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)

Herpetic stromal keratitis an inflammatory disease of the eye resulting from herpes simplex virus type 1 infection, is a common cause of blindness. The disease is generally considered to represent an immunopathologic response, but the exact mechanism remains in doubt and is subject to debate. We have investigated the nature of inflammatory cells in the eye and have isolated ocular cells to establish their phenotype and determine some of their functions. By means of immunocytochemistry and cytofluorography, the only T lymphocyte subset detectable at any stage of infection of BALB/c mice were CD4+ cells. However CD8+ T cells were readily detectable in draining lymph nodes (DLN). Assays for cells with HSV-1-specific cytotoxic function of both CD4+ class II restricted and CD8+ class I-restricted activity were performed. Although in DLN both cell types were found, among ocular cells only CD4+ cytotoxic cells were evident. The frequencies of CD4+ CTL-precursor in eyes were determined and found to be at least 8- to 10-fold less than found in DLN. The number of CTL-precursor in an individual eye was estimated to be 20 or less. Our results further support the notion that CD4+ mediate the immunopathology of herpetic stromal keratitis, but on quantitative grounds cast doubt on the idea that cytotoxicity is the principal mechanism involved.
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PMID:Phenotypic and functional studies on ocular T cells during herpetic infections of the eye. 134 9

Herpetic stromal keratitis (HSK) appears to represent an immunopathological reaction in which CD4+ T cells play a prominent role. However, the exact immunopathological mechanism(s) utilized by CD4+ T cells during HSK remains to be elucidated. In this study, the presence of cytotoxic CD4+ T lymphocytes in the cervical and retropharyngeal lymph nodes of Balb/c mice experiencing HSK was investigated. After in vitro depletion of CD4+ or CD8+ T cells with specific monoclonal antibodies and complement treatment, the cytotoxic functions of the remaining T cell populations were assayed by using target cells expressing either MHC Class I or both Class I and Class II. Our results showed the presence of a distinct cytotoxic T lymphocyte (CTL) population which was CD4+ and demonstrated lytic activity in a Class II-restricted fashion. Furthermore, these cells were able to develop into efficient effector CTL in the absence of CD8+ T lymphocytes as assessed by in vivo depletion experiments. Immunohistochemical methods were also utilized to show the presence of both CD4+ lymphocytes and I-A+ cells in the corneal tissues during HSK. These findings support the notion that direct lysis of infected Class II-bearing corneal cells by CD4+ CTL might be one of the mechanisms leading to stromal immunopathology in herpetic infections.
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PMID:MHC II-restricted, CD4+ cytotoxic T lymphocytes specific for herpes simplex virus-1: implications for the development of herpetic stromal keratitis in mice. 193 28

Interferons have been studied in animals and man for local and systemic viral infections that are either rare or common. Recent clinical studies in humans with purified or recombinantly derived interferons have demonstrated significant clinical response in rhinovirus common colds, herpetic keratitis, condyloma acuminata, and laryngeal papillomatosis. However, only 40 per cent of published papers with IFN have been appropriately controlled. The toxicity of these newer preparations when administered either topically or parenterally prevents their immediate licensing for general use. The toxic to therapeutic ratio for HuIFN and rIFN appears to be close to one in most clinical situations in which it has been tested. Although interferons have not proved to be the "penicillin" for viruses many thought they would become, basic in vitro work and clinical studies have contributed greatly to our understanding of host defense and immunopathology. Future studies must focus on increasing our understanding of the mechanisms of toxicity, in addition to devising controlled clinical trials with interferon alone or in combination with other antiviral agents. Thus, after 30 years of research on interferons, it would appear our work has just begun.
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PMID:Human interferon in viral diseases. 246 9

Our study was designed to investigate the mechanism of the stromal reaction in experimental ocular infection of murine eyes with herpes simplex virus (HSV). Severe stromal keratitis with scarring occurred in BALB/c mice after infection of the scarified cornea but similar reactions did not occur in athymic mice. However, if athymic mice were given adoptive transfers of lymphoid cells, a severe necrotizing and ulcerative keratitis accompanied by scarring resulted. The lesion progressed more quickly in recipients of lymphoid cells specifically immune to HSV and containing cytotoxic T-lymphocyte activity. In such mice, necrosis and ulceration were marked on the sixth day after transfer compared with 9-12 days for those given nonimmune cells. Removal of T-lymphocytes from the immune lymphoid population by treatment with specific antiserum and complement abrogated the adoptive transfer of the stromal reaction. Our results further demonstrate that stromal keratitis represents a host immunopathologic response to HSV infection in which T-lymphocytes are essential participants. Multiple mechanisms of T-cell immunopathology appear to be operating, including a reaction mediated by cytotoxic T-lymphocytes.
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PMID:Role of T-lymphocytes in the pathogenesis of herpetic stromal keratitis. 661 24

