title: Induction of autoantibody production is limited in nonautoimmune mice.
abstract: Many individuals develop a single or a few brief episodes of autoimmunity from which they recover. Mechanisms that quell pathologic autoimmunity following such a breakdown of self-tolerance are not clearly understood. In this study, we show that in nonautoimmune mice, dsDNA-specific autoreactive B cells exist but remain inactive. This state of inactivation in dsDNA-specific B cells could be disrupted by autoreactive Th cells; in this case T cells that react with peptides from the V(H) region of anti-DNA Abs (hereafter called anti-V(H) T cells). Immunization with anti-DNA mAb, its gamma-chain or peptides derived from its V(H) region induced anti-V(H) Th cells, IgG anti-dsDNA Ab, and proteinuria. The breakdown of B cell tolerance in nonautoimmune mice, however, was short-lived: anti-DNA Ab and nephritis subsided despite subsequent immunizations. The recovery from autoimmunity temporally correlated with the appearance of T cells that inhibited anti-DNA Ab production. Such inhibitory T cells secreted TGFbeta; the inhibition of anti-DNA Ab production by these cells was partly abolished by anti-TGFbeta Ab. Even without immunization, nonautoimmune mice possess T cells that can inhibit autoantibody production. Thus, inhibitory T cells in nonautoimmune mice may normally inhibit T-dependent activation of autoreactive B cells and/or reverse such activation following stimulation by Th cells. The induction of such inhibitory T cells may play a role in protecting nonautoimmune mice from developing chronic autoimmunity.
authors.affiliation: Department of Internal Medicine, University of Cincinnati College of Medicine and Veterans Affairs Medical Center, Cincinnati, OH 45220, USA. singhrm@email.uc.edu
authors.forename: Ram Raj
authors.initials: RR
authors.lastname: Singh
authors.forename: Fanny M
authors.initials: FM
authors.lastname: Ebling
authors.forename: D Alves
authors.initials: DA
authors.lastname: Albuquerque
authors.forename: Vijay
authors.initials: V
authors.lastname: Saxena
authors.forename: Vipin
authors.initials: V
authors.lastname: Kumar
authors.forename: Edward H
authors.initials: EH
authors.lastname: Giannini
authors.forename: Tony N
authors.initials: TN
authors.lastname: Marion
authors.forename: Fred D
authors.initials: FD
authors.lastname: Finkelman
authors.forename: Bevra H
authors.initials: BH
authors.lastname: Hahn
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000974:Antibodies, Antinuclear / Q000096:biosynthesis; D000937:Antigen-Antibody Reactions / Q000235:genetics; D001323:Autoantibodies / Q000096:biosynthesis*; D001324:Autoantigens / Q000276:immunology; D001327:Autoimmune Diseases / Q000276:immunology* / Q000378:metabolism; D016175:B-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D002460:Cell Line; D017635:Clonal Anergy / Q000235:genetics; D003433:Crosses, Genetic; D004247:DNA / Q000276:immunology; D005260:Female; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis; D006825:Hybridomas; D008180:Lupus Erythematosus, Systemic / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008814:Mice, Inbred NZB; D008969:Molecular Sequence Data; D011507:Proteinuria / Q000235:genetics / Q000276:immunology; D017634:Self Tolerance / Q000235:genetics; D013045:Species Specificity; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000502:physiology
chemical_list: D000974:Antibodies, Antinuclear; D001323:Autoantibodies; D001324:Autoantigens; D000949:Histocompatibility Antigens Class II; D016212:Transforming Growth Factor beta; D004247:DNA