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Purpose: MRL/MpJ-+/+ (MRL/+) and MRL/MpJ-lpr/lpr (MRL/lpr) mice show spontaneous development of a T-cell-driven lacrimal gland inflammation that is a model for Sjögren syndrome. The lacrimal gland lesions in these mice were evaluated by quantitative RT-PCR for selected cytokine mRNA for the relative contributions of T-helper (Th)1 versus Th2 immune responses and by RT-PCR and immunohistochemistry for the contribution of the interleukin (IL)-2/IL-2 receptor (IL-2R) autocrine pathway., Methods: RNA was isolated from lacrimal glands of MRL/+ mice ages 1 to 9 months and from MRL/lpr mice ages 1 through 5 months, and competitive RT-PCR was used to quantify mRNA for the cytokines IL-2, -4, -10, and -12 and interferon (IFN)-gamma. Frozen sections of lacrimal glands from MRL/+ and MRL/lpr mice ages 2 through 5 months were stained for the IL-2R., Results: IL-2 and -12 mRNA transcripts were below the limit of detection (<10(-3) fg/pg hypoxanthine phosphoribosyl transferase gene; HPRT) in both MRL/+ and MRL/lpr mice of all ages. When detectable, IFN-gamma transcripts were present in low amounts and were below the limit of detection in most samples. IL-4 transcripts were present in 100- to 1000-fold greater amounts than IFN-gamma transcripts. IL-10 transcripts were detectable in both MRL/+ and MRL/lpr mice. IL-2R typically was detected on less than 10% of lymphocytes infiltrating lacrimal gland lesions in both substrains., Conclusions: On the basis of RT-PCR for cytokine mRNA, autoimmune lacrimal gland lesions in MRL/+ and MRL/lpr mice appear to be largely Th2-mediated. There does not appear to be a direct role for the IL-2/IL-2R autocrine pathway within the microenvironment of the lacrimal gland.

Purpose: MRL/MpJ mice spontaneously develop lacrimal gland inflammation and are a model for the human disorder Sjögren's syndrome. MRL/MpJ-lpr/lpr (MRL/lpr) and MRL/Mp-+/+ (MRL/+) mice are congenic substrains, which differ only by a single autosomal recessive gene, the lpr mutation. This mutation results in defective Fas protein, defective lymphocytic apoptosis, and accelerated autoimmune lacrimal gland disease in MRL/lpr mice. We evaluated apoptosis in the lacrimal glands of MRL/lpr and MRL/+ mice., Methods: Inflammatory cells in the lacrimal glands of MRL/lpr and MRL/+ mice were evaluated for apoptosis with TUNEL staining and Fas and Fas ligand expression with immunohistochemistry., Results: MRL/lpr mice had a greater percentage of the lacrimal gland replaced by inflammatory infiltrate (30.3% +/- 7.0%) than did MRL/+ mice (13.0% +/- 3.0%, P = 0.02). However, similar amounts of lymphocytic apoptosis were present in the lacrimal glands of MRL/lpr and MRL/+ mice. The mean number of apoptotic cells per unit area of inflammation was 23.8 +/- 2.4 in MRL/lpr mice and 24.6 +/- 6.0 in MRL/+ mice (P = 0.91). Fas expression was absent on lymphocytes in MRL/lpr mice but was present on lymphocytes in MRL/+ mice. Fas ligand expression was present on epithelial structures in both substrains., Conclusions: The accelerated lacrimal gland disease inflammation in MRL/lpr mice does not appear to be due to decreased apoptosis in the microenvironment of the lacrimal gland of MRL/lpr mice. It appears that in MRL/lpr mice there is defective extrathymic lymphoid apoptosis, permitting a relatively greater expansion of autoreactive T cells, which subsequently invade the lacrimal gland.

Purpose: In MRL/Mp-lpr/lpr (MRL/lpr) and MRL/Mp-+/+ (MRL/+) mice, a T-cell-driven lacrimal gland inflammation spontaneously develops that is a model for Sjögren's syndrome. The lacrimal gland lesions in these mice were evaluated by immunohistochemistry for the relative contributions of T-helper (Th)1 versus Th2 immune responses., Methods: Frozen sections of lacrimal glands from MRL/lpr and MRL/+ mice ages 1 through 5 months were stained with monoclonal antibodies to the cytokines interferon (IFN)-gamma and interleukin (IL)4 and to the cell surface costimulatory molecules B7-1 and B7-2, which are associated with Th1 and Th2 responses, respectively., Results: The median proportion of cells staining for IL-4 ranged from 30% to 67% over time for MRL/lpr mice and from 30% to 55% for MRL/+ mice. The median proportion of cells staining for IFN-gamma ranged from 1% to 5% for MRL/lpr mice and from 0% to 3% for MRL/+ mice. The proportion of cells staining positively for IL-4 was significantly greater than for IFN-gamma in both MRL/lpr (mean difference, 33%; P = 0.0001) and MRL/+ mice (mean difference, 42%; P = 0.0002). The median proportion of cells staining positively for B7-2 ranged from 20% to 38% for MRL/lpr mice and from 16% to 34% for MRL/+ mice. The median proportion of cells staining for B7-1 ranged from 2% to 10% for MRL/lpr mice and from 2% to 5% for MRL/+ mice. The proportion of cells staining positively for B7-2 was significantly greater than for B7-1 for both MRL/lpr mice (mean difference, 15%; P = 0.001) and for MRL/+ mice (mean difference, 19%; P = 0.006)., Conclusions: On the basis of immunohistochemistry for cytokines and costimulatory molecules, inflammatory lacrimal gland lesions in MRL/lpr and MRL/+ mice appear to be a largely Th2 phenomenon.

