Lacrimal Gland Disease

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Douglas A. Jabs - One of the best experts on this subject based on the ideXlab platform.

  • inflammatory mediators in autoimmune Lacrimal Gland Disease in mrl mpj mice
    Investigative Ophthalmology & Visual Science, 2004
    Co-Authors: Douglas A. Jabs, R A Prendergast, Bella Lee, A P Hudson, Esen K. Akpek, Hervé C. Gérard, Yuewang Wei, Adam L. Campbell, Judith A Whittumhudson
    Abstract:

    PURPOSE. MRL/MpJ-fas/fas (MRL/) and MRL/MpJ-fas lpr / fas lpr (MRL/lpr) mice are congenic substrains of mice that have spontaneously developing Lacrimal and salivary Gland inflam- mation and are models for the human disorder Sjogren's syn- drome. Nitric oxide (NO) and tumor necrosis factor (TNF)- are proinflammatory and potential mediators of tissue damage. The presence of the inducible form of nitric oxide synthase (iNOS), which catalyzes the production of NO, and the pres- ence TNF- in the Lacrimal Glands of MRL/MpJ mice were assessed. METHODS. Lacrimal Glands from MRL/ and MRL/lpr mice, at ages 1 through 9 months, were evaluated by real-time RT-PCR for iNOS and TNF- mRNA and by immunohistochemistry for the presence of iNOS and of TNF-. Age-matched BALB/c Lacrimal Glands were used as the control. RESULTS. By quantitative real-time PCR (qPCR), mRNA for iNOS was detected in the Lacrimal Glands in significantly greater amounts in both MRL/ (median, normalized to 18S rRNA, 2.90; P 0.0003) and MRL/lpr mice (median 6.84, P 0.001) than in BALB/c mice (median 0.34). By qPCR, mRNA for TNF- in the Lacrimal Glands was detected in significantly greater amounts in aged MRL/ mice than in BALB/c mice (median, normalized to actin, 221.8 vs. 77.8, P 0.011) and in MRL/lpr mice than in BALB/c mice (median 136.7 vs. 72.5, P 0.001). Immunohistochemistry demonstrated both iNOS and TNF- in scattered mononuclear cells throughout the Lacrimal Glands and in mononuclear cells at the junction of the focal inflam- matory infiltrates and normal acinar tissue in both MRL/ and MRL/lpr mice.

  • Inflammatory mediators in autoimmune Lacrimal Gland Disease in MRL/Mpj mice.
    Investigative ophthalmology & visual science, 2004
    Co-Authors: Douglas A. Jabs, R A Prendergast, Bella Lee, A P Hudson, Esen K. Akpek, Hervé C. Gérard, Yuewang Wei, Adam L. Campbell, Judith A. Whittum-hudson
    Abstract:

    PURPOSE. MRL/MpJ-fas/fas (MRL/) and MRL/MpJ-fas lpr / fas lpr (MRL/lpr) mice are congenic substrains of mice that have spontaneously developing Lacrimal and salivary Gland inflam- mation and are models for the human disorder Sjogren's syn- drome. Nitric oxide (NO) and tumor necrosis factor (TNF)- are proinflammatory and potential mediators of tissue damage. The presence of the inducible form of nitric oxide synthase (iNOS), which catalyzes the production of NO, and the pres- ence TNF- in the Lacrimal Glands of MRL/MpJ mice were assessed. METHODS. Lacrimal Glands from MRL/ and MRL/lpr mice, at ages 1 through 9 months, were evaluated by real-time RT-PCR for iNOS and TNF- mRNA and by immunohistochemistry for the presence of iNOS and of TNF-. Age-matched BALB/c Lacrimal Glands were used as the control. RESULTS. By quantitative real-time PCR (qPCR), mRNA for iNOS was detected in the Lacrimal Glands in significantly greater amounts in both MRL/ (median, normalized to 18S rRNA, 2.90; P 0.0003) and MRL/lpr mice (median 6.84, P 0.001) than in BALB/c mice (median 0.34). By qPCR, mRNA for TNF- in the Lacrimal Glands was detected in significantly greater amounts in aged MRL/ mice than in BALB/c mice (median, normalized to actin, 221.8 vs. 77.8, P 0.011) and in MRL/lpr mice than in BALB/c mice (median 136.7 vs. 72.5, P 0.001). Immunohistochemistry demonstrated both iNOS and TNF- in scattered mononuclear cells throughout the Lacrimal Glands and in mononuclear cells at the junction of the focal inflam- matory infiltrates and normal acinar tissue in both MRL/ and MRL/lpr mice.

  • Chemokines in autoimmune Lacrimal Gland Disease in MRL/MpJ mice.
    Investigative ophthalmology & visual science, 2004
    Co-Authors: Esen K. Akpek, R A Prendergast, Douglas A. Jabs, Bella Lee, A P Hudson, Hervé C. Gérard, Judith A. Whittum-hudson
    Abstract:

    PURPOSE: MRL/MpJ-fas+/fas+ (MRL/+) and MRL/MpJ-fas(lpr)/fas(lpr) (MRL/lpr) mice undergo spontaneous development of inflammation of the Lacrimal and salivary Glands, similar to that in the human disorder Sjogren's syndrome. Previous work has shown that these lesions appear to be largely T helper (Th)-2-driven, as evidenced by the substantially greater expression of IL-4 than interferon-gamma. The relative contributions of selected chemokines associated with Th1 and Th2 immune responses were assessed. METHODS: Lacrimal Glands from MRL/+ and MRL/lpr mice, at ages 1.5 through 9 months were evaluated by immunohistochemistry for the chemokines monocyte chemoattractant protein (MCP)-1 (also known as chemokine ligand [CCL]-2), MCP-5 (CCL12), thymus activation regulated chemokine (TARC; or CCL17), and macrophage-derived chemokine (MDC; or CCL22). Additional Lacrimal Glands were tested by real-time RT-PCR for chemokines MCP-1 and -5, which are associated with Th2 and Th1 responses, respectively. RESULTS: By immunohistochemistry a significantly greater proportion of mononuclear inflammatory cells in the Lacrimal Gland lesions stained for MCP-1 (29%-48% depending on age) compared with MCP-5 (1%-3% depending on age) both in MRL/+ (mean difference 34.2%, P < 0.001) and MRL/lpr (mean difference 33.6%, P < 0.001) substrains. Real-time RT-PCR studies showed higher transcript levels of MCP-1 compared with MCP-5, in both MRL/+ (median difference, 37.3; P < 0.0001) and MRL/lpr (median difference, 77.1; P < 0.0001) mice. Relative transcripts of MCP-1 increased with age in both MRL/+ mice (P = 0.02) and MRL/lpr mice (P = 0.03). Staining for TARC was present on Lacrimal Gland ductular cells but not on the infiltrating lymphocytes, and staining for MDC was present on scattered individual cells throughout the Lacrimal Gland, but not on infiltrating lymphocytes. CONCLUSIONS: The predominant expression of a Th2-associated chemokine in the Lacrimal Gland lesions in this murine model of Sjogren's syndrome may contribute to the predominantly Th2-type lymphoid infiltrate in these tissues.

  • Pathogenesis of Autoimmune Lacrimal Gland Disease in MRL/MPJ Mice
    Advances in experimental medicine and biology, 2002
    Co-Authors: Douglas A. Jabs, R A Prendergast, Judith A. Whittum-hudson
    Abstract:

    MRL/MpJ mice spontaneously develop Lacrimal and salivary Gland inflammation and are a model for the human disorder Sjogren’s syndrome. 1-3 Two congenic substrains of MRL/MpJ mice exist, MRL/MpJ-+/+ (MRL/+) andMRL/MpJ-lpr/lpr(MRL/lpr). These substrains differ only at a single autosomal recessive gene locus, the1prmutation. This mutation results in altered Fas protein, defective lymphocyte apoptosis, defective clonal deletion of autoreactive T-cells in peripheral lymphoid organs and accelerated autoimmune Disease in MRL/lpr mice when compared to MRL/+ mice. 4.5 MRL/lpr mice typically die at 6 months of age, whereas MRL/+ mice often live to 2 years. Both substrains develop Lacrimal Gland inflammation, although the Lacrimal Gland Disease develops earlier in MRL/lpr than MRL/+ mice, and at comparable ages, MRL/lpr mice have more severe and extensive Disease.3 ; The Lacrimal Gland lesions in both substrains are composed largely of T-cells (approximately 80%), the majority of which are CD4+ T-cells. Lesser numbers of CD8+ T-cells, B-cells and macrophages are present. In aged (18-month) MRL/+, mice B-cells accumulate in the Lacrimal Gland lesions.2.3.6

  • pathogenesis of autoimmune Lacrimal Gland Disease in mrl mpj mice
    Advances in Experimental Medicine and Biology, 2002
    Co-Authors: Douglas A. Jabs, R A Prendergast, Judith A Whittumhudson
    Abstract:

    MRL/MpJ mice spontaneously develop Lacrimal and salivary Gland inflammation and are a model for the human disorder Sjogren’s syndrome. 1-3 Two congenic substrains of MRL/MpJ mice exist, MRL/MpJ-+/+ (MRL/+) andMRL/MpJ-lpr/lpr(MRL/lpr). These substrains differ only at a single autosomal recessive gene locus, the1prmutation. This mutation results in altered Fas protein, defective lymphocyte apoptosis, defective clonal deletion of autoreactive T-cells in peripheral lymphoid organs and accelerated autoimmune Disease in MRL/lpr mice when compared to MRL/+ mice. 4.5 MRL/lpr mice typically die at 6 months of age, whereas MRL/+ mice often live to 2 years. Both substrains develop Lacrimal Gland inflammation, although the Lacrimal Gland Disease develops earlier in MRL/lpr than MRL/+ mice, and at comparable ages, MRL/lpr mice have more severe and extensive Disease.3 ; The Lacrimal Gland lesions in both substrains are composed largely of T-cells (approximately 80%), the majority of which are CD4+ T-cells. Lesser numbers of CD8+ T-cells, B-cells and macrophages are present. In aged (18-month) MRL/+, mice B-cells accumulate in the Lacrimal Gland lesions.2.3.6

R A Prendergast - One of the best experts on this subject based on the ideXlab platform.

  • inflammatory mediators in autoimmune Lacrimal Gland Disease in mrl mpj mice
    Investigative Ophthalmology & Visual Science, 2004
    Co-Authors: Douglas A. Jabs, R A Prendergast, Bella Lee, A P Hudson, Esen K. Akpek, Hervé C. Gérard, Yuewang Wei, Adam L. Campbell, Judith A Whittumhudson
    Abstract:

    PURPOSE. MRL/MpJ-fas/fas (MRL/) and MRL/MpJ-fas lpr / fas lpr (MRL/lpr) mice are congenic substrains of mice that have spontaneously developing Lacrimal and salivary Gland inflam- mation and are models for the human disorder Sjogren's syn- drome. Nitric oxide (NO) and tumor necrosis factor (TNF)- are proinflammatory and potential mediators of tissue damage. The presence of the inducible form of nitric oxide synthase (iNOS), which catalyzes the production of NO, and the pres- ence TNF- in the Lacrimal Glands of MRL/MpJ mice were assessed. METHODS. Lacrimal Glands from MRL/ and MRL/lpr mice, at ages 1 through 9 months, were evaluated by real-time RT-PCR for iNOS and TNF- mRNA and by immunohistochemistry for the presence of iNOS and of TNF-. Age-matched BALB/c Lacrimal Glands were used as the control. RESULTS. By quantitative real-time PCR (qPCR), mRNA for iNOS was detected in the Lacrimal Glands in significantly greater amounts in both MRL/ (median, normalized to 18S rRNA, 2.90; P 0.0003) and MRL/lpr mice (median 6.84, P 0.001) than in BALB/c mice (median 0.34). By qPCR, mRNA for TNF- in the Lacrimal Glands was detected in significantly greater amounts in aged MRL/ mice than in BALB/c mice (median, normalized to actin, 221.8 vs. 77.8, P 0.011) and in MRL/lpr mice than in BALB/c mice (median 136.7 vs. 72.5, P 0.001). Immunohistochemistry demonstrated both iNOS and TNF- in scattered mononuclear cells throughout the Lacrimal Glands and in mononuclear cells at the junction of the focal inflam- matory infiltrates and normal acinar tissue in both MRL/ and MRL/lpr mice.

