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)

Corneal infection of BALB/c mice with herpes simplex virus type 1 results in a chronic inflammatory response in the stroma termed herpetic stromal keratitis (HSK). This disease is considered to be immunopathological and mediated primarily by CD4+ T cells of the type 1 cytokine profile. However, the nature of the antigens, virus or host derived, which drive the inflammatory response remains in doubt. In this study, the relevance of infection with replicating virus for the subsequent development of HSK was evaluated with immunocompetent mice as well as with SCID mice reconstituted with herpes simplex virus-immune CD4+ T cells. In the corneas of immunocompetent mice, infectious virus, viral antigen, and mRNA expression were detectable for only a brief period of time (< or = 7 days postinfection), and all were undetectable by the time clinical lesions were evident (10 to 15 days). Viral replication, however, was necessary for the development of HSK in both models, since infection with UV-inactivated virus or with mutant viruses which were incapable of multiple rounds of replication in vivo failed to induce HSK. The inactivated and mutant viral preparations did, however, stimulate T-cell immune responses in immunocompetent mice. The results are discussed in terms of possible involvement of host antigens exposed in response to transient progeny virion replication in the immune-privileged cornea.
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PMID:Viral replication is required for induction of ocular immunopathology by herpes simplex virus. 852 13

Herpetic stromal keratitis (HSK) has an immunopathological basis, thought primarily to involve a CD4+ T cell-mediated immune response to viral antigen. Other cell types, however, particularly those involved in nonspecific immunity, such as natural killer (NK) cells or neutrophils, may also contribute to tissue destruction in the cornea. The reconstituted SCID mouse model of HSK provides a powerful system in which to study the interactions of the innate and adaptive immune responses to herpes simplex virus type 1 corneal infection. In the present study, reconstituted SCID mice depleted of NK cells had a reduced incidence and severity of clinical and histopathological HSK. The levels of T cell cytokine protein and message in restimulated splenocytes and cytokine message in corneas did not differ between experimental groups. However, significantly fewer neutrophils were seen within the inflamed corneas of NK-depleted SCID mice. Therefore, endogenous NK cells may indirectly influence the severity of HSK in reconstituted SCID mice by affecting neutrophil migration into the cornea.
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PMID:The role of the innate immune system in the reconstituted SCID mouse model of herpetic stromal keratitis. 867 36

Infection of the mouse cornea with herpes simplex virus (HSV) results in an immunopathologic disease of the eye termed herpetic stromal keratitis (HSK), in which the principal orchestrator is the CD4+ T cell. The mouse genotype largely determines susceptibility or resistance to HSK. BALB/c mice (H2dIgh-1a) are susceptible, while its congenic C.B-17 strain (H2dIgh-1b), which differs only in the Ig heavy chain locus, is resistant to HSK. As the magnitude and duration of viral replication as well as anti-HSV immune responses were similar in both strains, it was determined whether resistance was due to failure of CD4+ T cells to organize the immunopathologic reaction. Adoptive transfer of HSV-primed or naive CD4+ T cells from resistant C.B-17 strain into HSV-infected SCID mice resulted in HSK lesions indistinguishable from those caused by similar transfers of BALB/c CD4+ T cells. Similar results were obtained with transfers of whole T cell populations as well as with unfractionated splenocytes from the resistant mice. These results show that while intact C.B-17 mice exhibit resistance to HSK, they possess potentially pathogenic CD4+ T cells in their repertoire. The data suggest that the HSV-infected SCID mouse provides a proinflammatory microenvironment that overrides regulatory controls and/or cause activation of quiescent cells into aggressive effector T cells that orchestrate HSK.
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PMID:Immunopathology of herpetic stromal keratitis: discordance in CD4+ T cell function between euthymic host and reconstituted SCID recipients. 955 4

Herpetic stromal keratitis (HSK) is a CD4+ T cell-controlled immunopathologic lesion in the eye that results from infection with herpes simplex virus (HSV). Target Ags involved in HSK remain undefined. In this study, we determined if HSK could be induced in animals genetically incapable of generating HSV Ag-specific CD4+ T cells. Mice bearing transgenic TCR specific to OVA peptide 323-339 (DO11.10) were crossed to SCID mice whose offspring (Tg-SCID) possessed CD4+ T cells, >98% of which expressed the OVA peptide-specific TCR. HSV infection of Tg-SCID mice was lethal, and mice failed to generate detectable T cell responses even after repeated immunization with a mutant avirulent virus (AN-1). Immunization with AN-1 virus followed by ocular challenge with HSV resulted in ocular inflammation before encephalitis, in contrast to the protection conferred in the control BALB/c and DO11.10 mice. These results indicate that clinical HSK may not require viral Ag recognition by CD4+ T cells and that T cells of irrelevant specificity can be recruited, activated, and driven into effector function in the HSV-infected cornea. This is suggested to represent a bystander activation effect resulting from the presence of proinflammatory mediators resulting from HSV replication.
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PMID:Virus-induced immunoinflammatory lesions in the absence of viral antigen recognition. 978 Feb 5

