Cellular Infiltrate in Rheumatoid Arthritis-associated Paracentral Corneal Ulceration.

PURPOSE: To investigate an immunopathogenesis of central and paracentral corneal ulceration associated with rheumatoid arthritis. METHODS: Sparse infiltrating cells in the ulcer area were identified by immunohistochemistry applied to archived formalin fixed, paraffin embedded tissues that had been recovered from patients undergoing penetrating keratoplasty necessitated by rheumatoid-associated central or paracentral corneal ulceration. RESULTS: Clinically, the ulcers presented as non-infiltrated lesions with a modicum of other ocular inflammation. Sparse T-lymphocytes were consistently identified in the subepithelial areas adjacent to the ulcer, with some neutrophils and macrophages in the stroma. B-lymphocytes were not detected. MHC Class II antigens reactivity was noted on some infiltrating cells and on corneal endothelium of two specimens. CONCLUSIONS: Immunohistochemistry of archival tissue facilitated detection and identification of sparse infiltrate in this infrequent corneal melting. Selective, consistent finding of T-lymphocyte infiltration in the ulcer area supports an immunopathogenesis of this clinical entity.

Regulation of endotoxin-induced keratitis by PECAM-1, MIP-2, and toll-like receptor 4.

PURPOSE: Bacterial lipopolysaccharide (LPS, endotoxin) is a potent stimulator of inflammatory responses and is likely to contribute to microbial keratitis and to the pathogenesis of sterile corneal ulcers. The purpose of the present study was to identify specific mediators of endotoxin-induced keratitis. METHODS: The corneal epithelium of BALB/c, C3H/HeJ, and C3H/HeN mice was abraded, and Pseudomonas aeruginosa endotoxin (10 microg in 1 microL) was added. Stromal thickness and haze were measured by in vivo scanning confocal microscopy, and neutrophil recruitment determined by immunohistochemistry. RESULTS: Pseudomonas endotoxin induced a significant increase in stromal thickness and haze compared with untreated control corneas at each time point examined, and the severity coincided with neutrophil infiltration into the corneal stroma. Furthermore, systemic depletion of neutrophils completely abrogated endotoxin-induced increases in stromal thickness and haze, indicating an essential role for these cells. Expression of platelet endothelial cell adhesion molecule (PECAM)-1 on vascular endothelium and production of macrophage inflammatory protein (MIP)-2 in the corneal stroma were also significantly elevated after exposure to endotoxin, and antibody blockade inhibited neutrophil recruitment to the cornea and abrogated endotoxin-induced increases in stromal thickness and haze. In LPS-hyporesponsive C3H/HeJ mice, PECAM-1 and MIP-2 were not upregulated after exposure to endotoxin, and endotoxin-induced keratitis did not develop in these mice. CONCLUSIONS: These findings demonstrate that endotoxin-induced keratitis is regulated by toll-like receptor-4 (TLR4)-dependent expression of PECAM-1 and MIP-2, which are essential for recruitment of neutrophils to this site and for development of endotoxin-induced stromal disease.

Tear cytokine response to multipurpose solutions for contact lenses.

PURPOSE: An increased risk of corneal infiltrative events has been noted with the use of certain contact lenses and multipurpose solutions (MPS). This study was designed to evaluate tear cytokine assay as a sensitive, objective, and quantitative measure of the ocular surface response to contact lens/MPS and to consider the assay's clinical relevance in the context of other measures of ocular surface response. METHODS: Two MPS, ReNu® Fresh™ (RNF) and Opti-Free® RepleniSH (OFR), were used with daily wear silicone hydrogel contact lenses in a randomized, prospective crossover study involving 26 subjects. Clinical data collection (conjunctival hyperemia, ocular surface sensitivity, solution induced corneal staining (SICS) test score, and subjective responses) and tear cytokine assays were conducted masked. Responses were tracked as change from baseline throughout the experimental schedule. RESULTS: SIMILAR RESPONSE PATTERNS FOR SEVERAL INFLAMMATORY CYTOKINES WERE SEEN THROUGHOUT BOTH PHASES: subjects who received OFR in Phase I had mean tear concentrations that were generally higher than those of the RNF Phase I group. OFR Phase I subjects had significant (P < 0.01) increases over baseline at day 1 and/or following washout for 13 cytokines (cc chemokine ligands [CCL] 3, CCL5, CCL11, granulocyte-macrophage colony-stimulating factor [GM-CSF], interferon [INF]-γ, interleukin [IL]-2, IL-4, IL-5, IL-6, IL-13, IL-15, IL-17, tumor necrosis factor [TNF]-α). These changes were not observed in RNF Phase I subjects, even though SICS test scores increased. Phase I OFR subjects also had increased dryness, while RNF Phase I subjects had decreased bulbar hyperemia. No changes were detected with respect to limbal hyperemia or surface sensitivity thresholds. CONCLUSION: The tear cytokine assay can detect and differentiate contact lens/MPS induced increases in inflammatory cytokines. Changes in cytokine levels were consistent with measurement of hyperemia and dryness but not with SICS scores, thereby suggesting a proinflammatory response to OFR compared to RNF that is not related to SICS test score. Tear cytokine profiles may be useful for reconciling clinical relevance of test results and in revealing signaling involved in the development of corneal infiltrative events.