  • pathogenesis of autoimmune Lacrimal Gland Disease in mrl mpj mice
    Advances in Experimental Medicine and Biology, 2002
    Co-Authors: Douglas A. Jabs, R A Prendergast, Judith A Whittumhudson
    Abstract:

    MRL/MpJ mice spontaneously develop Lacrimal and salivary Gland inflammation and are a model for the human disorder Sjogren’s syndrome. 1-3 Two congenic substrains of MRL/MpJ mice exist, MRL/MpJ-+/+ (MRL/+) andMRL/MpJ-lpr/lpr(MRL/lpr). These substrains differ only at a single autosomal recessive gene locus, the1prmutation. This mutation results in altered Fas protein, defective lymphocyte apoptosis, defective clonal deletion of autoreactive T-cells in peripheral lymphoid organs and accelerated autoimmune Disease in MRL/lpr mice when compared to MRL/+ mice. 4.5 MRL/lpr mice typically die at 6 months of age, whereas MRL/+ mice often live to 2 years. Both substrains develop Lacrimal Gland inflammation, although the Lacrimal Gland Disease develops earlier in MRL/lpr than MRL/+ mice, and at comparable ages, MRL/lpr mice have more severe and extensive Disease.3 ; The Lacrimal Gland lesions in both substrains are composed largely of T-cells (approximately 80%), the majority of which are CD4+ T-cells. Lesser numbers of CD8+ T-cells, B-cells and macrophages are present. In aged (18-month) MRL/+, mice B-cells accumulate in the Lacrimal Gland lesions.2.3.6

  • the role of fas fas ligand mediated apoptosis in autoimmune Lacrimal Gland Disease in mrl mpj mice
    Investigative Ophthalmology & Visual Science, 2001
    Co-Authors: Douglas A. Jabs, Judith A Whittumhudson, Bella Lee, R A Prendergast
    Abstract:

    PURPOSE. MRL/MpJ mice spontaneously develop Lacrimal Gland inflammation and are a model for the human disorder Sjogren's syndrome. MRL/MpJ-lpr/lpr (MRL/lpr) and MRL/Mp-1/1 (MRL/1) mice are congenic substrains, which differ only by a single autosomal recessive gene, the lpr mutation. This muta- tion 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/1 mice. METHODS. Inflammatory cells in the Lacrimal Glands of MRL/lpr and MRL/1 mice were evaluated for apoptosis with TUNEL staining and Fas and Fas ligand expression with immunohisto- chemistry. RESULTS. MRL/lpr mice had a greater percentage of the Lacrimal Gland replaced by inflammatory infiltrate (30.3% 6 7.0%) than did MRL/1 mice (13.0% 6 3.0%, P 5 0.02). However, similar amounts of lymphocytic apoptosis were present in the Lacrimal Glands of MRL/lpr and MRL/1 mice. The mean number of apoptotic cells per unit area of inflammation was 23.8 6 2.4 in MRL/lpr mice and 24.6 6 6.0 in MRL/1 mice (P 5 0.91). Fas expression was absent on lymphocytes in MRL/lpr mice but was present on lymphocytes in MRL/1 mice. Fas ligand ex- pression was present on epithelial structures in both sub- strains. CONCLUSIONS. The accelerated Lacrimal Gland Disease inflamma- tion 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 defec- tive extrathymic lymphoid apoptosis, permitting a relatively greater expansion of autoreactive T cells, which subsequently invade the Lacrimal Gland. (Invest Ophthalmol Vis Sci. 2001;42: 399 - 401)

  • Cytokines in autoimmune Lacrimal Gland Disease in MRL/MpJ mice.
    Investigative ophthalmology & visual science, 2001
    Co-Authors: Douglas A. Jabs, R A Prendergast, E M Rorer, A P Hudson, Judith A. Whittum-hudson
    Abstract:

    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. 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. 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. 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.

  • chemokines in autoimmune Lacrimal Gland Disease in mrl mpj mice
    Investigative Ophthalmology & Visual Science, 2000
    Co-Authors: Esen K. Akpek, Douglas A. Jabs, R A Prendergast, Bella Lee, A P Hudson, Hervé C. Gérard, Judith A Whittumhudson
    Abstract:

