title: Overexpression of activation-induced cytidine deaminase in B cells is associated with production of highly pathogenic autoantibodies.
abstract: 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.
authors.affiliation: Division of Clinical Immunology and Rheumatology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Hui-Chen
authors.initials: HC
authors.lastname: Hsu
authors.forename: Yalei
authors.initials: Y
authors.lastname: Wu
authors.forename: Pingar
authors.initials: P
authors.lastname: Yang
authors.forename: Qi
authors.initials: Q
authors.lastname: Wu
authors.forename: Godwin
authors.initials: G
authors.lastname: Job
authors.forename: Jian
authors.initials: J
authors.lastname: Chen
authors.forename: John
authors.initials: J
authors.lastname: Wang
authors.forename: Mary Ann V
authors.initials: MA
authors.lastname: Accavitti-Loper
authors.forename: William E
authors.initials: WE
authors.lastname: Grizzle
authors.forename: Robert H
authors.initials: RH
authors.lastname: Carter
authors.forename: John D
authors.initials: JD
authors.lastname: Mountz
mesh_terms: D000069594:Abatacept; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis*; D001327:Autoimmune Diseases / Q000209:etiology*; D001402:B-Lymphocytes / Q000201:enzymology* / Q000276:immunology*; D051940:B7-2 Antigen / Q000032:analysis; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology; D003564:Cytidine Deaminase / Q000037:antagonists & inhibitors / Q000502:physiology*; D005260:Female; D018796:Immunoconjugates / Q000235:genetics / Q000627:therapeutic use; D017578:Immunoglobulin Class Switching / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D017464:Receptors, Complement 3d / Q000032:analysis; D017455:Receptors, IgE / Q000032:analysis; D027041:Somatic Hypermutation, Immunoglobulin; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: D001323:Autoantibodies; D051940:B7-2 Antigen; C497965:Cd86 protein, mouse; D018796:Immunoconjugates; D017464:Receptors, Complement 3d; D017455:Receptors, IgE; D000069594:Abatacept; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase