Apoptosis in Patients With Posterior Uveitis

Chan, Chi‐Chao; Matteson, Dawn M.; Li, Qian; Whitcup, Scott M.; Nussenblatt, Robert B.

doi:10.1001/archopht.1997.01100160729010

Cited by 42 publications

(28 citation statements)

References 35 publications

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“…1A, arrows). This result agrees with previous observations obtained with different approaches or from human retina sections (11,22). Fas expression was specific to HRPE cells because it was not detectable in colon cancer cells RKO (Fig.…”

Section: Fas Receptor-rich Human Retina Cells Containing Hcmv Ie2 Aresupporting

confidence: 93%

The Immediate Early 2 Protein of Human Cytomegalovirus (HCMV) Mediates the Apoptotic Control in HCMV Retinitis through Up-Regulation of the Cellular FLICE-Inhibitory Protein Expression

Chiou

Yang

Lin

et al. 2006

The Journal of Immunology

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Human CMV (HCMV) is a widespread human pathogen that causes blindness by inducing retinitis in AIDS patients. Previously, we showed that viral immediate early 2 (IE2) protein may allow HCMV to evade the immune control by killing the Fas receptor-positive T lymphocytes attracted to the infected retina with increased secretion of Fas ligand (FasL). In this study, we further demonstrate that the secreted FasL also kills uninfected Fas-rich bystander retinal cells and that IE2 simultaneously protects the infected cells from undergoing apoptotic death, in part, by activating the expression of cellular FLIP (c-FLIP), an antiapoptotic molecule that blocks the direct downstream executer caspase 8 of the FasL/Fas pathway. c-FLIP induction requires the N-terminal 98 residues of IE2 and the c-FLIP promoter region spanning nucleotides −978 to −696. In vivo association of IE2 to this region, IE2-specific c-FLIP activation, and decrease of FasL-up-regulated activities of caspases 8 and 3 were all demonstrated in HCMV-infected human retinal cells. Moreover, c-FLIP up-regulation by IE2 appeared to involve PI3K and might also render cells resistant to TRAIL-mediated death. Finally, enhanced c-FLIP signals were immunohistochemically detected in IE-positive cells in the HCMV-infected lesions of the human retina. Taken together, these data demonstrate specific activation of c-FLIP by HCMV IE2 and indicate a novel role for c-FLIP in the pathogenesis of HCMV retinitis.

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Section: Fas Receptor-rich Human Retina Cells Containing Hcmv Ie2 Aresupporting

confidence: 93%

The Immediate Early 2 Protein of Human Cytomegalovirus (HCMV) Mediates the Apoptotic Control in HCMV Retinitis through Up-Regulation of the Cellular FLICE-Inhibitory Protein Expression

Chiou

Yang

Lin

et al. 2006

The Journal of Immunology

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“…In humans, functional mutations in the Fas gene leads to a range of autoimmune diseases, including uveitis (35). Previous reports have suggested that AqH from healthy subjects contains proapoptotic factors (36), and that Fas-induced apoptosis might be involved in the spontaneous resolution of inflammation observed in patients with acute anterior uveitis (13,15,16). The present report suggests that the ocular microenvironment in uveitis has no modulatory effect on Fas-induced apoptosis.…”

Section: Discussionsupporting

confidence: 46%

“…The absence of significant apoptosis in these samples therefore suggests insufficient triggering of the Fas pathway during inflammation, particularly because the ocular T cells were highly susceptible to Fas-induced apoptosis in vitro. There is evidence of reduced expression of FasL in the eye during inflammation, which would accord with this observation (16). In experimental models of uveitis, T cell apoptosis usually occurs within 2-3 days of the development of disease (37)(38)(39)(40).…”

Section: Discussionmentioning

confidence: 65%

“…Many studies have focused on Fas-mediated apoptosis during intraocular inflammation (13)(14)(15)(16), but the failure of many cases of uveitis to resolve suggests that SFD-induced apoptosis may be diminished. T lymphocytes can be protected from SFD-induced apoptosis by members of the common ␥-chain cytokine family, including IL-2, IL-4, IL-7, IL-9, and IL-15 (17), and type I IFNs (18).…”

mentioning

confidence: 99%

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Inhibition of T Cell Apoptosis in the Aqueous Humor of Patients with Uveitis by IL-6/Soluble IL-6 Receptor trans-Signaling

