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

HSV-induced Angiogenesis

The normal cornea is devoid of lymph vessels, which deliver antigen from peripheral sites of infection to draining lymph nodes, where the adaptive immune response is initiated, and blood vessels that deliver effector immune cells back to the site of initial infection. Lack of these vessels in the normal cornea partially accounts for the cornea's immune-privileged status.[54] Corneal infection with HSV-1 induces growth of both lymph (lymphangiogenesis) and blood (hemangiogenesis) vessels into the normally avascular cornea, leading to disruption of corneal immunoprivilege and subsequent immunopathology.

Although other members of the herpes virus family encode angiogenic proteins,[55,56] HSV-1 is not known to directly produce such factors. Nonetheless, proangiogenic cytokines of the VEGF family are upregulated in the murine cornea following HSV-1 infection.[57] Initial reports indicated the source of VEGF-A to be noninfected corneal epithelial cells neighboring HSV-infected cells, suggesting that HSV-infected cells were secreting a soluble mediator, acting in a paracrine fashion to induce VEGF production.[57,58] However, a recent report using, perhaps, more sensitive methodology, has identified HSV-infected epithelial cells as the primary source of VEGF-A.[59]

Hemangiogenesis is dependent on VEGF-A binding to the VEGF receptor (VEGFR)-1 or 2, while inflammatory lymphangiogenesis is predominantly mediated via VEGF-C or D signaling through VGFR-3.[60] However, VEGF-A has recently been shown to also mediate lymphangiogenesis following corneal HSV-1 infection.[59] In a murine model of HSK, blockade of VEGF-A-mediated signaling through VEGFR-1 and -2 diminished hemangiogenesis and abrogated HSK.[57,61] The effect of inhibiting lymphangiogenesis during corneal HSV-1 infection has yet to be studied. This is an important issue, as selective inhibition of lymphangiogenesis, compared with hemangiogenesis, prevented immune rejection of murine corneal transplants, which is also a CD4 T-cell-mediated immunopathology.[62]


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