Tolerance through indifference: autoreactive B cells to the nuclear antigen La show no evidence of tolerance in a transgenic model (original) (raw)
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Failed self-tolerance and autoimmunity in IgG anti-DNA transgenic mice
The Journal of Immunology
Transgenic mice were generated that express both the H and L chain genes derived from a hybridoma secreting an IgG2a mAb specific for ds- and ssDNA. This hybridoma is derived from a lupus mouse and can accelerate nephritis in young NZB x NZW F1 female mice and induce clinical nephritis in BALB/c mice. Some transgenic B cells did not exhibit allelic exclusion; they expressed both transgene-derived IgG and endogenous IgM intracellularly. Most of the B cells in transgenic mice expressed endogenous IgM, some of them expressed low levels of IgG on cell membranes. The transgenic mice, created in a strain not prone to SLE, expressed elevated serum IgG anti-DNA, and some developed clinical nephritis. The affinity of the spontaneously secreted IgG antibodies for dsDNA were similar in nephritic NZB x NZW F1 and transgenic mice. In contrast to the nontransgenic littermates, immunization of transgenic mice with murine DNA further enhanced serum levels of IgG anti-DNA in transgenic mice. Therefo...
The Journal of Immunology Tolerance to DNA in (NZB � NZW)F 1 Mice That Inherit an
2003
Lupus-prone (NZB � NZW)F 1 (BWF 1) mice were made transgenic (Tg) for an anti-DNA Ab inherited either as a conventional V H3H9- � H chain Tg (3H9-�) with or without a conventional V �8- � Tg, or a V H3H9 V H knock-in Tg allele (3H9R) with or without aV �4V � knock-in Tg allele (V �4R). V H3H9 yields an anti-DNA Ab with most L chains including an anti-ssDNA with the V �8Tg and an anti-dsDNA with the V �4 Tg. BWF 1 mice that inherited the conventional 3H9- � had normal serum IgM, little to none of which was encoded by 3H9-�, and only a small percentage of those mice had serum anti-DNA, none of which was transgene encoded. B cells expressing the conventional 3H9- � Tg were anergic. BWF 1 mice that inherited the knock-in 3H9R Tg allele also had normal serum IgM, one-half of which was encoded by 3H9R, and produced anti-DNA encoded by the Tg allele. Most B cells expressing the knock-in 3H9R Tg also had an anergic phenotype. The results indicate that autoimmune-prone BWF 1 mice initially d...
T Cell Tolerance to Germline-Encoded Antibody Sequences in a Lupus-Prone Mouse
The Journal of Immunology, 2005
The BCR V region has been implicated as a potential avenue of T cell help for autoreactive B cells in systemic lupus erythematosus. In principle, either germline-encoded or somatically generated sequences could function as targets of such help. Preceding studies have indicated that class II MHC-restricted T cells in normal mice attain a state tolerance to germline-encoded Ab diversity. In this study, we tested whether this tolerance is intact in systemic lupus erythematosus-prone (New Zealand Black ؋ SWR)F 1 mice (SNF 1 ). Using a hybridoma sampling approach, we found that SNF 1 T cells were tolerant to germline-encoded Ab sequences. Specifically, they were tolerant to germline-encoded sequences derived from a lupus anti-chromatin Ab that arose spontaneously in this strain. This was true both for diseased and prediseased mice. Thus, there does not appear to be a global defect in T cell tolerance to Ab V regions in this autoimmune-prone strain either before or during autoimmune disease. The Journal of Immunology, 2005, 175: 2184 -2190.
Journal of Experimental Medicine, 1991
Mice homozygous for the gene lpr develop marked lymphadenopathy and a spectrum of autoantibodies closely resembling that of human systemic lupus erythematosus. The unusual T cell phenotype of the expanded lymphocyte population and the T-dependence of several antibodies in this strain have suggested that primary T cell abnormalities underlie the autoimmune syndrome. Using double chimeras, we now show that expression of the lpr gene in B cells is absolutely necessary for autoantibody production. Combinations of antiThy 1 .2 + C' treated bone marrow from congenic strains of C57BL/6 mice, differing only at the immunoglobulin heavy chain (Igh) and lpr loci, were transferred into lethally irradiated B6/lpr mice . Double chimerism was documented by allotype-specific surface IgD and IgM immunofluorescence assay of peripheral blood and by allotype-specific enzyme-linked immunosorbent assay for total IgM in serum. Despite the presence of both +/+ and lpr B cells, IgM and IgG2a anti-chromatin as well as IgM anti-IgG were entirely the products of lpr B cells. Total serum IgG2a and IgG1 were also dominated by the 1pr phenotype but not to the same extent. A similar experiment using B6/lpr-Igh' recipients confirmed these findings . Additional experiments in which B6/lpr recipients were infused with ratios of donor bone marrow favoring B6 .C20 +/+ over B6/lpr showed that even though +/+ B cells were overrepresented, autoantibodies were only of the lpr allotype . In addition, in the presence of lpr B cells, normal B cells showed little response to an exogenous, T cell-dependent antigen. The data thus indicate that 1pr B cells manifest an intrinsic abnormality which is essential for autoantibody production in the lpr model.