    PURPOSE: MRL/MpJ-fas+/fas+ (MRL/+) and MRL/MpJ-fas(lpr)/fas(lpr) (MRL/lpr) mice undergo spontaneous development of inflammation of the Lacrimal and salivary Glands, similar to that in the human disorder Sjogren's syndrome. Previous work has shown that these lesions appear to be largely T helper (Th)-2-driven, as evidenced by the substantially greater expression of IL-4 than interferon-gamma. The relative contributions of selected chemokines associated with Th1 and Th2 immune responses were assessed. METHODS: Lacrimal Glands from MRL/+ and MRL/lpr mice, at ages 1.5 through 9 months were evaluated by immunohistochemistry for the chemokines monocyte chemoattractant protein (MCP)-1 (also known as chemokine ligand [CCL]-2), MCP-5 (CCL12), thymus activation regulated chemokine (TARC; or CCL17), and macrophage-derived chemokine (MDC; or CCL22). Additional Lacrimal Glands were tested by real-time RT-PCR for chemokines MCP-1 and -5, which are associated with Th2 and Th1 responses, respectively. RESULTS: By immunohistochemistry a significantly greater proportion of mononuclear inflammatory cells in the Lacrimal Gland lesions stained for MCP-1 (29%-48% depending on age) compared with MCP-5 (1%-3% depending on age) both in MRL/+ (mean difference 34.2%, P < 0.001) and MRL/lpr (mean difference 33.6%, P < 0.001) substrains. Real-time RT-PCR studies showed higher transcript levels of MCP-1 compared with MCP-5, in both MRL/+ (median difference, 37.3; P < 0.0001) and MRL/lpr (median difference, 77.1; P < 0.0001) mice. Relative transcripts of MCP-1 increased with age in both MRL/+ mice (P = 0.02) and MRL/lpr mice (P = 0.03). Staining for TARC was present on Lacrimal Gland ductular cells but not on the infiltrating lymphocytes, and staining for MDC was present on scattered individual cells throughout the Lacrimal Gland, but not on infiltrating lymphocytes. CONCLUSIONS: The predominant expression of a Th2-associated chemokine in the Lacrimal Gland lesions in this murine model of Sjogren's syndrome may contribute to the predominantly Th2-type lymphoid infiltrate in these tissues.

R A Prendergast - One of the best experts on this subject based on the ideXlab platform.

  • Inflammatory mediators in autoimmune Lacrimal Gland Disease in MRL/Mpj mice.
    Investigative ophthalmology & visual science, 2004
    Co-Authors: Douglas A. Jabs, R A Prendergast, Bella Lee, A P Hudson, Esen K. Akpek, Hervé C. Gérard, Yuewang Wei, Adam L. Campbell, Judith A. Whittum-hudson
    Abstract:

    PURPOSE. MRL/MpJ-fas/fas (MRL/) and MRL/MpJ-fas lpr / fas lpr (MRL/lpr) mice are congenic substrains of mice that have spontaneously developing Lacrimal and salivary Gland inflam- mation and are models for the human disorder Sjogren's syn- drome. Nitric oxide (NO) and tumor necrosis factor (TNF)- are proinflammatory and potential mediators of tissue damage. The presence of the inducible form of nitric oxide synthase (iNOS), which catalyzes the production of NO, and the pres- ence TNF- in the Lacrimal Glands of MRL/MpJ mice were assessed. METHODS. Lacrimal Glands from MRL/ and MRL/lpr mice, at ages 1 through 9 months, were evaluated by real-time RT-PCR for iNOS and TNF- mRNA and by immunohistochemistry for the presence of iNOS and of TNF-. Age-matched BALB/c Lacrimal Glands were used as the control. RESULTS. By quantitative real-time PCR (qPCR), mRNA for iNOS was detected in the Lacrimal Glands in significantly greater amounts in both MRL/ (median, normalized to 18S rRNA, 2.90; P 0.0003) and MRL/lpr mice (median 6.84, P 0.001) than in BALB/c mice (median 0.34). By qPCR, mRNA for TNF- in the Lacrimal Glands was detected in significantly greater amounts in aged MRL/ mice than in BALB/c mice (median, normalized to actin, 221.8 vs. 77.8, P 0.011) and in MRL/lpr mice than in BALB/c mice (median 136.7 vs. 72.5, P 0.001). Immunohistochemistry demonstrated both iNOS and TNF- in scattered mononuclear cells throughout the Lacrimal Glands and in mononuclear cells at the junction of the focal inflam- matory infiltrates and normal acinar tissue in both MRL/ and MRL/lpr mice.

  • Chemokines in autoimmune Lacrimal Gland Disease in MRL/MpJ mice.
    Investigative ophthalmology & visual science, 2004
    Co-Authors: Esen K. Akpek, R A Prendergast, Douglas A. Jabs, Bella Lee, A P Hudson, Hervé C. Gérard, Judith A. Whittum-hudson
    Abstract:

    PURPOSE: MRL/MpJ-fas+/fas+ (MRL/+) and MRL/MpJ-fas(lpr)/fas(lpr) (MRL/lpr) mice undergo spontaneous development of inflammation of the Lacrimal and salivary Glands, similar to that in the human disorder Sjogren's syndrome. Previous work has shown that these lesions appear to be largely T helper (Th)-2-driven, as evidenced by the substantially greater expression of IL-4 than interferon-gamma. The relative contributions of selected chemokines associated with Th1 and Th2 immune responses were assessed. METHODS: Lacrimal Glands from MRL/+ and MRL/lpr mice, at ages 1.5 through 9 months were evaluated by immunohistochemistry for the chemokines monocyte chemoattractant protein (MCP)-1 (also known as chemokine ligand [CCL]-2), MCP-5 (CCL12), thymus activation regulated chemokine (TARC; or CCL17), and macrophage-derived chemokine (MDC; or CCL22). Additional Lacrimal Glands were tested by real-time RT-PCR for chemokines MCP-1 and -5, which are associated with Th2 and Th1 responses, respectively. RESULTS: By immunohistochemistry a significantly greater proportion of mononuclear inflammatory cells in the Lacrimal Gland lesions stained for MCP-1 (29%-48% depending on age) compared with MCP-5 (1%-3% depending on age) both in MRL/+ (mean difference 34.2%, P < 0.001) and MRL/lpr (mean difference 33.6%, P < 0.001) substrains. Real-time RT-PCR studies showed higher transcript levels of MCP-1 compared with MCP-5, in both MRL/+ (median difference, 37.3; P < 0.0001) and MRL/lpr (median difference, 77.1; P < 0.0001) mice. Relative transcripts of MCP-1 increased with age in both MRL/+ mice (P = 0.02) and MRL/lpr mice (P = 0.03). Staining for TARC was present on Lacrimal Gland ductular cells but not on the infiltrating lymphocytes, and staining for MDC was present on scattered individual cells throughout the Lacrimal Gland, but not on infiltrating lymphocytes. CONCLUSIONS: The predominant expression of a Th2-associated chemokine in the Lacrimal Gland lesions in this murine model of Sjogren's syndrome may contribute to the predominantly Th2-type lymphoid infiltrate in these tissues.