Herpetic stromal keratitis (HSK) is an immunopathological lesion involving herpes simplex virus (HSV) infection and CD4(+) T cells of the Th1 phenotype, but the nature of the target antigens which drive HSK remains uncertain. In the present report we show that ovalbumin TCR-transgenic mice backcrossed to SCID mice unable to recognize HSV show clinical signs of HSK but die of viral encephalitis before the lesions become severe. However, passive transfer of anti-HSV serum at 24 h clears virus and affords protection from both HSK lesions and death. Adoptive transfer of CD8(+) T cells at 72 h usually conferred protection but animals developed severe corneal pathology by 3 weeks post infection. At this time viral antigens were not demonstrable in the cornea and the T cells in the inflammatory lesions were CD4(+)KJ1-26.1 idiotype positive, i. e. OVA peptide specific. These results indicate bystander activation of CD4(+) T cells in a virus-induced inflammatory milieu. This mechanism of immunoinflammation may represent an important component of any lesion which involves CD4(+) T cells.
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PMID:Bystander activation of CD4(+) T cells can represent an exclusive means of immunopathology in a virus infection. 1055 23

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

Herpes simplex virus infection of mouse corneas can lead to the development of an immunopathological lesion, termed herpetic stromal keratitis (HSK). Such lesions also occur in TCR-transgenic mice backcrossed to SCID (TgSCID) that are unable to mount detectable HSV-specific immune responses. The present study demonstrates that lesion expression in such mice depends on continuous viral replication, whereas in immunocompetent mice, lesions occurred even if virus replication was terminated at 4 days after infection. The continuous replication in TgSCID mice was considered necessary to produce an activating stimulus to CD4(+) T cells that invade the cornea. Lesions in TgSCID were resistant to control by cyclosporin A, but were inhibited by treatment with rapamycin. This result was interpreted to indicate that T cell activation involved a non-TCR-mediated cytokine-driven bystander mechanism. Bystander activation was also shown to play a role in HSK lesions in immunocompetent mice. Accordingly, in immunocompetent DO11.10 mice, lesions were dominated by KJ1.26(+) OVA-specific CD4(+) T cells that were unreactive with HSV. In addition, KJ1.26(+) HSV nonimmune cells parked in ocularly infected BALB/c mice were demonstrable in HSK lesions. These results provide insight for the choice of new strategies to manage HSK, an important cause of human blindness.
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PMID:Bystander activation involving T lymphocytes in herpetic stromal keratitis. 1150 38

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

Herpetic stromal keratitis (HSK), resulting from corneal HSV-1 infection, represents a T cell-mediated immunopathologic lesion. In T cell transgenic mice on a SCID or RAG knockout background, the T cells mediating lesions are unreactive to viral Ags. In these bystander models, animals develop ocular lesions but are unable to control infection. Transfer of HSV-immune cells into a CD8(+) T cell bystander model resulted in clearance of virus from eyes, animals survived, and lesions developed to greater severity. However, the adoptively transferred CD8(+) T cells were not evident in lesions, although they were readily detectable in the lymphoid tissues as well as in the peripheral and CNS. Our results indicate that viral-induced tissue damage can be caused by bystander cells, but these fail to control infection. Immune CD8(+) T cells trigger clearance of virus from the eye, but this appears to result by the T cells acting at sites distal to the cornea. A case is made that CD8(+) T cell control is expressed in the trigeminal ganglion, serving to curtail a source of virus to the cornea.
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PMID:Protective and pathological roles of virus-specific and bystander CD8+ T cells in herpetic stromal keratitis. 1558 85

Ocular infection with herpes simplex virus (HSV) causes a vision-impairing inflammatory reaction called herpetic stromal keratitis. In murine models, herpetic stromal keratitis lesions appear to be immunopathologic, mediated by CD4(+) T cells of Th1 phenotype. To provide insight about cytokine networks and signaling events involved in the development of aggressor CD4(+) T cells, ocular HSV infection was followed in mice deficient in Stat4 (Stat4(-/-) mice), the signal transducer for the cytokine interleukin-12 (IL-12). After ocular HSV infection of Stat4(-/-) and control BALB/c mice, clinical, histologic, and immunologic analyses were carried out. Further, to evaluate the involvement of Stat4 in the development of this aggressor population, naive CD4(+) T cells from Stat4(-/-) and BALB/c mice were adoptively transferred to C.B-17 SCID mice 1 day after corneal infection. Although Stat4(-/-) mice demonstrated increased susceptibility to lethal encephalitis and facial lesions, interestingly, these mice had less severe stromal keratitis in comparison to control animals. Adoptive transfer of naive CD4(+) T cells from Stat4(-/-) mice failed to produce disease in infected SCID recipients. The data imply a significant role of Stat4-mediated signaling events in the generation of an aggressor CD4(+) T cell population in stromal keratitis pathogenesis.
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PMID:Role of Stat4-mediated signal transduction events in the generation of aggressor CD4+ T cells in herpetic stromal keratitis pathogenesis. 1726 45


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