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Overexpression of Activation-Induced Cytidine Deaminase in B Cells Is Associated with Production of Highly Pathogenic Autoantibodies¹

Hui-Chen Hsu^*, Yalei Wu, PingAr Yang^*, Qi Wu^*, Godwin Job^*, Jian Chen^*, John Wang^*, Mary Ann V. Accavitti-Loper, William E. Grizzle, Robert H. Carter^*,¶ and John D. Mountz^2,*,¶

^* Division of Clinical Immunology and Rheumatology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294; Immunology/Arthritis Section, Department of Immunology, University of California, Veterans Affairs Medical Center, San Francisco, CA 94121; Epitope Recognition Immunoreagent Core, School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294; Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294; and ^¶ Veterans Administration Medical Center, Birmingham, AL 35233

Defective receptor editing or defective B cell checkpoints have been associated with increased frequency of multireactive autoantibodies in autoimmune disease. However, Ig somatic hypermutation and/or class switch recombination may be mechanisms enabling the development of pathogenic multireactive autoantibodies. In this study, we report that, in the BXD2 mouse model of autoimmune disease, elevated expression of activation-induced cytidine deaminase (AID) in recirculating follicular CD86⁺ subsets of B cells and increased germinal center B cell activity are associated with the production of pathogenic multireactive autoantibodies. CD4 T cells from BXD2 mice that expressed increased levels of CD28 and an increased proliferative response to anti-CD3 and anti-CD28 stimulation are required for this process. Inhibition of the CD28-CD86 interaction in BXD2 mice with AdCTLA4-Ig resulted in normalization of AID in the B cells and suppression of IgG autoantibodies. This treatment also prevented the development of germinal center autoantibody-producing B cells, suggesting that an optimal microenvironment enabling AID function is important for the formation of pathogenic autoantibodies. Taken together, our data indicate that AID expression in B cells is a promising therapeutic target for the treatment of autoimmune diseases and that suppression of this gene may be a molecular target of CTLA4-Ig therapy.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by a Birmingham Veterans Administration Medical Center Merit Review Grant (to J.D.M.) and a grant from Daiichi-Sankyo (to J.D.M.). H.-C.H. is a recipient of an Arthritis Foundation Arthritis Investigator Award.

² Address correspondence and reprint requests to Dr. John D. Mountz, University of Alabama at Birmingham, 1825 University Boulevard, Shelby Building Room 310, Birmingham, AL 35294. E-mail address: john.mountz{at}ccc.uab.edu

³ Abbreviations used in this paper: SLE, systemic lupus erythematosus; RA, rheumatoid arthritis; SHM, somatic hypermutation; CSR, class switch recombination; HSP, heat shock protein; GC, germinal center; AID, activation-induced cytidine deamination; FWR, framework region; SA, streptavidin; PNA, peanut lectin agglutinin; MZ, marginal zone; FO, follicular; FM, follicular mature; SMLR, syngeneic mixed lymphocyte response.

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