The induction of interleukin 2 (IL 2) responsiveness in autoimmune MRL-lpr/lpr mice
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Abstract MRL lpr/lpr mice suffer from a systemic lupus erythematosus‐like autoimmune disease. The lpr mutation impairs the normal transcription of the fas message, the product of which mediates apoptosis and presumably the proper selection of T cells. We have found an early expansion of CD4 + T cells bearing a distinctive Vβ8.3‐Dβ1.1‐Jβ1.1 T cell receptor β chain in the periphery of MRL lpr/lpr mice, which was not detected in MRL +/+ mice nor in the thymus of MRL lpr/lpr mice. Thus, since thymic selection is normal in MRL lpr/lpr mice, we propose that the lpr mutation results in defective negative selection at the periphery.
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RAを含むヒト膠原病と極めて類似した病態,病理を自然発症するMRL/Mp-lpr/lprマウスをモデルとして,その関節炎の発症を規定する遺伝子座を,膠原病を発症しないC3H/HeJ-lpr/lprマウスとのもどし交配系を用いてマッピングした.その結果,関節炎は複数の感受性および抵抗性遺伝子座に支配されていること,また,これらの感受性遺伝子座間に相加性および階層性が存在することが明らかとなった.しかもこれらは唾液腺炎,血管炎,腎炎の疾患感受性遺伝子座とは異なる領域にマップされ, RAが他の膠原病とは遺伝的に分離可能な遺伝子群により支配されている可能性が示唆された.これらはRAをポリジーン系疾患としてシミュレートする上で,また,膠原病の病像多様性の起源を説明する上でも重要な事実であると考えた.
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Systemic lupus erythematosus (SLE) is an autoimmune disease of unknown etiology accompanied by central nervous system involvement in up to 60% of patients. The current study chronicles the expression of cerebellar dysfunction in SLE using MRL-lpr/lpr mice as the experimental model. These mice spontaneously develop an illness that has immunological and clinical features of human lupus. We found that MRL-lpr/lpr mice manifest severe and progressive behavioral disturbances indicative of cerebellar dysfunction beginning at 11 weeks of age. Although the lpr gene is known to induce autoimmune features, immunologically normal mice rendered congenic for lpr failed to exhibit disturbances in cerebellar function. Because lupus is a cytokine-driven disease and overexpression of certain proinflammatory cytokines has been associated with neurodegeneration, the relationship between cerebellar dysfunction and cytokine gene expression was examined. Relative to immunologically normal CBA/J mice, the cerebellum of young (11-15 weeks of age) MRL-lpr/lpr mice contained high levels of interleukin (IL)-6 and interferon-gamma (IFNgamma) mRNA, which became even more pronounced in old (22-30 weeks of age) autoimmune mice. mRNA levels for the cytokines IL-1beta and IL-10 were elevated in the cerebellum of old, but not young, MRL-lpr/lpr mice relative to CBA/J. In contrast, the levels of cerebellar transcripts for IL-3 and tumor necrosis factor-alpha were comparable in autoimmune and normal mice, indicating that enhanced gene expression of IL-6, IFNgamma, IL-1beta, and IL-10 was selective. These results suggest a potential role for certain proinflammatory cytokines in the pathogenesis of cerebellar disturbances in SLE.
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MRL/Mp-lpr/lpr (MRL/l) mice which are lymphoproliferation (lpr) gene-congenic mice of MRL/Mp-+/+ (MRL/n) spontaneously develop glomerulonephritis, arteritis and arthritis characterized by the accumulation of macrophages. In this study we investigated the role of lpr gene expression on the functional activities of resident peritoneal macrophages of MRL strain of mice.MRL/l mice showed remarkable increase of lysosomal enzyme activities and superoxide release of macrophages compared with those of MRL/n mice. In another lpr congenic mice C57BL/6-lpr/lpr (B6/1) showed, however, neither lupus lesions nor the activation of macrophages in spite of the remarkable lymphoproliferation. These results may suggest the importance of background genes of MRL/Mp-+/+ strain of mice in addition to lpr gene expression for the activation of macrophages and further the development of murine lupus of MRL/l mice.