Purpose: MRL/Mp-lpr/lpr (MRL/lpr) mice spontaneously develop an autoimmune disease characterized by lymphoproliferation, vasculitis, glomerulonephritis, autoantibody production, and ocular and lacrimal gland inflammation. Lacrimal gland lesions in MRL/lpr mice are a model for the human disorder Sjögren's syndrome. The target organ lesions in MRL/lpr mice, including those in the eye and lacrimal gland, are composed largely of CD4+ T cells, with lesser numbers of CD8+ T cells and B cells. Cyclosporine therapy was evaluated for its effect on the autoimmune disease, particularly in the eye and lacrimal gland., Methods: MRL/lpr mice were administered cyclosporine intraperitoneally at a dosage of 2 mg daily from age 1 to 5 months. Animals were killed at 5 months and evaluated for the presence of autoimmune disease. Control groups consisted of animals given daily injections with either saline or the cyclosporine diluent., Results: Cyclosporine therapy was effective in reducing the ocular and lacrimal gland disease. Intraocular inflammation was present in 73% of control animals but in only 15% of cyclosporine-treated animals (P < 0.003). Multifocal lacrimal gland inflammatory infiltrates were present in 100% of controls but in only 23% of cyclosporine-treated animals (P < 0.0001). Mean percent area involved by lacrimal gland inflammation was reduced from 19.7% to 4.7% by cyclosporine therapy (P = 0.0003). Systemic autoimmune disease manifestations, including lymphoproliferation, vasculitis, glomerulonephritis, and serologic abnormalities, also were improved., Conclusions: Chronic cyclosporine therapy, started at an early age, is effective in controlling the autoimmune disease in MRL/lpr mice, including the ocular and lacrimal gland lesions.

Autoimmune MRL/lpr, MRL/+, and NZB/W mice all develop lacrimal gland inflammatory lesions, which consist of focal mononuclear inflammatory cell infiltrates. Each strain has a different immunocytochemical profile, which appears to be related to the underlying immunologic defects present in that mouse. The appearance of these lesions parallels the evolution of the systemic autoimmune disease. The lesions are dynamic over time with the early appearance of CD4+ T cells (helper T cells) for each strain. Subsequently, there is an accumulation of B cells over time in MRL/+ and NZB/W mice. In the two more rapidly evolving mouse models, MRL/lpr and NZB/W, there is a progressive decline in the percentage of CD8+ cells. Conversely, in the slowly evolving MRL/+ lacrimal gland lesions, there is a persistent and unchanging percentage of CD8+ T cells (suppressor/cytotoxic T cells). Autoimmune mice provide models for the human disorder Sjögren's syndrome and a mechanism for better understanding the immunopathogenesis of autoimmune lacrimal gland disease.

Lacrimal gland inflammation develops in a number of autoimmune mice, including the MRL/Mp-lpr/lpr (MRL/lpr), MRL/Mp(-)+/+ (MRL/+), and NZB x NZW F1 hybrid (NZB/W) strains. The authors studied the evolution of this process, MRL/lpr mice had inflammatory lesions at 4 weeks old. The lesions had enlarged by 2 months and were fully developed by 4 to 5 months of age. In MRL/+ mice, 4-week-old mice had no lesions, although some focal inflammation was detectable at 3 months old. Significant abnormalities were present at 6 months, and persisted and increased throughout life, with all mice having extensive lesions at 18 months or older. In NZB/W mice, the authors detected no lesions until 6 months of age, and these lesions were fully developed in 9 months. Immunocytochemical profiles, of the cell types infiltrating the lacrimal gland, showed differences not only between the strains, but also in each strain as inflammation progressed. All three types of mice had L3T4+ T cells as the major lymphocyte component, although MRL/+ had significantly more Lyt 2+ T cells than the other strains. NZB/W mice had significantly more B cells than the two MRL substrains. In both NZB/W and MRL/+ mice, there was a significant increase in the B cell population, and a decrease in the percentage of L3T4+ T cells. There was a significant decline in Lyt 2+ T suppressor/cytotoxic cells in both NZB/W and MRL/lpr mice. This last finding was consistent with the more rapid development of inflammation in these strains than in the MRL/+ mice, where Lyt 2+ T suppressor/cytotoxic cells persist. Together, these results indicate that the autoimmune response in murine models of Sjögren's syndrome is a dynamic, evolving process with strain-related changes in lymphocyte subsets.

Lacrimal gland inflammation develops in several strains of autoimmune mice, including MRL/Mp-lpr/lpr (MRL/lpr), MRL/Mp-+/+ (MRL/+), and NZBxNZW F1 hybrids (NZB/W). These mice all develop an autoimmune disease characterized by glomerulonephritis and autoantibody formation, but each strain has unique clinical features and immunologic abnormalities. Previous studies have suggested that the intrinsic immunologic defect in MRL/lpr mice may be at the level of T cells, while in NZB/W mice it appears to be B cell-mediated. Immunohistologic analysis of the lacrimal gland lesions was performed on all three strains. Although T cells predominated (MRL/lpr 85%, MLR/+ 78%, and NZB/W 57%), differences in the immunohistologic profiles did exist. NZB/W mice had a significantly higher percentage of B cells (33% vs. 10% for MRL/lpr and 13% for MRL/+) and a correspondingly lower percentage of T cells. MRL/lpr mice differed from MRL/+ mice in that they exhibited a significantly higher percentage of helper T cells (63% vs. 49%) and a lower percentage of suppressor/cytotoxic T cells (14% vs. 30%). Class II antigen expression could be detected on the mononuclear cells at inflammatory sites within the lacrimal glands of all three strains, suggesting T cell activation and an active autoimmune immunologic event occurring in the lacrimal gland.