  • Pathogenesis of Autoimmune Lacrimal Gland Disease in MRL/MPJ Mice
    Advances in experimental medicine and biology, 2002
    Co-Authors: Douglas A. Jabs, R A Prendergast, Judith A. Whittum-hudson
    Abstract:

    MRL/MpJ mice spontaneously develop Lacrimal and salivary Gland inflammation and are a model for the human disorder Sjogren’s syndrome. 1-3 Two congenic substrains of MRL/MpJ mice exist, MRL/MpJ-+/+ (MRL/+) andMRL/MpJ-lpr/lpr(MRL/lpr). These substrains differ only at a single autosomal recessive gene locus, the1prmutation. This mutation results in altered Fas protein, defective lymphocyte apoptosis, defective clonal deletion of autoreactive T-cells in peripheral lymphoid organs and accelerated autoimmune Disease in MRL/lpr mice when compared to MRL/+ mice. 4.5 MRL/lpr mice typically die at 6 months of age, whereas MRL/+ mice often live to 2 years. Both substrains develop Lacrimal Gland inflammation, although the Lacrimal Gland Disease develops earlier in MRL/lpr than MRL/+ mice, and at comparable ages, MRL/lpr mice have more severe and extensive Disease.3 ; The Lacrimal Gland lesions in both substrains are composed largely of T-cells (approximately 80%), the majority of which are CD4+ T-cells. Lesser numbers of CD8+ T-cells, B-cells and macrophages are present. In aged (18-month) MRL/+, mice B-cells accumulate in the Lacrimal Gland lesions.2.3.6

  • The role of Fas-Fas ligand-mediated apoptosis in autoimmune Lacrimal Gland Disease in MRL/MpJ mice.
    Investigative ophthalmology & visual science, 2001
    Co-Authors: Douglas A. Jabs, Judith A. Whittum-hudson, Bella Lee, R A Prendergast
    Abstract:

    PURPOSE. MRL/MpJ mice spontaneously develop Lacrimal Gland inflammation and are a model for the human disorder Sjogren's syndrome. MRL/MpJ-lpr/lpr (MRL/lpr) and MRL/Mp-1/1 (MRL/1) mice are congenic substrains, which differ only by a single autosomal recessive gene, the lpr mutation. This muta- tion 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/1 mice. METHODS. Inflammatory cells in the Lacrimal Glands of MRL/lpr and MRL/1 mice were evaluated for apoptosis with TUNEL staining and Fas and Fas ligand expression with immunohisto- chemistry. RESULTS. MRL/lpr mice had a greater percentage of the Lacrimal Gland replaced by inflammatory infiltrate (30.3% 6 7.0%) than did MRL/1 mice (13.0% 6 3.0%, P 5 0.02). However, similar amounts of lymphocytic apoptosis were present in the Lacrimal Glands of MRL/lpr and MRL/1 mice. The mean number of apoptotic cells per unit area of inflammation was 23.8 6 2.4 in MRL/lpr mice and 24.6 6 6.0 in MRL/1 mice (P 5 0.91). Fas expression was absent on lymphocytes in MRL/lpr mice but was present on lymphocytes in MRL/1 mice. Fas ligand ex- pression was present on epithelial structures in both sub- strains. CONCLUSIONS. The accelerated Lacrimal Gland Disease inflamma- tion 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 defec- tive extrathymic lymphoid apoptosis, permitting a relatively greater expansion of autoreactive T cells, which subsequently invade the Lacrimal Gland. (Invest Ophthalmol Vis Sci. 2001;42: 399 - 401)

  • Th1 versus Th2 immune responses in autoimmune Lacrimal Gland Disease in MRL/Mp mice.
    Investigative ophthalmology & visual science, 2000
    Co-Authors: Douglas A. Jabs, Judith A. Whittum-hudson, Bella Lee, R A Prendergast
    Abstract:

    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 Sjogren'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.

Bella Lee - One of the best experts on this subject based on the ideXlab platform.

  • Inflammatory mediators in autoimmune Lacrimal Gland Disease in MRL/Mpj mice.
    Investigative ophthalmology & visual science, 2004
    Co-Authors: Douglas A. Jabs, R A Prendergast, Bella Lee, A P Hudson, Esen K. Akpek, Hervé C. Gérard, Yuewang Wei, Adam L. Campbell, Judith A. Whittum-hudson
    Abstract:

    PURPOSE. MRL/MpJ-fas/fas (MRL/) and MRL/MpJ-fas lpr / fas lpr (MRL/lpr) mice are congenic substrains of mice that have spontaneously developing Lacrimal and salivary Gland inflam- mation and are models for the human disorder Sjogren's syn- drome. Nitric oxide (NO) and tumor necrosis factor (TNF)- are proinflammatory and potential mediators of tissue damage. The presence of the inducible form of nitric oxide synthase (iNOS), which catalyzes the production of NO, and the pres- ence TNF- in the Lacrimal Glands of MRL/MpJ mice were assessed. METHODS. Lacrimal Glands from MRL/ and MRL/lpr mice, at ages 1 through 9 months, were evaluated by real-time RT-PCR for iNOS and TNF- mRNA and by immunohistochemistry for the presence of iNOS and of TNF-. Age-matched BALB/c Lacrimal Glands were used as the control. RESULTS. By quantitative real-time PCR (qPCR), mRNA for iNOS was detected in the Lacrimal Glands in significantly greater amounts in both MRL/ (median, normalized to 18S rRNA, 2.90; P 0.0003) and MRL/lpr mice (median 6.84, P 0.001) than in BALB/c mice (median 0.34). By qPCR, mRNA for TNF- in the Lacrimal Glands was detected in significantly greater amounts in aged MRL/ mice than in BALB/c mice (median, normalized to actin, 221.8 vs. 77.8, P 0.011) and in MRL/lpr mice than in BALB/c mice (median 136.7 vs. 72.5, P 0.001). Immunohistochemistry demonstrated both iNOS and TNF- in scattered mononuclear cells throughout the Lacrimal Glands and in mononuclear cells at the junction of the focal inflam- matory infiltrates and normal acinar tissue in both MRL/ and MRL/lpr mice.