Staphylococcus aureus-induced corneal inflammation is dependent on Toll-like receptor 2 and myeloid differentiation factor 88.

Toll-like receptors (TLRs) expressed by the corneal epithelium represent a first line of host defense to microbial keratitis. The current study examined the role of TLR2, TLR4, and TLR9 and the common adaptor molecule myeloid differentiation factor 88 (MyD88) in a Staphylococcus aureus model of corneal inflammation. The corneal epithelia of C57BL/6, TLR2(-/-), TLR4(-/-), TLR9(-/-), and MyD88(-/-) mice were abraded using a trephine and epithelial brush and were exposed to heat- or UV-inactivated S. aureus clinical strain 8325-4 and other clinical isolates. Corneal thickness and haze were measured by in vivo confocal microscopy, neutrophil recruitment to the corneal stroma was quantified by immunohistochemistry, and cytokine production was measured by enzyme-linked immunosorbent assay. The exposure of corneal epithelium to S. aureus induced neutrophil recruitment to the corneal stroma and increased corneal thickness and haze in control C57BL/6 mice but not in TLR2(-/-) or MyD88(-/-) mice. The responses of TLR4(-/-) and TLR9(-/-) mice were similar to those of C57BL/6 mice. S. aureus-induced cytokine production by corneal epithelial cells and neutrophils was also significantly reduced in TLR2(-/-) mice compared with that in C57BL/6 mice. These findings indicate that S. aureus-induced corneal inflammation is mediated by TLR2 and MyD88 in resident epithelial cells and infiltrating neutrophils.

Contact lens-associated corneal infiltrates.

PURPOSE This review article examines recent studies pertaining to contact lens-associated corneal infiltrates (CLACI) that occur in the absence of culture-proven microbial infection. METHODS The literature was reviewed in regard to the clinical appearance, incidence and risk, etiology, pathophysiology, differential diagnosis, and management of CLACI. Recent insights are presented in the context of future directions for prevention of CLACI. RESULTS Contact lens-associated corneal infiltrates may manifest in various forms that require careful observational skills to ensure proper diagnosis. Although the reported incidence of CLACI varies widely, even a low percentage of contact lens wearers would constitute a substantial number of affected individuals. Any one or a combination of multiple mechanical, hypoxic, or toxic stimuli associated with contact lens use can induce proinflammatory responses that lead to infiltration of inflammatory cells into the cornea. A number of candidate cytokines, chemokines, adhesion molecules, and so forth have been identified. In addition to differentiation from microbial keratitis, CLACI also should be differentiated from ocular disorders not associated with contact lenses but involving corneal infiltrates and from contact lens-associated disorders that may resemble infiltrates. Management of CLACI can range from simple monitoring of the patient to the use of pharmacologic intervention. CONCLUSIONS The small percentage of affected lens wearers translates into a notable number of individuals who, although not experiencing a vision-threatening event, are inconvenienced by the development of infiltrates. Design of preventive measures for CLACI should focus on the elimination of various mechanical, hypoxic, and toxic stimuli that can induce infiltrates and on the approaches for molecular intervention of the inflammatory cascade initiated by the stimuli.