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Abstract The activation of T lymphocytes requires both Ag-mediated signaling through the TCR as well as costimulatory signals transmitted through B7-1 and/or B7-2 with CD28. The interference of B7-mediated costimulatory signals has been proposed as one immunotherapeutic intervention for the prevention autoimmune disease. This study has examined autoantibody responses and autoimmune pathology in a murine model of human systemic lupus erythematosus (SLE), the MRL-lpr/lpr mouse, genetically deficient in B7-1 or B7-2, or in mice treated with B7-1/B7-2 blocking Abs. In contrast to other studies of murine models of SLE, MRL-lpr/lpr mice treated with B7 blocking Abs exhibit strong anti-small nuclear ribonucleoprotein (snRNP) and anti-DNA autoantibody responses with some changes in isotype switching as compared with untreated animals. All MRL-lpr/lpr mice deficient in B7-1 or B7-2 produce anti-snRNP and anti-DNA titers with isotypes virtually identical with wild-type animals. However, the absence of B7-2 costimulation did interfere with the spontaneous activation and the accumulation of memory CD4+ or CD8+ T lymphocytes characteristic of wild-type MRL-lpr/lpr mice. IgG and C3 complement deposition was less pronounced in the kidneys of B7-2 deficient MRL-lpr/lpr mice, reflecting their lessor degree of glomerulonephritis. By comparison, B7-1-deficient MRL-lpr/lpr mice had more severe IgG and C3 deposits in glomeruli.
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Mechanisms responsible for the development of autoimmune skin disease in humans and animal models with lupus remain poorly understood. In this study, we have investigated the role of CD1d, an antigen-presenting molecule known to activate natural killer T cells, in the development of inflammatory dermatitis in lupus-susceptible MRL-lpr/lpr mice. In particular, we have established MRL-lpr/lpr mice carrying a germ-line deletion of the CD1d genes. We demonstrate that CD1d-deficient MRL-lpr/lpr mice, as compared with wild-type littermates, have more frequent and more severe skin disease, with increased local infiltration with mast cells, lymphocytes and dendritic cells, including Langerhans cells. CD1d-deficient MRL-lpr/lpr mice had increased prevalence of CD4(+) T cells in the spleen and liver and of TCR alpha beta (+)B220(+) cells in lymph nodes. Furthermore, CD1d deficiency was associated with decreased T cell production of type 2 cytokines and increased or unchanged type 1 cytokines. These findings indicate a regulatory role of CD1d in inflammatory dermatitis. Understanding the mechanisms by which CD1d deficiency results in splenic T cell expansion and cytokine alterations, with increased dermal infiltration of dendritic cells and lymphocytes in MRL-lpr/lpr mice, will have implications for the pathogenesis of inflammatory skin diseases.
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Abstract MRL/Mpj-lpr/lpr (MRL/lpr) mice develop autoimmune disorders, including lymphoproliferation, glomerulonephritis, autoantibody production, and hypergammaglobulinemia. To investigate the role of the costimulatory molecule CD28 in the development of these disorders, MRL/lpr mice lacking CD28 were generated by gene targeting. Compared with CD28+/+ MRL/lpr mice, CD28−/− MRL/lpr mice showed decreased lymphadenopathy but increased splenomegaly associated with the expansion of abnormal B220+ TCRαβ+ T cells. Although levels of IgM Abs were unchanged in CD28−/− MRL/lpr mice, the production of anti-DNA IgG Abs and IgG rheumatoid factors were suppressed. IgG deposition in the glomeruli was markedly decreased, and the development of glomerulonephritis was significantly retarded. Furthermore, renal vasculitis and arthritis were absent in CD28−/− MRL/lpr mice. These results indicate that, although CD28 is not required for the generation of the abnormal T cell population in MRL/lpr mice, it does play an important role in the development of autoimmune disease in these animals.
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