Defining the mechanisms of B cell initiated autoimmune disease

• Published in: The Journal of immunology (1950) Vol. 204; no. 1_Supplement; pp. 218 - 218.5
• Main Authors: Bazile, Cassandra A, Wright, Jacqueline A, Clark, Emily S, Carlesso, Gianluca, Gao, Linlin, Mahmoud, Tamer, Boucher, Justin, Kleiman, Eden, Satterthwaite, Anne B, Harhaj, Edward, Khan, Wasif N
• Format: Journal Article
• Language: English
• Published: 01.05.2020
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.204.Supp.218.5

Abstract Systemic lupus erythematosus (SLE) afflicts more than 1.5 million individuals in the United States with very limited and debilitating therapeutic options. The etiology of the disease remains unclear. It is hypothesized that in SLE, peripheral B cell tolerance is breached by inappropriate survival of autoreactive cells. Consistently, overexpression of B cell activating factor (BAFF), a key regulator of B cell survival can rescue autoreactive B cells and contribute to autoimmune disease. BAFF counters apoptosis in part through decreasing BH3-only pro-apoptotic protein Bim. Notably, both BAFF and Bim are physiological regulators of B cell tolerance. Therefore, to define the role of B cells and B cell tolerance in the initiation and progression of autoimmune disease we created a mouse model wherein gene encoding Bim is selectively deleted in B cells (B.Bimf/f). Initial analyses of these mice suggest that B cells can initiate an autoimmune pathogenesis phenotypically similar to SLE, with mice exhibiting splenomegaly and increased CD21loCD23lo B cells. Given that persistent activity of NF-kB in B cells can also result in autoimmune diseases, we are now investigating whether the persistent NF-kB and dysregulated apoptosis can synergize in SLE pathogenesis. To that end, we have crossed B.Bimf/f mice with a mouse line that lacks a recently discovered potential negative regulator of NF-kB, ZFAND6 (B.Bimf/f x ZfanD6−/−). Preliminary findings suggest that the compound mutant mice display exacerbated autoimmune symptoms with higher incidence of splenomegaly and kidney pathology. These preliminary results suggest that a breach in tolerance (B.Bimf/f ) and persistent NF-kB activity cooperate in the initiation and severity of SLE pathogenesis.