencing in splenic marginal zone lymphoma reveals mutations in genes involved in marginal zone differentiation

“…[22][23][24] Recently, Oldham et al demonstrated that BRIGHT transgenic mice exhibit defects in B-cell maturation and that constitutive Bright expression predisposes B cells to the development of marginal zone differentiation. 25 BTK, which was found to be mutated in one patient here, has a crucial role in B-cell development, marginal zone differentiation and signalling through the BCR/Bruton's tyrosine kinase (BTK) pathway. 26 Interestingly, BTK associates with ARID3A to bind DNA.…”

The Transcription Factor ARID3a Is Important for In Vitro Differentiation of Human Hematopoietic Progenitors

“…Human ARID3a and the mouse orthologue, Bright ( B cell r egulator of i mmuno g lobulin h eavy chain t ranscription) bind to sequences 5′ of some IgH promoters and to the matrix attachment regions (MARs) that flank the intronic IgH enhancer (5–9), where, in association with Bruton’s tyrosine kinase (Btk) and the transcription factor II-I (TFII-I), they upregulate IgH transcription in activated B cells (10, 11). Additional studies with transgenic mice that over-expressed Bright/ARID3a indicated roles for this protein in marginal zone versus follicular B cell fate decisions, and as a contributing factor for production of autoantibodies (12, 13). …”