Induction of autoantibody production is limited in nonautoimmune mice.
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.
Singh
Ram Raj
RR
Department of Internal Medicine, University of Cincinnati College of Medicine and Veterans Affairs Medical Center, Cincinnati, OH 45220, USA. singhrm@email.uc.edu
Ebling
Fanny M
FM
Albuquerque
D Alves
DA
Saxena
Vijay
V
Kumar
Vipin
V
Giannini
Edward H
EH
Marion
Tony N
TN
Finkelman
Fred D
FD
Hahn
Bevra H
BH
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
D000974:Antibodies, Antinuclear; D001323:Autoantibodies; D001324:Autoantigens; D000949:Histocompatibility Antigens Class II; D016212:Transforming Growth Factor beta; D004247:DNA