Taken together these data suggest that decreased cRel expression may be a general characteristic of PBs and PCs irrespective of the nature of stimulation and tissue environment
Taken together these data suggest that decreased cRel expression may be a general characteristic of PBs and PCs irrespective of the nature of stimulation and tissue environment. Repression of is required for ASC differentiation To test the second model prediction that repression is functionally required for ASC differentiation, we used the BCL1 cell collection, which is capable of stimulus-responsive differentiation into ASCs, as obvious by gene expression signature (Sciammas and Davis, 2004) and antibody production (Lin et al., 1997; Sciammas and Davis, 2004). a multi-scale model revealed that dynamic repression of cRel controls the switch from B-cell proliferation to ASC generation phases and hence the respective cell populace dynamics. Our studies provide a mechanistic explanation of how dysregulation of this bi-stable circuit may result in pathologic B-cell populace phenotypes and present avenues for diagnostic stratification and treatment. Leuprolide Acetate Suggested revision: Precise regulation of transcription factor NFkB mediates efficient activation of B-cells and their subsequent differentiation to antibody secreting cells (ASCs). To obtain a quantitative understanding of how specific NFB dimers control ASC differentiation, we developed a mathematical model that investigated NFkB subunits cRel and RelA as unique regulators. This model predicted that cRel inhibits ASC generation. Indeed, cRel was dynamically repressed during ASC differentiation, and ectopic cRel expression blocked ASC differentiation by inhibiting the transcription factor Blimp1. Conversely, Blimp1 inhibited cRel expression by binding the locus. Including this bi-stable circuit of mutual cRel-Blimp1 antagonism into a multi-scale model revealed that dynamic repression of cRel controls the switch from B-cell proliferation to ASC generation phases and hence the respective cell populace dynamics. Our studies provide a mechanistic explanation of how dysregulation of this bi-stable circuit may result in pathologic B-cell populace phenotypes and present avenues for diagnostic stratification and treatment. reveal that while NFB cRel enables proliferation, it must be downregulated during differentiation. Multi-scale modeling shows how coordinated cRel and RelA dynamics control B cell populations in health and disease. Introduction The production of antibody is usually important for an effective immune response and efficacy of vaccination. Recognition of foreign antigen prospects to profound changes within secondary lymphoid organs with the formation of the germinal center (GC) and extrafollicular foci that allow for the ARHGEF7 rapid growth of antigen-specific B-cell clones to produce neutralizing antibody and memory B-cells. Indeed, T-cell impartial (TI) and T-cell dependent (TD) activation of B cells generates rapidly proliferating cells known as activated B cells (ABCs). ABCs may differentiate into actively cycling short lived plasmablasts (PBs), which develop in the early phases of an immune response, and quiescent long-lived plasma cells (PCs), which reside in a specialized bone marrow niche. As both PBs and PCs are capable of generating antibody, they are referred Leuprolide Acetate to as antibody secreting cells (ASCs) (Shapiro-Shelef and Calame, 2005). The transition of ABCs to ASCs is usually coordinated by changes in signaling, gene expression and chromatin regulatory networks. ABC-specific transcription factors such as Pax5 and Bach2, and ASC-specific transcription factors such as Blimp1, regulate unique genetic programs (Kallies et al., 2007; Nutt et al., 2015). Misregulation of these mutually inhibiting transcription factors, caused by common mutations, can result in B cell lymphomas with poor prognosis (Mandelbaum et al., 2010; Nutt et al., 2015; Xia et al., 2017). Transcription factor NFB is also dysregulated in many B cell lymphomas (Shaffer et al., 2002b) and its inhibition is usually lethal to these transformed cells (Ceribelli et al., 2014; Staudt, 2010). NFB is usually a key inflammatory and immune transcription factor consisting of a dozen dimers composed from three activation domain-containing Leuprolide Acetate proteins (cRel, RelA, RelB) and two dimerization partners (p50, p52) (Hoffmann and Baltimore 2006). In ABCs the NFB dimers RelA:p50 and cRel:p50 are induced (Kaileh and Sen, 2012). While cRel activity is required for cell survival, growth and division during B cell activation (Pohl et al., 2002; Shokhirev et Leuprolide Acetate al., 2015), RelA is required for the generation of GC-derived PCs by contributing to Blimp1 activation (Heise et al., 2014). Thus, both cRel and RelA are indispensable for humoral immunity but for different functional reasons. However, a recent study showed that in the genetic disease B cell growth with NFB and T Cell Anergy (BENTA), constitutively active NFB results.