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

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

Herpetic stromal keratitis (HSK), resulting from ocular infection with herpes simplex virus (HSV), is thought to represent a T cell mediated immunopathologic lesion. Antigens recognized by the inflammatory T cells remain unresolved and non-TCR mediated activation of T cells (bystander activation) is considered as also involved. This report documents further evidence for the bystander activation mechanisms using three T cell transgenic RAG-/- mouse strains. Accordingly HSK occurred in PCC RAG-/-, P14 RAG-/-, and OT-1 RAG-/- mice. In none of the models could HSV specific T cell reactivity be demonstrated and animals were unprotected from lesion development by immunization prior to HSV ocular infection. The results support the role of bystander activation as a mechanism of T cell mediated immunopathology and show that CD8(+) as well as CD4(+) T cells can participate in HSK lesion development.
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PMID:Herpetic stromal keratitis in the absence of viral antigen recognition. 1257 29

CD4(+)CD25(+) regulatory T cells (T(reg)) can inhibit a variety of autoimmune and inflammatory diseases, but their involvement in regulating virus-induced immunopathology is not known. We have evaluated the role of T(reg) in viral immunopathological lesion stromal keratitis. This frequent cause of human blindness results from a T cell-mediated immunoinflammatory response to HSV in the corneal stroma. The results show that lesions were significantly more severe if mice were depleted of T(reg) before infection. The T(reg) was also shown to modulate lesion expression induced by adoptive transfer of pathogenic CD4(+) T cells in infected SCID recipients. The mechanism of T(reg) control of stromal keratitis involved suppressed antiviral immunity and impaired expression of the molecule required for T cell migration to lesion sites. Interestingly, T(reg) isolated from ocular lesions in nondepleted mice showed in vitro inhibitory effects involving IL-10, but were not very effective in established lesions. Our results decipher the in vivo role of T(reg) in a virus-induced immunopathology and imply that manipulation of regulatory cell function represents a useful approach to control viral-induced immunoinflammatory disease.
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PMID:CD4+CD25+ regulatory T cells control the severity of viral immunoinflammatory lesions. 1503 24

Approximately 7 days after HSV-1 corneal infection, BALB/c mice develop tissue-destructive inflammation in the cornea termed herpes stromal keratitis (HSK), as well as periocular skin lesions that are characterized by vesicles, edema, and fur loss. CD4(+) T cells and Th1 cytokines contribute to both the immunopathology in the cornea and the eradication of viral replication in the skin. We demonstrate that disruption of CD40/CD154 signaling does not impact the initial expansion of CD4(+) T cells in the draining lymph nodes, but dramatically reduces the persistence and Th1 polarization of these cells. Despite the reduced Th1 response, CD154(-/-) mice developed HSK and periocular skin disease with similar kinetics and severity (as assessed by clinical examination) as wild-type (WT) mice. However, when the composition of the inflammatory infiltrate was examined by flow cytometric analysis, CD154(-/-) mice exhibited significantly fewer CD4(+) and CD8(+) T cells and neutrophils than WT mice at the peak of HSK. Moreover, CD4(+) T cells from infected corneas of CD154(-/-) mice produced significantly less IFN-gamma than those of WT mice when stimulated with viral Ags in vitro. The IFN-gamma production of cells from infected corneas of WT mice was not affected by addition of anti-CD154 mAb to the stimulation cultures. This suggests that CD154 signaling is required at the inductive phase, but not at the effector phase, of the Th1 response within the infected cornea. We conclude that local disruption of CD40/CD154 signaling is not likely to be a useful therapy for HSK.
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PMID:CD154 signaling regulates the Th1 response to herpes simplex virus-1 and inflammation in infected corneas. 1524 Jul 15


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