Herpes simplex keratitis and dendritic cells at the crossroads: lessons from the past and a view into the future.

Massachusetts Eye and Ear Infirmary, Boston, MA 02114, USA.
International Ophthalmology Clinics 02/2009; 49(1):53-62. DOI: 10.1097/IIO.0b013e3181924dd8
Source: PubMed
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    ABSTRACT: PURPOSE: The secreted Ly6/uPAR-related protein-1 (Slurp1), associated with the hyperkeratotic disorder Mal-de-Meleda, is abundantly expressed in corneas. Here, we examine its corneal expression and functions. Methods:Gene expression was quantified by qPCR, immunoblots and immunofluorescent staining. Effect of Klf4 on Slurp1 promoter was evaluated by chromatin immunoprecipitation (ChIP) and transient transfections. Adenoviral vectors were used to express Slurp1 in corneas. Leukocytic infiltration in bacterial lipopolysaccharides (LPS), Herpes Simplex Virus Type-1 (HSV-1) or adenovirus (serotype-5) treated mouse corneas was characterized by flow cytometry. RESULTS: Corneal expression of Slurp1 increased sharply upon mouse eyelid opening, concurrent with the elevated expression of Klf4. Slurp1 was significantly decreased in Klf4-conditional null (Klf4CN) corneas which displayed elevated expression of cytokines and cytokine receptors, and neutrophil influx consistent with a pro-inflammatory environment. In additional models of corneal inflammation, Slurp1 expression was abrogated within 24h of LPS injection, HSV-1 or adenoviral infection, accompanied by a predominantly neutrophilic infiltrate. Neutrophilic infiltration was enhanced in HSV-1 infected Klf4CN corneas lacking Slurp1. SLURP1 promoter activity was stimulated by KLF4, suppressed by IL-4, IL-13 and TNFα, and unperturbed by interferon-γ (IFN-γ). Slurp1 downregulation and neutrophil influx were comparable in HSV-1 infected wild type (WT) and IFNγ -/- mouse corneas. Mouse corneas infected with Slurp1-expressing adenoviral vectors displayed reduced signs of inflammation and restricted neutrophilic infiltration compared with those infected with control vectors. CONCLUSIONS: Klf4 regulates the expression of Slurp1, a key immunomodulatory peptide that is abundantly expressed in healthy corneas and is downregulated in pro-inflammatory conditions.
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    ABSTRACT: An exuberant corneal pannus usually develops in adults with a history of surgery or trauma in the anterior central stroma and appears as a glistening, vascularized, moderately elevated, well circumscribed white nodule. We describe a 78–year-old woman with such a pannus, which in the past has typically been referred to as keloidal or hypertrophic. The involved eye had only light perception, and she underwent a penetrating keratoplasty that improved her vision to 20/100.. Histopathologic and immunohistochemical evaluations of a the specimen disclosed a reactive spindle cell stromal proliferation of myofibroblasts that were smooth muscle actin positive with a low Ki67 proliferation index. Desmin, caldesmon, and calponin were negative, in keeping with the incomplete myofilamentary differentiation of a myofibroblast. There was a generous admixture of CD68/163- positive histiocytes and dispersed C3/5-positive T-lymphocytes. An absence of CD138 and IgG4-positive plasma cells ruled out an IgG4 related disease. For a lesion to be keloidal, the collagen must adopt a thick hyaline character, sharp edges, and a sparsity of intervening cells and vessels. A hypertrophic pannus would be composed of large swollen cells not necessarily increased in number. We therefore recommend adoption of the term hyperplastic for lesions like that described here because of the obvious increase in cellularity from proliferating myofibroblasts and the lack of true keloidal collagen.
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