A human La/SS-B (hLa)-specific TCR/hLa neo-self antigen double transgenic mouse model was developed and used to investigate cellular tolerance and autoimmunity to the ubiquitous RNA-binding La antigen often targeted in systemic lupus erythematosus and Sjögren's syndrome. Extensive thymic clonal deletion of CD4+ T cells occurred in H-2k/k double transgenic mice presenting high levels of the I-Ek-restricted hLa T cell epitope. In contrast, deletion was less extensive in H-2k/b double transgenic mice presenting lower levels of the epitope, and some surviving thymocytes were positively selected as thymic regulatory T cells (tTreg). These mice remained serologically tolerant to hLa and healthy. H-2k/b double transgenic mice deficient of all endogenous Tcra genes, a deficiency known to impair Treg development and function, produced IgG anti-hLa autoantibodies and displayed defective tTreg development. These autoimmune mice had interstitial lung disease characterized by lymphocytic aggregates containing transgenic T cells with an activated, effector memory phenotype. Salivary gland infiltrates were notably absent. Thus, expression of nuclear hLa antigen induces thymic clonal deletion and tTreg selection, and lymphocytic infiltration of the lung is a consequence of La-specific CD4+ T cell autoimmunity.

Objectives-The objectives of this study were to determine whether late apoptotic cell material directly induces autoantibodies characteristic of systemic lupus erythematosus (SLE) and to investigate the innate recognition pathways involved.Methods-B6, B6.MyD88 −/− , B6.TLR7 −/− and B6.TLR9 −/− mice were subcutaneously injected with B6 syngeneic late apoptotic thymocytes (SLATs) without adjuvant on d0, 10, 24 and 37. Sera were tested for IgG antibodies to histones and dsDNA by ELISA and Crithidia luciliae indirect immunofluorescence. IgG and C3 deposition in kidney glomeruli was assessed by immunostaining and fluorescence microscopy.Results-SLAT injections induced anti-dsDNA and anti-histone antibodies of the IgG1 and IgG2b isotypes in B6 but not MyD88 −/− mice. TLR7 −/− and TLR9 −/− mice injected with SLATs produced delayed or slightly more robust responses, respectively. SLAT injections induced IgG deposits in renal glomeruli of B6, TLR7 −/− and TLR9 −/− mice that were absent in MyD88 −/− mice. Unlike B6 and TLR9 −/− animals, TLR7 −/− mice failed to exhibit IgG co-localized glomerular C3 deposits and demonstrated autoantibodies of primarily the IgG2a isotype.Conclusions-Late apoptotic cell-induced anti-histone and anti-dsDNA antibodies require MyD88 but not TLR9. Moreover, TLR7 promotes glomerular C3 deposition, possibly through a mechanism of altered antibody isotype switching.