Delayed Type Hypersensitivity in the Pathogenesis of Recurrent Herpes Stromal Keratitis

Hawthorne, Kristen M.; Dana, Reza; Chodosh, James

doi:10.3109/08820538.2011.588659

Cited by 8 publications

(6 citation statements)

References 54 publications

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“…As a consequence, most corneal disease associated with HSV-1 infection is the result of recrudescence of a latent infection whereby virus is reactivated in the trigeminal ganglia and then returns to the cornea where it restimulates a memory immune response that was initially generated during primary infection (32,33). This immune response is characterized by an influx of CD4 and CD8 conventional T cells, neutrophils, macrophages, and NK and NKT cells (7,21,33,34). The role that each of these subsets of cells plays in corneal disease has been the subject of numerous publications (7,8).…”

Section: Discussionmentioning

confidence: 99%

CXCL9 compensates for the absence of CXCL10 during recurrent Herpetic stromal keratitis

et al. 2017

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Herpetic stromal keratitis (HSK) is a disease that is typically associated with reactivation of a latent HSV-1 infection. This disease is driven, in part, by chemokines that recruit leukocytes to the cornea. Surprisingly, neutralization of CXCL10 significantly reduced disease, while B6-CXCL10−/− mice exhibited worse disease compared with similarly infected wild-type controls. We hypothesized that compensatory up-regulation of CXCL9 occurs in the absence of CXCL10. Analysis of CXCL9 expression in HSV-1-infected B6 mice and B6-CXCL10−/− mice revealed significantly more CXCL9 in B6-XCL10−/− mice. Treatment of B6 and B6-CXCL10−/− mice with neutralizing antibodies to CXCL9 reduced HSK scores in B6-CXCL10−/−, but not B6 mice. We conclude that CXCL10 production worsens HSK and that CXCL9 may compensate in CXCL10-deficient animals. These studies identify the critical role that CXCL10 plays in the pathogenesis of recurrent HSK, and that CXCL9 displays its importance when CXCL10 is absent.

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Section: Discussionmentioning

confidence: 99%

CXCL9 compensates for the absence of CXCL10 during recurrent Herpetic stromal keratitis

et al. 2017

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“…Indeed, severing of latently infected TG neurons/nerve endings during excision of the host cornea is considered a sufficient stimulus to induce HSV-1 reactivation with anterograde virus transport to the graft site resulting either in direct viral damage or indirect damage due to an antigen-specific T-cell recall response. 10 – 12 Human clinical studies have shown HSV-1 DNA as well as virus particles in host corneas, in donor-rejected corneas, and in aqueous samples from patients with rejecting corneal grafts, 13 and has led to the common practice of antiviral prophylaxis as part of the management of HSK patients. Experimental studies in rabbits have also shown an increase in viral shedding in tear fluid after lamellar corneal grafts with some epithelial lesions but without development of HSK.…”

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confidence: 99%

High-Risk Corneal Graft Rejection in the Setting of Previous Corneal Herpes Simplex Virus (HSV)-1 Infection

Kuffová

Knickelbein

Tian

et al. 2016

Invest. Ophthalmol. Vis. Sci.

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PurposeThe “high-risk phenotype” of corneal graft recipients is considered to be related to preexisting vascularization such as that associated with herpes simplex virus-1 (HSV-1) keratitis (HSK). The purpose of this study was to investigate the immunologic mechanisms underlying accelerated corneal graft rejection using a mouse model of HSK.MethodsHerpes simplex virus type 1 keratitis was induced in BALB/c mice. Syngeneic and allogeneic (C57BL/6 mice) corneal grafts were performed in mice with HSK at different times after infection. Some grafts were performed on HSV-infected CD4 T cell–deficient BALB/c mice. Clinical, histologic, immunologic, and virus detection studies were performed on samples of cornea, draining lymph node (LN), and trigeminal ganglion (TG) cells.ResultsCorneal grafts in mice with HSK rejected with higher frequency and more rapid tempo compared with grafts in uninfected mice. In corneas with HSK and vascularization at the time of grafting, both syngeneic and allogeneic corneal grafts failed with similar frequency and tempo. However, in the absence of preexisting inflammation and vascularization, syngeneic grafts were accepted when the grafts were performed at a late time point after HSV infection (42 days), whereas allografts were rejected at this time. In contrast, syngeneic grafts in nonvascularized HSV-infected recipients failed if they were performed within 10 days of HSV infection, an effect that was dependent on CD4 T cells, as demonstrated using CD4 deficient mice. Importantly, a variably sustained but strongly positive anti-HSV T-cell response was detected in allografted HSK recipients with a similar but lesser response in syngeneic hosts.ConclusionsA previous HSV-1 corneal infection predisposes donor grafts to a high risk of failure by both innate and adaptive immune mechanisms in which an anti-HSV CD4 T-cell response plays a prominent role.

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“…The surgical excision of corneas also severs the corneal sensory nerves and can cause HSV-1 reactivation and recurrent infection in the transplanted cornea. Thus, the risk of transplant rejection due to recurrence of HSV-1, inflammation, and angiogenesis limits the long-term benefits of these surgical interventions [ 293 , 341 , 342 , 343 ].…”

Section: Hsk Therapeutic Strategies and Challengesmentioning

confidence: 99%

Role of Innate Interferon Responses at the Ocular Surface in Herpes Simplex Virus-1-Induced Herpetic Stromal Keratitis

et al. 2023

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Herpes simplex virus type 1 (HSV-1) is a highly successful pathogen that primarily infects epithelial cells of the orofacial mucosa. After initial lytic replication, HSV-1 enters sensory neurons and undergoes lifelong latency in the trigeminal ganglion (TG). Reactivation from latency occurs throughout the host’s life and is more common in people with a compromised immune system. HSV-1 causes various diseases depending on the site of lytic HSV-1 replication. These include herpes labialis, herpetic stromal keratitis (HSK), meningitis, and herpes simplex encephalitis (HSE). HSK is an immunopathological condition and is usually the consequence of HSV-1 reactivation, anterograde transport to the corneal surface, lytic replication in the epithelial cells, and activation of the host’s innate and adaptive immune responses in the cornea. HSV-1 is recognized by cell surface, endosomal, and cytoplasmic pattern recognition receptors (PRRs) and activates innate immune responses that include interferons (IFNs), chemokine and cytokine production, as well as the recruitment of inflammatory cells to the site of replication. In the cornea, HSV-1 replication promotes type I (IFN-α/β) and type III (IFN-λ) IFN production. This review summarizes our current understanding of HSV-1 recognition by PRRs and innate IFN-mediated antiviral immunity during HSV-1 infection of the cornea. We also discuss the immunopathogenesis of HSK, current HSK therapeutics and challenges, proposed experimental approaches, and benefits of promoting local IFN-λ responses.

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Delayed Type Hypersensitivity in the Pathogenesis of Recurrent Herpes Stromal Keratitis

Cited by 8 publications

References 54 publications

CXCL9 compensates for the absence of CXCL10 during recurrent Herpetic stromal keratitis

CXCL9 compensates for the absence of CXCL10 during recurrent Herpetic stromal keratitis

High-Risk Corneal Graft Rejection in the Setting of Previous Corneal Herpes Simplex Virus (HSV)-1 Infection

Role of Innate Interferon Responses at the Ocular Surface in Herpes Simplex Virus-1-Induced Herpetic Stromal Keratitis

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