  • inflammatory mediators in autoimmune Lacrimal Gland Disease in mrl mpj mice
    Investigative Ophthalmology & Visual Science, 2004
    Co-Authors: Douglas A. Jabs, R A Prendergast, Bella Lee, A P Hudson, Esen K. Akpek, Hervé C. Gérard, Yuewang Wei, Adam L. Campbell, Judith A Whittumhudson
    Abstract:

    PURPOSE. MRL/MpJ-fas/fas (MRL/) and MRL/MpJ-fas lpr / fas lpr (MRL/lpr) mice are congenic substrains of mice that have spontaneously developing Lacrimal and salivary Gland inflam- mation and are models for the human disorder Sjogren's syn- drome. Nitric oxide (NO) and tumor necrosis factor (TNF)- are proinflammatory and potential mediators of tissue damage. The presence of the inducible form of nitric oxide synthase (iNOS), which catalyzes the production of NO, and the pres- ence TNF- in the Lacrimal Glands of MRL/MpJ mice were assessed. METHODS. Lacrimal Glands from MRL/ and MRL/lpr mice, at ages 1 through 9 months, were evaluated by real-time RT-PCR for iNOS and TNF- mRNA and by immunohistochemistry for the presence of iNOS and of TNF-. Age-matched BALB/c Lacrimal Glands were used as the control. RESULTS. By quantitative real-time PCR (qPCR), mRNA for iNOS was detected in the Lacrimal Glands in significantly greater amounts in both MRL/ (median, normalized to 18S rRNA, 2.90; P 0.0003) and MRL/lpr mice (median 6.84, P 0.001) than in BALB/c mice (median 0.34). By qPCR, mRNA for TNF- in the Lacrimal Glands was detected in significantly greater amounts in aged MRL/ mice than in BALB/c mice (median, normalized to actin, 221.8 vs. 77.8, P 0.011) and in MRL/lpr mice than in BALB/c mice (median 136.7 vs. 72.5, P 0.001). Immunohistochemistry demonstrated both iNOS and TNF- in scattered mononuclear cells throughout the Lacrimal Glands and in mononuclear cells at the junction of the focal inflam- matory infiltrates and normal acinar tissue in both MRL/ and MRL/lpr mice.

  • Chemokines in autoimmune Lacrimal Gland Disease in MRL/MpJ mice.
    Investigative ophthalmology & visual science, 2004
    Co-Authors: Esen K. Akpek, R A Prendergast, Douglas A. Jabs, Bella Lee, A P Hudson, Hervé C. Gérard, Judith A. Whittum-hudson
    Abstract:

    PURPOSE: MRL/MpJ-fas+/fas+ (MRL/+) and MRL/MpJ-fas(lpr)/fas(lpr) (MRL/lpr) mice undergo spontaneous development of inflammation of the Lacrimal and salivary Glands, similar to that in the human disorder Sjogren's syndrome. Previous work has shown that these lesions appear to be largely T helper (Th)-2-driven, as evidenced by the substantially greater expression of IL-4 than interferon-gamma. The relative contributions of selected chemokines associated with Th1 and Th2 immune responses were assessed. METHODS: Lacrimal Glands from MRL/+ and MRL/lpr mice, at ages 1.5 through 9 months were evaluated by immunohistochemistry for the chemokines monocyte chemoattractant protein (MCP)-1 (also known as chemokine ligand [CCL]-2), MCP-5 (CCL12), thymus activation regulated chemokine (TARC; or CCL17), and macrophage-derived chemokine (MDC; or CCL22). Additional Lacrimal Glands were tested by real-time RT-PCR for chemokines MCP-1 and -5, which are associated with Th2 and Th1 responses, respectively. RESULTS: By immunohistochemistry a significantly greater proportion of mononuclear inflammatory cells in the Lacrimal Gland lesions stained for MCP-1 (29%-48% depending on age) compared with MCP-5 (1%-3% depending on age) both in MRL/+ (mean difference 34.2%, P < 0.001) and MRL/lpr (mean difference 33.6%, P < 0.001) substrains. Real-time RT-PCR studies showed higher transcript levels of MCP-1 compared with MCP-5, in both MRL/+ (median difference, 37.3; P < 0.0001) and MRL/lpr (median difference, 77.1; P < 0.0001) mice. Relative transcripts of MCP-1 increased with age in both MRL/+ mice (P = 0.02) and MRL/lpr mice (P = 0.03). Staining for TARC was present on Lacrimal Gland ductular cells but not on the infiltrating lymphocytes, and staining for MDC was present on scattered individual cells throughout the Lacrimal Gland, but not on infiltrating lymphocytes. CONCLUSIONS: The predominant expression of a Th2-associated chemokine in the Lacrimal Gland lesions in this murine model of Sjogren's syndrome may contribute to the predominantly Th2-type lymphoid infiltrate in these tissues.

