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K. V. Thomas, J. P. Arth, F. Lin, F.-Q. An, N. Muqim, J. H. Lass, J. Huang, M. E. Medof; The Role of the Complement System in Herpes Stromal Keratitis. Invest. Ophthalmol. Vis. Sci. 2008;49(13):5145. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
In Herpes Stromal Keratitis (HSK), host T cell responses against virally infected corneal cells are responsible for disease. In view of recent findings concerning connections between complement and T cell activation, we undertook this study to examine the role of the complement system in host immune and inflammatory responses that occur in the cornea in this disease.
Corneas of wild-type (WT) mice and mice devoid of C3a receptor (C3aR), C5a receptor (C5aR), both C3aR and C5aR, C3, C5, factor D, and decay accelerating factor (DAF) - a cell membrane C3/C5 convertase regulator which shields self cells from complement activation on their surfaces - (strain BALB-C) were scarified and infected with the KOS strain of HSV. The mice were monitored and scored for disease severity on days 1, 3, 9, and 14 post infection. Corneas from mice randomly selected and sacrificed on days 3, 9, and 14 were sent for histology and virology. Spleen cells of the randomly selected mice were assayed for IFN gamma and other cytokine responses.
Preliminary results demonstrate an atypical clinical immune response in C3aR knockouts as compared to the WT. Superficial damage to the epithelium was observed post infection day 1 and day 3 in both WT and C3aR KO mice. Stromal keratitis developed in 6/10 WT mice on day 9 as seen by corneal opacity and stromal edema on biomicrosopic examination (2 with less than 25% opacification, 4 with 25-50% opacification). By day 14, 1 WT mouse developed a corneal perforation. In the C3aR KO, 0/6 mice developed HSK by day 9, whereas 1/6 mice developed a mild corneal opacity (less than 25% opacification) by day 14. Investigations in progress are examining the clinical, histopathological, cytological and T cell responses in the other knockouts.
Past studies of HSK using animal models have demonstrated the immune system, predominately the CD4+ T-cell response, as the major cause of pathology in the disease. Whether, and if so, how the complement system participates in this adaptive immune response in this disease is ill defined. Our results so far indicate that complement, through its impact on T cell responses, plays an important role in the immunopathogenesis of HSK.
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