Loss of SWI/SNF Complex Subunit Arid1a in B Cells Promotes Inflammation and Perturbs Germinal Center B Cell Responses

The Switch/Sucrose Non-Fermentable (SWI/SNF) complex is a major mediator of nucleosomal remodeling in eukaryotic genomes and plays a crucial role in the regulation of chromatin accessibility and establishment of gene expression programs. SWI/SNF complex is comprised of ~15 protein subunits, many of which are frequently mutated in several solid tumors and hematological malignancies, including B cell lymphomas. Among SWI/SNF subunits, ARID1a, ARID1B, and SMARCA4 are each mutated in ~10% of Diffuse Large B-Cell Lymphomas, which is a germinal center B cell-derived malignancy representing 95% of all adult lymphomas. Germinal Centers (GC) are microanatomical sites in secondary lymphoid tissues where B cells undergo activation and differentiation, however the role of SWI/SNF complex in GC B cell biology and development of GC-derived malignancies has not been studied.

To address this, we investigated the role of Arid1a, the core subunit of SWI/SNF complex, in GC B cell differentiation and function. Using genetic mouse models with constitutive (CD19 Cre) and activation induced (Cg1 Cre) B cell-specific deletion of Arid1a, our studies revealed that Arid1a is indispensable for the formation of germinal centers. Arid1a-deficient B cells show profound defects in affinity maturation and fail to mount high-affinity antibody responses. However, in contrast, under in vitro conditions mimicking germinal centers, Arid1a-deficient B cells can efficiently undergo activation and class switch recombination, suggesting that Arid1a-deficient B cells are not inherently defective in their ability to proliferate and differentiate in response to stimulation. Interestingly, while Arid1a-deficient activated B cells display a global reduction in chromatin accessibility, this was also accompanied by induction of inflammatory gene and accessibility signatures. A careful examination of B cell-specific Arid1a-deficient mice demonstrated no apparent defects in the initiation of GC response, though, the sustenance of B cells in the GCs was severely compromised. In addition, Arid1a-deficient GC precursors effectively promoted the differentiation of T follicular helper cells, but also enhanced recruitment of inflammatory monocytes and neutrophils at both early and late stages post-immunization, compared to control mice. These studies suggest that Arid1a loss in B cells instigates an inflammatory milieu which may contribute to a pre-mature termination of GC program. Overall, our studies establish a critical role of SWI/SNF complex in GC B cell biology and provides insights for how loss of Arid1a could contribute to pathogenesis of B cell lymphomas. Our work is consistent with recent paradigms highlighting detrimental effects of an inflammatory micro-environment on germinal centers, which is commonly observed in patients with severe bacterial and viral infections.