Pathogenesis and Treatment Modalities of Superior Limbic Keratoconjunctivitis

• Main Authors: Yi-Chen Sun, 孫逸珍
• Other Authors: 胡芳蓉
• Format: Others
• Language: en_US
• Published: 2018
• Online Access: http://ndltd.ncl.edu.tw/handle/2hke4m

博士 === 國立臺灣大學 === 臨床醫學研究所 === 106 === Superior limbic keratoconjunctivitis (SLK) is an ocular surface disorder characterized by unilateral or bilateral redundancy of the superior bulbar conjunctiva with inflammation of the superior palpebral and bulbar conjunctiva. While SLK has been known as an inflammatory disease, the pathogenesis at molecular level remains largely unexplored. To this end, we first established a tissue collection including superior bulbar conjunctiva and tear samples from SLK patients and normal subjects. Matrix metalloproteinase (MMP)-1 and -3 were the main focus of our study due to their overexpression in conjunctivochalasis, a pathological process associated with redundant inferior bulbar conjunctiva. We found that MMP-1 and -3 immunostaining were more prominent in the subepithelial stroma of the SLK patients than that in controls. Consistently, the primary cultivated conjunctival fibroblasts obtained from SLK patients were also found with apparent overexpression of MMP-1 and -3, comparing with those from normal subjects. Furthermore, in order to provide a molecular basis for the clinical application of mast cell stabilizer in the treatment of SLK, we also investigated the roles of stem cell factor (SCF) and thymic stromal lymphopoietin (TSLP), two factors involving mast cell migration and activation, in SLK. We found that the intensity of SCF and TSLP immunostaining were higher in the conjunctival epithelium of SLK patients than control subjects, and that the TSLP grading is significantly correlated with the number of mast cells. In addition, because tear cytokine profile has been represented as an objective and quantifiable measure of inflammatory ocular surface disorder, we also intended to investigate whether tear cytokine is indeed imbalance in SLK patients. We found that the level of monocyte chemoattractant protein (MCP)-1 is augmented in SLK patients prior to treatment and is subsequently decreased following the medical or surgical treatment of SLK. To enhance the translational significance of our study on SLK, we also conducted the associated studies with respect to its clinical diagnosis as well as treatment. Positive fluorescein staining over superior limbal area is among several key characteristics for SLK diagnosis. Despite the use of fluorescein as a marker dye for the evaluation of tight junctional permeability is widely accepted, the interpretation of corneal fluorescein staining is still not in consensus. Based on our in vitro as well as in vivo experiments employing the rabbit model, we found that, rather than a passive permeabilization, fluorescein ingress in corneal epithelial cell is in fact mediated by the monocarboxylate transporter (MCT) family. Future investigation of MCT-mediated transport on human corneal epithelial cells may potentially benefit differential diagnosis and contribute better understandings of ocular surface disorders. Regarding the treatment, although topical medication is usually the first-line treatment choice for SLK, surgical intervention is thus far the most effective modality to manage this disease. To explore the possibility of improving the effectiveness of surgical treatment, we conduct a study analyzing the outcome of the modified surgical modality, of which the superior bulbar conjunctival resection combined with Tenon’s capsule excision, on SLK patients who were unresponsive to medical treatment. In all operated eyes, the clinical symptoms and signs subsided significantly three months after operation. Only three out of 40 eyes (7.5%) had recurrence from the margin of conjunctival resection, and this was relieved after reoperation. This suggests that the modified modality has great promise as the routine surgical treatment for SLK patients. In conclusion, this Ph.D. study primarily focuses on SLK molecularly and clinically. We showed higher levels of MMP-1, MMP-3, SCF, and TSLP in conjunctival subepithelial stroma and epithelial cell, respectively. Also, a prominent number of mast cell was noted in the surgical specimens. In the tear sample collection, we found a significant differential expression of tear MCP-1 and IL-6 before and after medical/surgical treatment. In patients unresponsive to medical treatment, we performed conjunctival resection combined with Tenon’s capsule excision, which is very effective to relieve patients’ symptoms and signs. In the future, although mechanical friction force over the ocular surface is considered the primary cause of SLK, this concept has yet clearly and directly demonstrated. In this regard, we set to develop a device that allows us to determine the role of mechanical friction force on the pathogenesis of SLK unambiguously. In cooperation with National Chin-Hwa University bioengineering department, we established so-called “the modulated friction force device” to directly test the effect of mechanical friction force on the genesis of SLK. We believe our endeavor will improve our understanding on SLK, ultimately benefiting patients afflicted by this disease.