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(Investigative Ophthalmology and Visual Science. 2008;49:1488-1495.)
© 2008 by The Association for Research in Vision and Ophthalmology, Inc.
DOI:  10.1167/iovs.07-1107
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Activated Inflammatory Infiltrate in HSV-1-Infected Corneas without Herpes Stromal Keratitis

Sherrie J. Divito1 and Robert L. Hendricks2,3,4

1From the Graduate Program in Immunology and the 2Departments of Ophthalmology, 3Molecular Genetics and Biochemistry, and 4Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.

PURPOSE. To investigate herpes stromal keratitis (HSK) immunopathology by studying HSV-1-infected corneas that fail to develop HSK.

METHODS. Plaque assay quantified HSV-1 in the tear film of infected mice. FACS analysis enumerated corneal leukocytic infiltrate and characterized infiltrate phenotypically after staining for activation and regulatory T cell (Treg) markers and for markers of antigen-presenting cell (APC) maturation. Treg cells were depleted in vivo using anti-CD25 mAb. Luminex analysis quantified the amount of cytokines and chemokines expressed in corneal tissue homogenate.

RESULTS. Infected corneas without HSK exhibited a pronounced leukocytic infiltrate containing a significantly higher proportion and nearly identical absolute number of activated CD4+ T cells 15 days after infection when compared with those with HSK. Moreover, the frequency and absolute number of regulatory CD4+ T cells (Tregs) was lower in nondiseased corneas, and Treg depletion did not influence HSK incidence. The frequency of mature, immunogenic DCs and the ratio of mature DCs to CD4+ T cells were nearly identical in corneas with and without HSK. The authors observed a reduced population of neutrophils and reduced expression of neutrophil chemoattractants MIP-1β and keratinocyte chemoattractant and the neutrophil-attracting cytokine IL-6 in corneas without HSK.

CONCLUSIONS. These findings demonstrate that HSV-1-infected corneas can retain clarity in the presence of a substantial secondary leukocytic infiltrate, that activated CD4+ T cells, while necessary, are not sufficient for HSK development, that susceptibility to HSK is not determined by Tregs, and that clinical disease correlates with the accumulation of a critical mass of neutrophils through chemoattraction.






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