Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022568 (keratitis)
 5,133 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Inflammation of the corneal stroma (stromal keratitis) is a serious complication of infection with the nematode parasite Onchocerca volvulus. Because stromal keratitis is believed to be immunologically mediated in humans, we used a murine model to examine the role of T cells and T helper cell cytokines in the immunopathogenesis of these eye lesions. BALB/c mice immunized subcutaneously and injected intrastromally with soluble O. volvulus antigens (OvAg) developed pronounced corneal opacification and neovascularization. The corneal stroma was edematous and contained numerous eosinophils and mononuclear cells. Stromal keratitis in immunized mice was determined to be T cell dependent based on the following observations: (a) T cell-deficient nude mice immunized and injected intrastromally with OvAg fail to develop corneal pathology; and (b) adoptive transfer of spleen cells from OvAg-immunized BALB/c mice to naive nude mice before intrastromal injection of OvAg results in development of keratitis. OvAg-stimulated lymph node and spleen cell cytokine production was dependent on CD4 cells and included interleukin (IL)-4 and IL-5, but not interferon gamma, indicating a predominant T helper type 2 cell-like response. Inflamed corneas from immunized BALB/c mice and from reconstituted nude mice had greatly elevated CD4 and IL-4 gene expression compared with interferon gamma. Mice in which the IL-4 gene was disrupted failed to develop corneal disease, demonstrating that IL-4 is essential in the immunopathogenesis of O. volvulus-mediated stromal keratitis.
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PMID:Interleukin 4 and T helper type 2 cells are required for development of experimental onchocercal keratitis (river blindness). 756 96

Corneal infection with herpes simplex virus in mice induces an inflammatory response in the stroma (herpetic stromal keratitis (HSK)) that appears to represent an immunopathologic reaction in which T cells of the CD4+ subset act as the essential participants. To assess the role of T cell cytokines at different clinical phases of HSK, corneas and draining lymph node (DLN) cells were collected and the levels of mRNA thought to be representative of type 1 and type 2 T cells were quantitated by reverse transcription-PCR. In the corneas collected before the onset of clinical disease, IFN-gamma and IL-4 mRNA were detectable, with levels of IFN-gamma 5- to 15-fold higher than IL-4. During the onset and peak expression of clinical disease, type 1 cytokines IFN-gamma and IL-2 were predominant in the corneas, and IL-4 levels were either very low or undetectable. Neither IL-10 nor IL-5 mRNA was present. After 3 wk postinfection, when some animals with mild disease began to recover, high levels of type 2 cytokine mRNA, particularly IL-10, were present. In addition, only during the recovery phase was IL-10 mRNA present in DLN samples. Levels of transcriptional activity for cytokine mRNA during clinical HSK were higher in corneas than in the corresponding DLN samples. The results indicate that IL-10 may be involved in HSK resolution and that the stimuli for cytokine induction in the cornea may differ from those in the DLN.
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PMID:T cell cytokine mRNA expression during the course of the immunopathologic ocular disease herpetic stromal keratitis. 772 30

Corneal inflammation similar to human onchocercal keratitis can be induced in mice by subcutaneous immunization of a soluble extract of Onchocerca volvulus (OvAg) followed by direct injection of OvAg into the corneal stroma. Previous studies have shown that corneal pathology is associated with increased systemic and corneal Th2 cytokine expression and that IL-4 gene knockout (IL-4-/-) mice develop less severe or no O. volvulus-mediated keratitis. The current study examined the contribution of Th2 cytokines to the diminished OvAg-induced corneal immunopathology observed in IL-4-/- mice. IL-4-/- mice (129Sv x C57B1/6), wild-type F2 littermates (IL-4+/+), and C57B1/6 mice were sensitized by repeated subcutaneous immunization with OvAg. Ten days after the final immunization, mice were sacrificed, spleens were removed, and cells were incubated with OvAg. Cells from immunocompetent C57B1/6 and IL-4+/+ mice produced IL-4 and IL-5, but no IFN-gamma, whereas cells from IL-4-/- mice had elevated IFN-gamma and no IL-4. Interestingly, cells from these animals produced levels of IL-5 protein equivalent to those of C57B1/6 and IL-4+/+ mice. To determine cytokine production in corneas during the onset of onchocercal keratitis, OvAg-immunized mice were injected intracorneally with OvAg, and cytokine gene expression in the cornea was determined by RT-PCR. Temporal analysis of cytokine gene expression in corneas of immunocompetent mice showed that the Th2-associated cytokines IL-4, IL-5, IL-10, and IL-13 were produced within 1 day of intrastromal injection, with sustained elevations for 10 days. Maximal IFN-gamma mRNA levels were not detected until Day 10. This was in contrast to IL-4-/- mice in which IFN-gamma appeared at Day 1 and remained elevated for at least 10 days. Moreover, in corneas from IL-4-/- mice, all Th2 cytokines with the exception of IL-4 were up-regulated and expressed with kinetics similar to that of IL-4+/+ littermates. Histologically, corneas from IL-4-/- mice were less edematous and contained fewer eosinophils and other inflammatory cells than those from immunocompetent controls. As there was no difference in peripheral eosinophil levels, these data indicate that the diminished severity of onchocercal keratitis in IL-4-/- mice is not due to failure to develop systemic or local Th2 cytokine responses or to produce eosinophils, but that IL-4 may be involved in recruitment of eosinophils and other inflammatory cells into the corneal stroma.
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PMID:Onchocerca volvulus-mediated keratitis: cytokine production by IL-4-deficient mice. 893 77

