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

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


Future Virology. 2010;5(6):699-708. 

In This Article

HSK Immunopathology

The majority of our understanding of HSK pathogenesis stems from the study of experimental animal models, with the murine model being the most common. With most strains of HSV-1, live virus is cleared from the corneal surface within 1 week of infection.[17] During this period, the innate immune system, including neutrophils, natural killer (NK) cells, and γδ T cells, is activated and recruited to the site of infection within the cornea. Upon entry into the cornea, these cells release cytokines that can inhibit viral replication, but can also cause tissue damage and attract further immune cells to the site.

Corneal stromal disease begins after most viral antigens are cleared from the epithelium. HSK begins to develop 7–10 days after murine corneal infection, as indicated by corneal opacity, blood vessel growth into the avascular cornea, and substantial infiltration of leukocytes. Early studies demonstrated that T-cell-deficient mice do not develop HSK, and T-cell adoptive transfer could reconstitute the disease.[18,19] Subsequent studies have demonstrated a major role for CD4 T cells and their Th1 cytokines in mediating HSK.[20,21] Costimulatory interactions, including B7.1/B7.2 on antigen-presenting cells with CD28 on T cells, in the cornea are required for efficient HSK immunopathology, while OX40–OX40 ligand and CD40–CD40 ligand interactions appear to be dispensable for disease development.[22–24] In addition, CD8 T cells have been shown to mediate a transient form of HSK in the absence of CD4 T cells, or when mice are infected with certain strains of HSV-1.[25,26]

Antigen-presenting cells, such as dendritic cells (DCs) and macrophages, which were previously thought to be absent in the cornea, are now known to be located in the basal layer of the corneal epithelium and throughout the corneal stroma, respectively.[27] During HSV-1 infection of the epithelium, these DCs may play a role in priming the immune response by acquiring viral antigens from infected epithelial cells in the cornea, and directly presenting them to naive T cells in the lymph nodes, or by becoming infected and migrating to the lymph nodes, where resident lymph node DCs could cross-present viral antigens to T cells, as seen in the cutaneous HSV-1 infection model.[28]

An initial DC infiltrate from the limbus at approximately 5 days postinfection is followed by a second massive DC infiltration into the cornea at 10 days postinfection, coincident with HSK onset.[22] Studies that involved depletion of DCs suggest a role for these cells in the presentation of HSV-1 antigens to CD4 T cells, which also infiltrate the cornea during HSK. An HSK reactivation model showed a direct correlation between the quantity of DCs in the cornea and corneal opacification.[29] Furthermore, bilateral HSV-1 infection of mice following monocular DC depletion showed HSK development in the nondepleted eye only, indicating that DCs may be involved in the effector phase of the inflammatory response.[30] However, one caveat to these early depletion experiments is uncertainty about the specificity of depletion for DCs and the efficacy in depleting all DC subpopulations. Therefore, further studies employing more specific methods of DC depletion are needed to clarify the role of DCs in HSK.


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