  • the role of fas fas ligand mediated apoptosis in autoimmune Lacrimal Gland Disease in mrl mpj mice
    Investigative Ophthalmology & Visual Science, 2001
    Co-Authors: Douglas A. Jabs, Judith A Whittumhudson, Bella Lee, R A Prendergast
    Abstract:

    PURPOSE. MRL/MpJ mice spontaneously develop Lacrimal Gland inflammation and are a model for the human disorder Sjogren's syndrome. MRL/MpJ-lpr/lpr (MRL/lpr) and MRL/Mp-1/1 (MRL/1) mice are congenic substrains, which differ only by a single autosomal recessive gene, the lpr mutation. This muta- tion 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/1 mice. METHODS. Inflammatory cells in the Lacrimal Glands of MRL/lpr and MRL/1 mice were evaluated for apoptosis with TUNEL staining and Fas and Fas ligand expression with immunohisto- chemistry. RESULTS. MRL/lpr mice had a greater percentage of the Lacrimal Gland replaced by inflammatory infiltrate (30.3% 6 7.0%) than did MRL/1 mice (13.0% 6 3.0%, P 5 0.02). However, similar amounts of lymphocytic apoptosis were present in the Lacrimal Glands of MRL/lpr and MRL/1 mice. The mean number of apoptotic cells per unit area of inflammation was 23.8 6 2.4 in MRL/lpr mice and 24.6 6 6.0 in MRL/1 mice (P 5 0.91). Fas expression was absent on lymphocytes in MRL/lpr mice but was present on lymphocytes in MRL/1 mice. Fas ligand ex- pression was present on epithelial structures in both sub- strains. CONCLUSIONS. The accelerated Lacrimal Gland Disease inflamma- tion 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 defec- tive extrathymic lymphoid apoptosis, permitting a relatively greater expansion of autoreactive T cells, which subsequently invade the Lacrimal Gland. (Invest Ophthalmol Vis Sci. 2001;42: 399 - 401)

  • The role of Fas-Fas ligand-mediated apoptosis in autoimmune Lacrimal Gland Disease in MRL/MpJ mice.
    Investigative ophthalmology & visual science, 2001
    Co-Authors: Douglas A. Jabs, Judith A. Whittum-hudson, Bella Lee, R A Prendergast
    Abstract:

    PURPOSE. MRL/MpJ mice spontaneously develop Lacrimal Gland inflammation and are a model for the human disorder Sjogren's syndrome. MRL/MpJ-lpr/lpr (MRL/lpr) and MRL/Mp-1/1 (MRL/1) mice are congenic substrains, which differ only by a single autosomal recessive gene, the lpr mutation. This muta- tion 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/1 mice. METHODS. Inflammatory cells in the Lacrimal Glands of MRL/lpr and MRL/1 mice were evaluated for apoptosis with TUNEL staining and Fas and Fas ligand expression with immunohisto- chemistry. RESULTS. MRL/lpr mice had a greater percentage of the Lacrimal Gland replaced by inflammatory infiltrate (30.3% 6 7.0%) than did MRL/1 mice (13.0% 6 3.0%, P 5 0.02). However, similar amounts of lymphocytic apoptosis were present in the Lacrimal Glands of MRL/lpr and MRL/1 mice. The mean number of apoptotic cells per unit area of inflammation was 23.8 6 2.4 in MRL/lpr mice and 24.6 6 6.0 in MRL/1 mice (P 5 0.91). Fas expression was absent on lymphocytes in MRL/lpr mice but was present on lymphocytes in MRL/1 mice. Fas ligand ex- pression was present on epithelial structures in both sub- strains. CONCLUSIONS. The accelerated Lacrimal Gland Disease inflamma- tion 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 defec- tive extrathymic lymphoid apoptosis, permitting a relatively greater expansion of autoreactive T cells, which subsequently invade the Lacrimal Gland. (Invest Ophthalmol Vis Sci. 2001;42: 399 - 401)

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  • Inflammatory mediators in autoimmune Lacrimal Gland Disease in MRL/Mpj mice.
    Investigative ophthalmology & visual science, 2004
    Co-Authors: Douglas A. Jabs, R A Prendergast, Bella Lee, A P Hudson, Esen K. Akpek, Hervé C. Gérard, Yuewang Wei, Adam L. Campbell, Judith A. Whittum-hudson
    Abstract:

    PURPOSE. MRL/MpJ-fas/fas (MRL/) and MRL/MpJ-fas lpr / fas lpr (MRL/lpr) mice are congenic substrains of mice that have spontaneously developing Lacrimal and salivary Gland inflam- mation and are models for the human disorder Sjogren's syn- drome. Nitric oxide (NO) and tumor necrosis factor (TNF)- are proinflammatory and potential mediators of tissue damage. The presence of the inducible form of nitric oxide synthase (iNOS), which catalyzes the production of NO, and the pres- ence TNF- in the Lacrimal Glands of MRL/MpJ mice were assessed. METHODS. Lacrimal Glands from MRL/ and MRL/lpr mice, at ages 1 through 9 months, were evaluated by real-time RT-PCR for iNOS and TNF- mRNA and by immunohistochemistry for the presence of iNOS and of TNF-. Age-matched BALB/c Lacrimal Glands were used as the control. RESULTS. By quantitative real-time PCR (qPCR), mRNA for iNOS was detected in the Lacrimal Glands in significantly greater amounts in both MRL/ (median, normalized to 18S rRNA, 2.90; P 0.0003) and MRL/lpr mice (median 6.84, P 0.001) than in BALB/c mice (median 0.34). By qPCR, mRNA for TNF- in the Lacrimal Glands was detected in significantly greater amounts in aged MRL/ mice than in BALB/c mice (median, normalized to actin, 221.8 vs. 77.8, P 0.011) and in MRL/lpr mice than in BALB/c mice (median 136.7 vs. 72.5, P 0.001). Immunohistochemistry demonstrated both iNOS and TNF- in scattered mononuclear cells throughout the Lacrimal Glands and in mononuclear cells at the junction of the focal inflam- matory infiltrates and normal acinar tissue in both MRL/ and MRL/lpr mice.

