T cell-independent spontaneous loss of tolerance by anti-double-stranded DNA B cells in C57BL/6 mice.
Systemic lupus erythematosus is characterized by loss of tolerance to DNA and other nuclear Ags. To understand the role of T cells in the breaking of tolerance, an anti-DNA site-specific transgenic model of spontaneous lupus, B6x56R, was studied. T cells were eliminated by crossing B6x56R with CD4(-/)(-) or TCRbeta(-/-)delta(-/-) mice, and the effects on anti-dsDNA serum levels, numbers of anti-dsDNA Ab-secreting cells, and isotypes of anti-dsDNA were analyzed. In addition, the development and activation of B cells in these mice were examined. Surprisingly, the presence of T cells made little difference in the development and character of the serum anti-dsDNA Ab in B6x56R mice. At 1 mo of age, anti-dsDNA Abs were somewhat lower in mice deficient in alphabeta and gammadelta T cells. Levels of Abs later were not affected by T cells, nor was autoantibody class switching. B cell activation was somewhat diminished in T cell-deficient mice. Thus, in the B6 background, the presence of an anti-dsDNA transgene led the production of autoantibodies with a specificity and isotype characteristic of murine systemic lupus erythematosus with little influence from T cells. TLR9 also did not appear to play a role. Although we do not yet understand the mechanism of this failure of immunoregulation, these results suggest that similar processes may influence autoimmunity associated with clinical disease.
Tsao
Patricia Y
PY
Department of Medicine, Division of Rheumatology, University of Pennsylvania, Philadelphia, PA 19104-6100, USA.
Jiao
Jing
J
Ji
Mei Qing
MQ
Cohen
Philip L
PL
Eisenberg
Robert A
RA
D000818:Animals; D000974:Antibodies, Antinuclear / Q000235:genetics / Q000276:immunology; D034961:Antigens, Nuclear / Q000235:genetics / Q000276:immunology*; D015551:Autoimmunity / Q000235:genetics; D001402:B-Lymphocytes / Q000276:immunology*; D003433:Crosses, Genetic; D004247:DNA / Q000276:immunology*; D019674:Genes, T-Cell Receptor beta / Q000235:genetics / Q000276:immunology; D019675:Genes, T-Cell Receptor gamma / Q000235:genetics / Q000276:immunology; D007108:Immune Tolerance / Q000235:genetics; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D013601:T-Lymphocytes / Q000276:immunology*; D051217:Toll-Like Receptor 9 / Q000235:genetics / Q000276:immunology
D000974:Antibodies, Antinuclear; D034961:Antigens, Nuclear; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9; D004247:DNA