Dissertation
Dissertation > Medicine, health > Ophthalmology > Eye pigment layer ( uvea ) disease > Other uveal diseases

IL-17RC hypomethylation experience influence the clinical mechanism of traditional Chinese medicine for the treatment of uveitis and uveitis

Author WuWenZuo
Tutor JinMing
School Beijing University of Traditional Chinese Medicine
Course Traditional Chinese Medicine
Keywords CD8~+T cells DNA methylation IL-17RC clinical experience uveitis ocularsarcoidosis traditional Chinese medicine
CLC R773.9
Type PhD thesis
Year 2014
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Background:Sarcoidosis is a multi-system chronic disease that is characterized by its pathological hallmark, the non-caseating granuloma, and is one of the common causes of eye inflammation. Up to24%of ocular sarcoidosis patients develop severe vision impairment, including10%with visual disability and blindness. However, early intervention can significantly improve the prognosis. Uveitis is the most common manifestation of ocular sarcoidosis. To date, diagnosis of ocular sarcoidosis still exist many difficulties. Skin, peripheral lymph nodes and lung tissue biopsy is the gold standard for diagnosis, but the invasion methods would bring harm to patients with no doubt. Therefore, the discovery of new diagnostic markers which would be used to improve the safety and accuracy of diagnosis and the treatment has a significant clinical meaning.The invention of epigenetic methods opened a new chapter for studying disease pathogenesis. DNA methylation is one of the prevalent epigenetic modifications in senior animals. IL-17RC resides in cell membrane as a transmembrane protein with the function of a co-receptor of IL-17subsets, and the specific binding would activate of multiple signal transduction pathways and promote inflammation formation. Recent literature indicated the hypo-methylation of IL-17RC promoter had an association with inflammation, exudation and CNV formation in the eyes. Therefore, we speculate DNA methylation abnormalities of IL-17RC promoter may be involved in the development of ocular sarcoidosis.Uveitis is the main form of ocular sarcoidosis, and the treatment is local or systemic application of glucocorticoids which can be combined with immunosuppressive and biological agents. However, side effects are obvious, and it’s easy to produce glucocorticoids dependent and withdrawal rebound. A valuable clinical experience of ProfJin Ming using combined uveitis treatments of traditional Chinese medicine and Western medicine deserves younger workers to inherit and carry forward.Objective:1.To investigate the correlation between DNA methylation status of IL-17RC promoter and ocular sarcoidosis. To detect IL-17RC expression with IL-17induced. To preliminary discuss the role of IL-17RC promoter methylation status in molecular pathogenesis of ocular sarcoidosis.2.Uveitis is the main clinical symptom of ocular sarcoidosis with limited western medicine treatments. Therefore part two summarized the clinical experience of uveitis treatment of Professor Jin Ming guide the clinical.Methods:l.Take ocular sarcoidosis group and healthy control group as the objects, methylation-dependent restriction enzyme digestion method was used to detect the DNA methylation level of IL-17RC promoter. Flow cytometry was used to measure the expression of IL-17RC of immune cells in peripheral blood. Elisa was used to measure the concentration of IL-17in serum. HE was used to observe the ocular tissue morphology. IL-17RC expression in ocular tissue was measured using immunohistochemistry, while IL-17RC mRNA expression done by RT-PCR. Use IL-17inducing CD8+T cells which were activated with anti-CD3and anti-CD28antibodies for3days, then IL-17RC expression of CD8+T cells was detected by flow cytometry.2. Search and read uveitis literatures, read through and investigate the publications of Prof.Jin. Wrote down the prescriptions, took notes of the diagnostic thoughts, medication features, and summarized the clinical experience of uveitis.Results:1.Compare to the healthy control, a significantly lower level of DNA methylation was found on the IL17RC promoter in sarcoidosis patients (P<0.01), which led to an elevated expression of IL-17RC on CD8+T cells in peripheral blood (P<0.05). A significant increase of IL-17concentration in the serum level in patients with ocular sarcoidosis was found as compared to healthy controls (P<0.01). HE showed granulomas existed in ocular tissue in both quiet and active ocular sarcoidosis patients, but IL-17RC protein, C-R scar as well as IL-17RC mRNA expression appeared only in the retinal tissue of active inflammation region(P<0.01). CD8+T cells expressed more IL-17RC after IL-17inducing as compared to the ones without IL-17inducing, but only the result in treated group in healthy group had a significant meaning(P<0.01).2.Prof.Jin Ming advocated "disease differentiation by Western medicine, syndrome differentiation by traditional Chinese medicine" as the principle, used western system examinations, specialized instrument examinations of ophthalmology and traditional Chinese "Inspection, auscultation and olfaction, inquiry, and pulse-taking and palpation" together to obtain first-hand history and clinical data. She also advocated it should link the eye disease to the whole system as to general analyze. Uveitis is a very complex disease with etiology involving Xiqi invasion, dampness, heat toxin, blood stasis and organs weakness, mostly affects liver, gallbladder and kidney. The pathogenesis is complicated, while the course is lingering. In the diagnosis, Prof.Jin Ming proposed not only differentiate syndrome according to the theory of traditional Chinese medicine, but also should subdivide the course into small stages by using special instruments, combine macro differentiation with microscopic examination, so as to understand the disease condition on multi-level and achieve the optimal effect. In the syndrome differentiation, Prof.Jin is not rigidly constrained by the common classification, but adjusts to changing circumstances, and modifies prescriptions with syndrome according to the specific syndromes. In treatment, Prof.Jin propose of early intervention to improve the prognosis. In addition, she especially values liver and kidney of five round theory in uveitis treatment, and flexible uses of Longdanxiegan decoction (pill) and Liuweidihuang decoction which shows effective. In addition, Prof.Jin summarizes a principle of combined use of traditional Chinese medicine according to the glucocorticoids application characteristics of uveitis. In early stage, traditional Chinese medicine plays a hormone-like role which can reduce the dosage of hormone, and prevents disease progression with the function to evacuate wind, heat and dampness, give priority to eliminate xiqi. The characteristic of acute stage is to apply a large dose of oral glucocorticoids to control inflammation, and combine with immunosuppressive agents if there is severe condition. Traditional Chinese medicine can decrease the side effects caused by glucocorticoids and immunosuppressive, and shorten the course of disease. Treatment in this stage is to purge fire, heat and dampness in liver and gallbladder, prompt blood circulation, dispel dampness, detoxification so as to supplement and attack at same time. In later stage of glucocorticoids withdraw process, it’s easy to produce glucocorticoids dependence and rebound. It should highlight the traditional Chinese medicine characteristic of strengthening vital qi to regulate the immune function, help smooth glucocorticoids decrement, consolidate curative effect, and reduce recurrence rate and complications. Because patients with glucocorticoids taken for a long time have a deficiency of vital qi, so traditional Chinese medicine cure for complementing qi, nourishing liver and kidney in this stage.Conclusion:1.IL-17RC promoter is hypo-methylated modified in ocular sarcoidosis patients, which indicated its correlation with ocular sarcoidosis, and the hypo-methylation modification of IL-17RC promoter could be used as a epigenetic marker of ocular sarcoidosis. Elevated IL-17RC+CD8+T cells in Peripheral blood played a certain role in the development of sarcoidosis. IL-17RC expression is associated with inflammation degree and the severity of disease activity. Increased IL-17RC in patients with ocular sarcoidosis may be due to the high concentration of IL-17in peripheral blood.2.In order to achieve optimal effect of uveitis treatment, it should use combination of TCM and western medicine, foster strengths and circumvent weaknesses, and use multiple methods.

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