Curnow

Scheel‐Toellner

Jenkinson

et al. 2004

The Journal of Immunology

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A fundamental mechanism of immune privilege in the eye is the induction of T lymphocyte apoptosis. Intraocular inflammation in uveitis implies compromise of immune privilege. This study sought to determine whether apoptosis of T cells is actively inhibited in patients with uveitis and by what pathways this may occur. Apoptotic lymphocytes were found to be absent from aqueous humor (AqH) of virtually all patients with recent-onset uveitis. However, T cells removed from the eye were highly susceptible to both spontaneous and Fas ligand-induced apoptosis in vitro. AqH from patients with uveitis had no modulatory effect on Fas ligand-induced apoptosis, but strongly suppressed survival factor deprivation-induced apoptosis. In contrast, noninflammatory AqH from patients undergoing cataract surgery had no modulatory effects on apoptosis at all. These data suggest that triggering of the Fas pathway is diminished in uveitis, and also that homeostatic resolution through survival factor deprivation-induced apoptosis is inhibited by factors present in AqH. The most widely recognized pathways, common γ-chain cytokines and type I IFNs, did not contribute to AqH-mediated T cell survival. High levels of both IL-6 and soluble IL-6R were found in AqH. IL-6 alone did not induce T cell survival, because IL-6R expression on T cells in AqH was too low to facilitate signaling. However, combinations of IL-6 and soluble IL-6R were highly effective inhibitors of T cell apoptosis, suggesting that the trans-signaling pathway is likely to be a key mediator of T cell apoptosis inhibition mediated by uveitis AqH.

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“…The population of autoreactive lymphocytes lodged in the vitreous in chronic uveitis appears to be unable to exit the eye and does not readily undergo apoptosis. 3,4 It has been proposed that this induces the collection of a 'sump' of inflammatory cells lodged in the vitreous that may be reactivated to cause an uveitic exacerbation. 5 Pars plana vitrectomy (PPV) physically removes the vitreous humour and in the case of EPU, any inflammatory cells that might be trapped in it.…”

Section: Introductionmentioning

confidence: 99%

Vitreous surgery in the management of chronic endogenous posterior uveitis

Scott

Haynes

Orr

et al. 2003

Eye

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Objectives There is evidence that pars plana vitrectomy (PPV) has a beneficial effect on the clinical course of chronic endogenous posterior uveitis (EPU) possibly by physically removing any resident inflammatory cells with the vitreous. We assessed the anatomical and therapeutic effects of PPV performed on patients with chronic EPU for any indication. Patients and methods Retrospective review of 41 eyes of 38 consecutive patients with EPU who underwent a PPV for any reason, over a 5-year period. The mean age of the patients was 36.2 years, 46% of the eyes had intermediate uveitis, 32% panuveitis, and 22% posterior uveitis. The visual acuity, disease activity, and the requirement for medications to control it were recorded for 12 months pre-and postoperatively.Results Overall, 61% of the eyes gained more than 2 Snellen lines (Po0.001) and the incidence of cystoid macular oedema (CMO) significantly reduced from 44 to 20% (Po0.05). Postoperatively, there was a significant decrease in the recurrence rate of intermediate uveitis, posterior uveitis, and panuveitis (Po0.001). The use of systemic and local depot immunosuppressive agents did not change over the study period, although the use of topical agents increased (Po0.05). Conclusion PPV appears to have a beneficial effect on the clinical course of EPU in selected cases. This may be mediated by the physical clearance of inflammatory debris, the anti-inflammatory effect of replacing vitreous by aqueous humour, by a reduction of CMO and/or the anatomical correction of sight-threatening retinal pathology.

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Apoptosis in Patients With Posterior Uveitis

Cited by 42 publications

References 35 publications

The Immediate Early 2 Protein of Human Cytomegalovirus (HCMV) Mediates the Apoptotic Control in HCMV Retinitis through Up-Regulation of the Cellular FLICE-Inhibitory Protein Expression

The Immediate Early 2 Protein of Human Cytomegalovirus (HCMV) Mediates the Apoptotic Control in HCMV Retinitis through Up-Regulation of the Cellular FLICE-Inhibitory Protein Expression

Inhibition of T Cell Apoptosis in the Aqueous Humor of Patients with Uveitis by IL-6/Soluble IL-6 Receptor trans-Signaling

Vitreous surgery in the management of chronic endogenous posterior uveitis

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