  • Chemokines in autoimmune Lacrimal Gland Disease in MRL/MpJ mice.
    Investigative ophthalmology & visual science, 2004
    Co-Authors: Esen K. Akpek, R A Prendergast, Douglas A. Jabs, Bella Lee, A P Hudson, Hervé C. Gérard, Judith A. Whittum-hudson
    Abstract:

    PURPOSE: MRL/MpJ-fas+/fas+ (MRL/+) and MRL/MpJ-fas(lpr)/fas(lpr) (MRL/lpr) mice undergo spontaneous development of inflammation of the Lacrimal and salivary Glands, similar to that in the human disorder Sjogren's syndrome. Previous work has shown that these lesions appear to be largely T helper (Th)-2-driven, as evidenced by the substantially greater expression of IL-4 than interferon-gamma. The relative contributions of selected chemokines associated with Th1 and Th2 immune responses were assessed. METHODS: Lacrimal Glands from MRL/+ and MRL/lpr mice, at ages 1.5 through 9 months were evaluated by immunohistochemistry for the chemokines monocyte chemoattractant protein (MCP)-1 (also known as chemokine ligand [CCL]-2), MCP-5 (CCL12), thymus activation regulated chemokine (TARC; or CCL17), and macrophage-derived chemokine (MDC; or CCL22). Additional Lacrimal Glands were tested by real-time RT-PCR for chemokines MCP-1 and -5, which are associated with Th2 and Th1 responses, respectively. RESULTS: By immunohistochemistry a significantly greater proportion of mononuclear inflammatory cells in the Lacrimal Gland lesions stained for MCP-1 (29%-48% depending on age) compared with MCP-5 (1%-3% depending on age) both in MRL/+ (mean difference 34.2%, P < 0.001) and MRL/lpr (mean difference 33.6%, P < 0.001) substrains. Real-time RT-PCR studies showed higher transcript levels of MCP-1 compared with MCP-5, in both MRL/+ (median difference, 37.3; P < 0.0001) and MRL/lpr (median difference, 77.1; P < 0.0001) mice. Relative transcripts of MCP-1 increased with age in both MRL/+ mice (P = 0.02) and MRL/lpr mice (P = 0.03). Staining for TARC was present on Lacrimal Gland ductular cells but not on the infiltrating lymphocytes, and staining for MDC was present on scattered individual cells throughout the Lacrimal Gland, but not on infiltrating lymphocytes. CONCLUSIONS: The predominant expression of a Th2-associated chemokine in the Lacrimal Gland lesions in this murine model of Sjogren's syndrome may contribute to the predominantly Th2-type lymphoid infiltrate in these tissues.

  • Pathogenesis of Autoimmune Lacrimal Gland Disease in MRL/MPJ Mice
    Advances in experimental medicine and biology, 2002
    Co-Authors: Douglas A. Jabs, R A Prendergast, Judith A. Whittum-hudson
    Abstract:

    MRL/MpJ mice spontaneously develop Lacrimal and salivary Gland inflammation and are a model for the human disorder Sjogren’s syndrome. 1-3 Two congenic substrains of MRL/MpJ mice exist, MRL/MpJ-+/+ (MRL/+) andMRL/MpJ-lpr/lpr(MRL/lpr). These substrains differ only at a single autosomal recessive gene locus, the1prmutation. This mutation results in altered Fas protein, defective lymphocyte apoptosis, defective clonal deletion of autoreactive T-cells in peripheral lymphoid organs and accelerated autoimmune Disease in MRL/lpr mice when compared to MRL/+ mice. 4.5 MRL/lpr mice typically die at 6 months of age, whereas MRL/+ mice often live to 2 years. Both substrains develop Lacrimal Gland inflammation, although the Lacrimal Gland Disease develops earlier in MRL/lpr than MRL/+ mice, and at comparable ages, MRL/lpr mice have more severe and extensive Disease.3 ; The Lacrimal Gland lesions in both substrains are composed largely of T-cells (approximately 80%), the majority of which are CD4+ T-cells. Lesser numbers of CD8+ T-cells, B-cells and macrophages are present. In aged (18-month) MRL/+, mice B-cells accumulate in the Lacrimal Gland lesions.2.3.6

  • The role of Fas-Fas ligand-mediated apoptosis in autoimmune Lacrimal Gland Disease in MRL/MpJ mice.
    Investigative ophthalmology & visual science, 2001
    Co-Authors: Douglas A. Jabs, Judith A. Whittum-hudson, Bella Lee, R A Prendergast
    Abstract:

    PURPOSE. MRL/MpJ mice spontaneously develop Lacrimal Gland inflammation and are a model for the human disorder Sjogren's syndrome. MRL/MpJ-lpr/lpr (MRL/lpr) and MRL/Mp-1/1 (MRL/1) mice are congenic substrains, which differ only by a single autosomal recessive gene, the lpr mutation. This muta- tion 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/1 mice. METHODS. Inflammatory cells in the Lacrimal Glands of MRL/lpr and MRL/1 mice were evaluated for apoptosis with TUNEL staining and Fas and Fas ligand expression with immunohisto- chemistry. RESULTS. MRL/lpr mice had a greater percentage of the Lacrimal Gland replaced by inflammatory infiltrate (30.3% 6 7.0%) than did MRL/1 mice (13.0% 6 3.0%, P 5 0.02). However, similar amounts of lymphocytic apoptosis were present in the Lacrimal Glands of MRL/lpr and MRL/1 mice. The mean number of apoptotic cells per unit area of inflammation was 23.8 6 2.4 in MRL/lpr mice and 24.6 6 6.0 in MRL/1 mice (P 5 0.91). Fas expression was absent on lymphocytes in MRL/lpr mice but was present on lymphocytes in MRL/1 mice. Fas ligand ex- pression was present on epithelial structures in both sub- strains. CONCLUSIONS. The accelerated Lacrimal Gland Disease inflamma- tion 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 defec- tive extrathymic lymphoid apoptosis, permitting a relatively greater expansion of autoreactive T cells, which subsequently invade the Lacrimal Gland. (Invest Ophthalmol Vis Sci. 2001;42: 399 - 401)

  • Cytokines in autoimmune Lacrimal Gland Disease in MRL/MpJ mice.
    Investigative ophthalmology & visual science, 2001
    Co-Authors: Douglas A. Jabs, R A Prendergast, E M Rorer, A P Hudson, Judith A. Whittum-hudson
    Abstract:

    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. 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. 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. 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.

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