Herpes simplex virus-induced stromal keratitis: role of T-lymphocyte subsets in immunopathology

Abstract

Herpetic stromal keratitis (SK), a frequent cause of visual impairment, is considered to represent an immune-mediated inflammatory response to persistent herpes simplex virus virions or subcomponents within the corneal stroma. The experimental disease in mice involves the essential participation of T lymphocytes, but the role of T-lymphocyte subsets in either mediating or controlling the disease is uncertain. In this report, rat monoclonal antibodies were used to selectively deplete mice in vivo of CD4+ (helper-inducer) and CD8+ (cytotoxic-suppressor) T-cell populations and the effect on herpetic SK was evaluated. As measured by flow cytometry, mice treated with anti-CD4 monoclonal antibody (GK 1.5) were >95% depleted of CD4+ T lymphocytes and mice treated with anti-CD8 monoclonal antibody (2.43) were 90% depleted of CD8+ T lymphocytes. Depleted and nonspecific mouse ascites-treated control mice were infected topically on the corneas with herpes simplex virus type 1, and the induction of various immune parameters during the acute infection was evaluated. CD4+-depleted mice failed to produce either a significant antiviral antibody or delayed-type hypersensitivity response but were capable of producing normal cytotoxic T-lymphocyte responses. In contrast, CD8+-depleted mice produced antiviral antibody and delayed-type hypersensitivity responses comparable with those in control animals, but cytotoxic T-lymphocyte responses were markedly reduced. Clinical observations of the corneas revealed that SK in CD4+-depleted mice was significantly reduced, whereas in CD8+-depleted mice SK developed more rapidly, was more severe, and involved a greater percentage of mice. These observations implicate the CD4+ T-lymphocyte subset as the principal mediators of SK and CD8+ T lymphocytes as possible regulators that control the severity of SK.

Elucidating the protective and pathologic T cell species in the virus-induced corneal immunoinflammatory condition herpetic stromal keratitis

“…As is evident from the RAGϪ/Ϫ mouse adoptive transfer experiments, protection from HSK and lethal encephalitis occurs when HSV-reactive CD8 ϩ T cells alone are present. This is in line with previous studies in immunocompetent mice, showing that removing CD8 ϩ T cells worsens lesions and increases susceptibility to encephalitis [9,20]. The presence of CD4 ϩ T cells will, however, inevitably lead to corneal disease, regardless of the presence or absence of HSV-reactive CD8 ϩ T cells.…”

Cytologic findings, and feline herpesvirus DNA andChlamydophila felisantigen detection rates in normal cats and cats with conjunctival and corneal lesions

“…By contrast, we rarely detected FHV‐1 DNA in cats with stromal keratitis in this study (3/11 cats using nPCR). Similar to herpetic stromal keratitis in humans infected with herpes simplex virus type 1, feline herpetic stromal keratitis is probably caused by an immunologic event 9,32,39–44 . Viral replication is probably the primary cause for the pathologic event in the cornea; however, controversy remains as to the identity of the persistent antigenic stimulus.…”

Interferon gamma regulates platelet endothelial cell adhesion molecule 1 expression and neutrophil infiltration into herpes simplex virus-infected mouse corneas.

“…Toward this end, we have established a mouse model of the disease. Using the mouse model, we and others have demonstrated that corneal destruction is not a direct effect of the virus, but rather is the consequence of a T lymphocyte response to HSV antigens (2)(3)(4)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36). Paradoxically, a T lymphocyte response also contributes to prevention of virus spread to the periocular skin and to the brain (29,34).…”