Herpes Stromal Keratitis: Erosion of Ocular Immune Privilege by Herpes Simplex Virus

Jared E Knickelbein; Kristine-Ann Buela; Robert L Hendricks

Disclosures

Future Virology. 2010;5(6):699-708. 

In This Article

Theories of CD4 T-cell-mediated HSK Pathogenesis

Despite extensive investigations into the mechanisms of CD4 T-cell-mediated HSK, the nature of the stimulus/stimuli that activate CD4 T cells within the corneal stroma remains controversial. Replicating virus is undetectable in murine corneas by the onset of HSK, and is often undetectable in human corneas with HSK as well. This begs the question of what stimulates CD4 T cells to initiate HSK. Three models of CD4 T-cell activation have been proposed that are not necessarily mutually exclusive. One theory suggests that the bystander activation by cytokines present during the course of viral replication in the cornea enables CD4 T cells of any specificity to mediate HSK.[31] Support for this theory stems from studies of transgenic mice whose T cells express only the T-cell receptor specific for ovalbumin and, thus, are incapable of mounting an anti-HSV T-cell response. HSV-1 corneal infection of these mice resulted in HSK, which was mediated by ovalbumin-specific CD4 T cells. However, these mice were unable to control viral replication in the cornea, and treatment with acyclovir to inhibit viral replication abrogated stromal inflammation. The latter observation demonstrated that CD4 T cells only receive sufficient bystander stimulation to initiate HSK in the special circumstance where HSV-1 replication is not controlled in the cornea. This model would not adequately explain HSK pathogenesis under circumstances where the replicating virus is absent at the onset of disease.

Another study proposed that HSK is the consequence of an attack of autoreactive T cells, which arise as a result of molecular mimicry by a common peptide in HSV-1 UL6 and a corneal protein.[32] However, these findings might be specific to the congenic mice used in this study, since investigators have been unable to isolate CD4 T cells specific for UL6 or corneal proteins from corneas with HSK in other mouse strains or in humans.[33,34] Furthermore, polymorphisms within the UL6 gene of HSV-1 were not associated with varying presentations of recurrent HSV keratitis (i.e., HSK vs epithelial lesions without stromal involvement) in human patients.[35]

A third theory of HSK pathogenesis suggests a major role for HSV-specific CD4 T cells in triggering stromal inflammation. In support of this notion, HSV-specific CD4 T-cell clones have been derived from human and mouse corneas at various stages of HSK.[36] It has also been shown that induction of specific T-cell tolerance to HSV-1 antigens reduces susceptibility to HSK,[37] consistent with a requisite role for HSV-specific CD4 T cells in mediating pathology. Collectively, these studies suggest that HSV-specific CD4 T cells are generally required to trigger HSK, but are consistent with a contribution of bystander, and possibly autoimmune, activation in amplification of the inflammatory response.

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