OBF-1 is essential for the generation of antibody-secreting cells and the development of autoimmunity in MRL-lpr mice Jinxin Zuo a,c , Hailiang Ge b , Guoqiang Zhu c , Patrick Matthias d , Jian Sun a,b, * a Health Science Institute, Shanghai Institutes for Biological Sciences & Shanghai JiaoTong University School of Medicine, Chinese Academy of Sciences, Shanghai 200025, People’s Republic of China b Shanghai Institute of Immunology, Shanghai JiaoTong University School of Medicine, Shanghai 200025, People’s Republic of China c University of Yangzhou School of Veterinary Medicine, Yangzhou 225009, People’s Republic of China d Friedrich Miescher Institute for Biomedical Research, Novartis Research Foundation, CH-4058 Basel, Switzerland Received 2 March 2007; revised 6 May 2007; accepted 7 May 2007 Abstract As reported previously, the lack of the transcriptional co-activator OBF-1 prevented development of autoimmunity in Aiolos knockout mice. To further investigate the role and mechanism of OBF-1 in autoimmunity, we crossed OBF-1 null mice with MRL-lpr mice and generated OBF- 1-deficent MRL-lpr mice. OBF-1 deletion abrogated all autoantibodies in the MRL-lpr mice, including anti-dsDNA Ab and anti-Sm Ab. The failure to produce autoantibodies was not related to development of immature or mature B cells, but correlated with severely reduced antibody- secreting cells (ASCs). The loss of OBF-1 protected against hypergammaglobulinemia, immune complex deposition, glomerulonephritis, and early mortality in MRL-lpr mice. In addition, accumulation of CD4  CD8  B220 þ CD3 þ T cells that characteristically develop in Fas mutation mice were markedly reduced in MRL-lpr mice without OBF-1. These results identify OBF-1 as a critical gene in the development of autoan- tibodies and reveal an essential role for OBF-1 in the generation of antibody/autoantibody-secreting cells in vivo. Ó 2007 Elsevier Ltd. All rights reserved. Keywords: OBF-1/OCA-B/Bob1; Autoantibody; Antibody-secreting cells; Systemic lupus erythematosus; MRL-lpr mice 1. Introduction OBF-1, also known as OCA-B or Bob-1, is a B cell-specific transcriptional co-activator that interacts with the POU domain of Oct-1 or Oct-2, and forms a ternary complex with the oc- tamer motif ATG CAA AT in Ig gene promoters and enhancers [1e5]. Targeted disruption of OBF-1 impairs B cell develop- ment at multiple stages [6e10]. The most striking phenotypes of OBF-1 null mice are the lack of germinal centers (GCs) and severely diminished IgG antibody responses [6e8]; however, class switch recombination appears to be normal in these mice [7]. Although OBF-1 promotes Ig gene transcription in vitro, OBF-1 null mice have mostly normal expression of the Ig genes, except for a subset of the k light-chain [11,12]. It has been previously reported that Aiolos knockout mice develop phenotypes of autoimmune disease that resemble hu- man systemic lupus erythematosus (SLE) and that the lack of OBF-1 prevents the development of autoantibodies and immune complex-mediated glomerulonephritis in Aiolos knockout mice [13]. These findings prompted us to further investigate the effect of OBF-1 on autoimmunity. The MRL/MpJ-Fas lpr/lpr (MRL-lpr) mouse is a well-defined mouse model that sponta- neously develops a severe autoimmune disease similar to that of human SLE [14,15]. For this research effort, we crossed OBF-1 null mice with MRL-lpr mice and generated OBF- 1-deficent MRL-lpr mice. Our results show that the lack of Abbreviations: GC, germinal center; SLE, systemic lupus erythematosus; ASCs, antibody-secreting cells; PAS, periodic acid-Schiff; MRL-lpr, MRL/ MpJ-Fas lpr/lpr ; RF, rheumatoid factor. * Corresponding author at: Laboratory of B cell and Autoantibody, Health Science Institute, 225 South Chongqing Road, Shanghai 200025, People’s Republic of China. Tel./fax: þ86 21 6385 2729. E-mail address: jsun@sibs.ac.cn (J. Sun). 0896-8411/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.jaut.2007.05.001 Journal of Autoimmunity 29 (2007) 87e96 www.elsevier.com/locate/jautimm