Spontaneous Loss of Tolerance of Autoreactive B Cells in Act1 -Deficient Rheumatoid Factor Transgenic 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: United States 01.09.2013
• Subjects: Adaptor Proteins, Signal Transducing - deficiency; Adaptor Proteins, Signal Transducing - immunology; Animals; Antibody Formation; Autoantibodies - biosynthesis; Autoantibodies - immunology; Autoimmunity - immunology; B-Cell Activating Factor - immunology; B-Lymphocytes - immunology; Enzyme-Linked Immunosorbent Assay; Flow Cytometry; Mice; Mice, Inbred BALB C; Mice, Transgenic; Rheumatoid Factor - genetics; Rheumatoid Factor - immunology; Self Tolerance - immunology
• ISSN: 0022-1767; 1550-6606; 1550-6606
• DOI: 10.4049/jimmunol.1300152

Self-reactive B cells in BALB/c AM14 transgenic (Tg) rheumatoid factor mice are not subject to central or peripheral tolerization. Instead, they remain at a stage of “clonal ignorance”; that is, they do not proliferate and differentiate into Ab-forming 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 Abs. Three- to 5-mo-old AM14 Tg Act1−/− mice showed significant expansion of AM14 Tg B cells, including a 2- to 3-fold increase in the spleen and cervical lymph nodes compared with AM14 Tg Act1+/+ mice. Furthermore, in the presence of endogenous self-Ag (IgHa congenic background), AM14 Tg Act1−/− B cells were spontaneously activated and differentiated into Ab-forming cells. In contrast with previous studies using AM14 Tg MLR.Faslpr mice, we found that a significant number of AM14 Tg cells AM14 Tg Act1−/− mice displayed phenotypic characteristics of germinal center 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.