Corneal inflammation (keratitis) is a major cause of visual impairment in Onchocerca volvulus infection. Previous studies showed that onchocercal keratitis can be induced in mice following s.c. immunization and intracorneal injection with soluble O. volvulus Ags (OvAg), and that the inflammatory response is dependent on T cells and IL-4. Since recombinant IL-12 impairs IL-4-dependent, Th2-mediated responses in other parasitic infections and in models of allergic asthma, the present study was undertaken to determine the effect of IL-12 on onchocercal keratitis. Mice were injected i.p. with IL-12 or saline at the time of initial sensitization to OvAg. Surprisingly, IL-12 treatment caused significant exacerbation of corneal pathology, which was associated with increased eosinophil and mononuclear cell infiltration into the corneal stroma. Consistent with the well-documented effect of IL-12 on Th1 cell development, corneas of IL-12-treated animals had elevated expression of the Th1 cytokine IFN-gamma and diminished expression of the Th2 cytokines IL-4, IL-5, IL-10, and IL-13. However, corneas from these animals also had marked elevation of alpha- and beta-chemokines known to be active on eosinophils and mononuclear cells, including IFN-gamma-inducible protein (IP)-10, macrophage inflammatory protein-1alpha, macrophage inflammatory protein-1beta, JE/monocyte chemotactic protein-1, RANTES (regulated upon activation, normal T expressed and secreted), and eotaxin. Together, these data indicate that IL-12 exacerbates OvAg-mediated corneal pathology by enhancing chemokine expression and recruitment of inflammatory cells.
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PMID:IL-12 exacerbates helminth-mediated corneal pathology by augmenting inflammatory cell recruitment and chemokine expression. 899

Sclerosing keratitis is the major cause of blindness due to onchocerciasis which results from chronic infection with the filarial parasite Onchocerca volvulus. Using a murine model of onchocercal sclerosing keratitis, we have demonstrated previously that predominantly (> 85%) CD3 + /CD4+ T-cells as well as the IL-2 receptor bearing cells infiltrate into the cornea in vivo during development and progress of the disease. The identification of CD4+ subsets TH1 and TH2 based on the cytokine secretion patterns of murine T-lymphocytes has been useful for understanding the immune basis of resistance and pathogenesis in murine models of several parasitic diseases. The present investigation was carried out to demonstrate whether the local immune response at the corneal lesion due to onchocercal interstitial keratitis correlated with such distinct patterns of cytokine production. For that purpose, mRNA was extracted separately from corneas obtained from the diseased eyes and the normal eyes of A/J mice with onchocercal interstitial keratitis, reverse transcribed and amplified by the polymerase chain reaction with four different cytokine specific primers. In corneas obtained from the eyes affected with onchocercal interstitial keratitis, mRNAs coding for IL-4 and IL-5 were up-regulated compared to the normal eyes having no lesions from the same animals. However, the levels of mRNAs for IL-2 and IFN gamma were found to be the same in the diseased and normal eyes. Taken together, these data suggest that IL-4 and IL-5 producing TH2-lymphocytes are active at the corneal lesion due to onchocercal interstitial keratitis.
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PMID:In vivo molecular analysis of cytokines in a murine model of ocular onchocerciasis. I. Up-regulation of IL-4 and IL-5 mRNAs and not IL-2 and IFN gamma mRNAs in the cornea due to experimental interstitial keratitis. 903 Sep 83

This review has sought to demonstrate that eosinophils have an important role in the immunopathology of onchocercal dermatitis and keratitis. The most compelling evidence is the consistent presence of eosinophils and eosinophil granule proteins at the site of tissue damage, either after parasite death or direct injection of parasite antigens. A more definitive role for eosinophils in onchocercal keratitis will be determined using IL-5 gene knockout mice (an animal model of onchocercal dermatitis has yet to be established). Identification of chemoattractants and adhesion molecules necessary for eosinophil recruitment will indicate possible approaches to immune intervention.
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PMID:Immunopathology of onchocerciasis: a role for eosinophils in onchocercal dermatitis and keratitis. 910 64

Herpetic stromal keratitis (HSK) is a corneal disease initiated by a herpes simplex virus (HSV) infection with a postulated T cell-mediated immunopathology. To study the antigen specificity of cornea-infiltrating T cells in HSK patients, T cells were isolated and expanded by mitogenic stimulation from corneas of 2 patients with HSV-1-mediated HSK. A substantial number of the T cell clones (TCCs) obtained from these T cell lines were HSV-specific. All HSV-specific TCCs were of the CD3+CD4+CD8- phenotype. These TCCs responded to autologous HSV-infected corneal keratocytes, which expressed HLA class II molecules following incubation with interferon-gamma. Upon HSV-specific stimulation, all TCCs secreted interleukin-4, interleukin-5, and interferon-gamma. The data presented suggest that HSV-specific CD4+ T cells play a role in the immunopathogenesis of HSK in humans and that corneal keratocytes may act as antigen-presenting cells in this local T cell response.
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PMID:Identification and characterization of herpes simplex virus-specific CD4+ T cells in corneas of herpetic stromal keratitis patients. 946 44

