T Cell-Independent Spontaneous Loss of Tolerance by Anti-Double-Stranded DNA B Cells in C57BL/6 Mice

• Published in: The Journal of immunology (1950) 2008-12, Vol.181 (11), p.7770-7777
• Main Authors: Tsao, Patricia Y, Jiao, Jing, Ji, Mei Qing, Cohen, Philip L, Eisenberg, Robert A
• Format: Article
• Language: English
• Subjects: Animals; Antibodies, Antinuclear - genetics; Antibodies, Antinuclear - immunology; Antigens, Nuclear - genetics; Antigens, Nuclear - immunology; Autoimmunity - genetics; B-Lymphocytes - immunology; Crosses, Genetic; DNA - immunology; Genes, T-Cell Receptor beta - genetics; Genes, T-Cell Receptor beta - immunology; Genes, T-Cell Receptor gamma - genetics; Genes, T-Cell Receptor gamma - immunology; Immune Tolerance - genetics; Lupus Erythematosus, Systemic - genetics; Lupus Erythematosus, Systemic - immunology; Mice; Mice, Inbred BALB C; Mice, Transgenic; T-Lymphocytes - immunology; Toll-Like Receptor 9 - genetics; Toll-Like Receptor 9 - immunology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.181.11.7770

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.