Spontaneous loss of tolerance of autoreative B cell in Act1-deficient AM14 Tg rheumatoid factor (RF) mice

• Published in: The Journal of immunology (1950) Vol. 191; no. 5; pp. 2155 - 2163
• Main Authors: Giltiay, Natalia V., Lu, Yi, Cullen, Jaime L., Jørgensen, Trine N., Shlomchik, Mark J., Li, Xiaoxia
• Format: Journal Article
• Language: English
• Published: 31.07.2013
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1300152

Self-reactive B cells in BALB/c AM14 transgenic (AM14 Tg) rheumatoid factor (RF) mice are not subject to central or peripheral toleralization. Instead, they remain at a stage of “clonal ignorance”, i.e. they do not proliferate and differentiate into Ab-producing cells. However, the immunoregulatory mechanisms that prevent autoantibody production in these mice remain unclear. In this study, we show that crossing AM14 Tg mice to a mouse strain deficient in Act1, a molecule involved in the regulation of BAFF-R and CD40-signaling in B cells, results in spontaneous activation of AM14 Tg B cells and production of AM14-specific antibodies. Three to five-month old AM14 Tg Act1 −/− mice showed significant expansion of AM14 Tg B cells, including a 2–3 fold increase in the spleen and cLNs compared to AM14 Tg Act1 +/+ mice. Furthermore, in the presence of endogenous self-Ag (IgH a congenic background), AM14 Tg Act1 −/− B cells were spontaneously activated and differentiated into antibody forming cells (AFC). In contrast with previous studies using AM14 Tg MLR.Fas lpr mice, we found that a significant number of AM14 Tg cells AM14 Tg Act1 −/− mice displayed phenotypic characteristics of GC B cells. Anti-CD40L treatment significantly limited the expansion and activation of AM14 Tg Act1 −/− B cells, suggesting that CD40L-mediated signals are required for the retention of these cells. Our results support the important role of Act1 in the regulation of self-reactive B cells and reveal how Act1 functions to prevent the production of autoantibodies.