To investigate the role of cytokines in the pathogenesis of acute herpetic keratitis (HK), we examined the kinetics of cytokine expression in the corneas and the trigeminal ganglia (TG) of C57BL/6Cr (B6) mice after herpes simplex virus type 1 (HSV-1) infection and observed the influence of the targeted disruption of interferon-gamma (IFN-gamma) gene on the clinical course of HK and/or viral clearance. Following corneal infection with HSV-1 Amakata strain, all corneas developed a typical dendritic keratitis. Quantitative analysis using enzyme-linked immunosorbent assay (ELISA) revealed that the expression of interleukin-1alpha (IL-1alpha), IL-5, IL-6, and IFN-gamma in corneas and TGs significantly elevated immediately after infection, peaked between days 2 and 7 postinfection (p.i.), and then diminished. One exception was IFN-gamma, whose expression significantly persisted in the TGs until day 30 p.i. An additional experiment using IFN-gamma-/- (gko) mice revealed that there was no significant difference in the peak level of viral replication in corneas and TGs between gko and B6 mice, although gko mice showed a significant delay of virus clearance in both corneas and TGs (p < 0.005) and higher mortality rate than B6 mice after HSV-1 infection (p < 0.01). These data suggest that the production of proinflammatory cytokines closely correlates with the pathogenesis of HK, and that IFN-gamma plays an important role in enhancing viral clearance from the cornea and TG.
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PMID:Kinetics of cytokine production in the cornea and trigeminal ganglion of C57BL/6 mice after corneal HSV-1 infection. 1043 61

Invasion of the corneal stroma by neutrophils and eosinophils and subsequent degranulation disrupts corneal clarity and can result in permanent loss of vision. In the current study, we used a model of helminth-induced inflammation to demonstrate a novel role for Ab in mediating recruitment of these inflammatory cells to the central cornea. C57BL/6 and B cell-deficient (microMT) mice were immunized s. c. and injected intrastromally with Ags from the parasitic helminth Onchocerca volvulus (which causes river blindness). C57BL/6 mice developed pronounced corneal opacification, which was associated with an Ag-specific IL-5 response and peripheral eosinophilia, temporal recruitment of neutrophils and eosinophils from the limbal vessels to the peripheral cornea and subsequent migration to the central cornea. In contrast, the corneas of microMT mice failed to develop keratitis after intrastromal injection of parasite Ags unless Ags were injected with immune sera. Eosinophils were recruited from the limbal vessels to the peripheral cornea in microMT mice, but failed to migrate to the central cornea, whereas neutrophil recruitment was impaired at both stages. With the exception of IL-5, T cell responses and peripheral eosinophils were not significantly different between C57BL/6 and microMT mice. Taken together, these findings not only demonstrate that Ab is required for the development of keratitis, but also show that recruitment of neutrophils to the cornea is Ab-dependent, whereas eosinophil migration is only partially dependent upon Ab interactions.
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PMID:An essential role for antibody in neutrophil and eosinophil recruitment to the cornea: B cell-deficient (microMT) mice fail to develop Th2-dependent, helminth-mediated keratitis. 1052 1

Herpes stromal keratitis (HSK) is a prevalent and frequently vision-threatening disease associated with herpes simplex virus type 1 (HSV-1) infection. In mice, HSK progression occurs after viral clearance and requires T cells and neutrophils. One model implicates Th1-like CD4 T cells with cross-reactivity between the HSV-1 protein UL6 and a corneal autoantigen. HSK can be prevented by establishing specific immunological tolerance. However, HSK can also occur in T-cell receptor-transgenic X SCID mice lacking HSV-specific T cells. To study the pathogenesis of HSK in the natural host species, we measured local HSV-specific T-cell responses in HSK corneas removed at transplant surgery (n = 5) or control corneas (n = 2). HSV-1 DNA was detected by PCR in two specimens. HSV-specific CD4 T cells were enriched in three of the five HSK specimens and were not detectable in the control specimens. Reactivity with peptide epitopes within the tegument proteins UL21 and UL49 was documented. Responses to HSV-1 UL6 were not detected. Diverse HLA DR and DP alleles restricted these local responses. Most clones secreted gamma interferon, but not interleukin-5, in response to antigen. HSV-specific CD8 cells were also recovered. Some clones had cytotoxic-T-lymphocyte activity. The diverse specificities and HLA-restricting alleles of local virus-specific T cells in HSK are consistent with their contribution to HSK by a proinflammatory effect.
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PMID:Tegument-specific, virus-reactive CD4 T cells localize to the cornea in herpes simplex virus interstitial keratitis in humans. 1106 87


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