Autoimmune uveitis is a kind of intraocular inflammatory disorder that can lead to permanent blindness.  Some patients fail to respond to the steroids that are the current standard treatment, while some develop serious side-effects. Lacking an effective treatment, autoimmune uveitis has become a chronic, recurrent eye disease.

The Chinese University of Hong Kong′s (CUHK) Faculty of Medicine (CU Medicine) conducted a study on autoimmune uveitis and has found its disease mechanism, which opens up a new direction for treatment.  Researchers identified a neuroendocrine growth hormone-releasing hormone (GHRH) pathway developing disease-causing T Helper 17 (Th17) cells that promote autoimmune uveitis.  The team also discovered existing approved drugs that can suppress the GHRH pathway and could be developed as novel treatments.  Details have been published in the international journal Nature Communications.

Uveitis is a chronic, recurrent eye disease which is difficult to treat

The uvea is a middle layer of the eye, located between the sclera and the retina, which is also referred to as the vascular tunic.  It has functions such as adjusting to different levels of light and supplying nutrients to the eyeball.  Uveitis can be infectious and non-infectious.  Infectious uveitis is generated by specific agents such as bacteria or viruses, whereas the cause of non-infectious uveitis, including autoimmune uveitis, is normally unknown.  Patients frequently exhibit lymphocyte responses to retinal antigens and the disease may lead to autoimmune disorders.

Professor Clement CY THAM, Chairman and S. H. Ho Professor of Ophthalmology and Visual Sciences in the Department of Ophthalmology and Visual Sciences at CU Medicine, said, ‶Eye redness, pain and blurred vision are some common symptoms of uveitis.  The prevalence of uveitis in China is reportedly about 150 per 100,000 people each year.  Though the prevalence is not high, autoimmune uveitis is a chronic, recurrent health problem with no effective cure which bothers many.″

Dr Simon KH SZETO, Assistant Professor in the Department of Ophthalmology and Visual Sciences at CU Medicine, added, ‶Steroids are the standard treatment option for autoimmune uveitis but some patients do not respond, and long-term, high-dose steroids can lead to many systemic complications.  They may have to seek second-line treatment, including second-line immunosuppressive drugs or biologics, but some patients may still respond poorly or may develop side-effects from these drugs.  We therefore see an urgent need to look for new treatment options for autoimmune uveitis patients.″

GHRH antagonist alleviates Th17-mediated ocular inflammation

Researchers from CU Medicine′s Department of Ophthalmology and Visual Sciences used the Experimental Autoimmune Uveitis (EAU), an animal model mimicking human autoimmune uveitis, to investigate the pathogenesis of the eye disease.  They found an elevated expression of GHRH and GHRH receptors in the retina of EAU mice.  GHRH signalling promotes dysregulation of Th17 cell differentiation, which produces proinflammatory cytokines.

Dr CHU Wai-kit, Research Assistant Professor in the Department of Ophthalmology and Visual Sciences at CU Medicine, said, ‶Our study showed GHRH receptors are important regulators of Th17 cell differentiation in Th17 cell-mediated ocular and neural inflammation.  Inhibiting the signalling pathway by GHRH antagonists can reduce the number of Th17 cells and suppress autoimmune uveitis.  GHRH receptor inhibitors are difficult to translate into clinical use, but we have identified a downstream signalling pathway, JAK-STAT3, along with existing approved drugs that can suppress it and could be developed as novel treatments.″

Dr DU Lin, Postdoctoral Fellow in the Department of Ophthalmology and Visual Sciences at CU Medicine, added, ‶Th17 can cause other autoimmune diseases, including rheumatoid arthritis and multiple sclerosis.  We found GHRH receptors on T cells which promote Th17 cell differentiation in autoimmunity. Under the same theory, GHRH receptor inhibitors can potentially suppress autoimmune neuroinflammation.″

Appendix – About ‶lymphocytes″, ‶Th17 cell differentiation″ and ‶proinflammatory cytokines″

Lymphocytes
Lymphocytes are a type of white blood cell, part of the immune system.  They are a key component of the adaptive immune response and play a crucial role in recognising and eliminating pathogens, as well as maintaining immune memory.

Th17 cell differentiation
Th17 cell differentiation refers to the process by which naive T cells, a type of immune cell, develop into Th17 cells.  This differentiation process is driven by specific cytokines and signalling molecules.

Proinflammatory cytokines
Proinflammatory cytokines are a group of signalling molecules that play a key role in promoting inflammation in the body.  They are produced by various cells in the immune system, such as macrophages and T cells, in response to infection, injury or other immune stimuli.

2023年11月21日

中大研究發現自身免疫性眼發炎發病機制 有助開闢新療法

自身免疫性葡萄膜炎是一種由眼球內組織發炎引致的眼疾，可導致永久失明。類固醇是現時的標準治療方式，但對部分患者的治療成效不佳，或出現嚴重副作用。由於缺乏有效治療，自身免疫性葡萄膜炎演變成慢性或慣性復發的眼疾。

香港中文大學（中大）醫學院研究團隊研究自身免疫性葡萄膜炎的發病機制，發現一條釋放神經內分泌生長激素的生物路徑GHRH （growth hormone-releasing hormone pathway），可以誘發致病細胞Th17分化，演變為自身免疫性葡萄膜炎。團隊並發現部分註冊藥物可抑制GHRH路徑，有望成為新療法。研究結果已在國際科學期刊《自然通訊》發表。

葡萄膜炎易復發且難治

葡萄膜為眼球的內層組織，位置在鞏膜與視網膜之間，由於顏色呈深紫色，故稱葡萄膜。它亦被稱為色素膜和血管膜，具有遮光、供給眼球營養的功能。葡萄膜炎的成因可分為感染性和非感染性（包括自身免疫性）。感染性葡萄膜炎是由細菌或病毒感染引起，而大多數非感染性葡萄膜炎患者沒有確定的病因，患者的淋巴細胞經常對視網膜抗原表現出異常反應，長期可演變成自身免疫疾病。

中大醫學院眼科及視覺科學學系系主任兼何善衡眼科及視覺科學講座教授譚智勇教授解釋：「葡萄膜炎的常見症狀有紅眼、疼痛和視力模糊。據估算，中國每年每十萬人中有150人患上葡萄膜炎。雖然患病率不高，但自身免疫性葡萄膜炎是一種慢性、慣性復發的疾病，目前沒有有效的根治方法，因此為患者帶來極大困擾。」

中大醫學院眼科及視覺科學學系助理教授司徒家浩醫生補充：「類固醇是自身免疫性葡萄膜炎的標準治療方法，但對部分患者並不奏效，而且長期服用高劑量類固醇可引致併發症。二線治療包括二線免疫系統抑制藥物或生物製劑，但仍然無法保證療效，同時也會有不少副作用。因此，我們迫切需要尋找新的治療選擇。」

GHRH抑制劑可緩解由致病細胞Th17引起的眼部炎症

中大醫學院眼科及視覺科學學系研究團隊利用實驗小鼠模型，模擬自身免疫性葡萄膜炎的患者，了解當中的發病機制。研究人員在實驗小鼠的視網膜內，發現GHRH及GHRH受體的表達水平上升。GHRH 路徑的訊息傳遞會誘使致病細胞 Th17 分化過程出現失調，激發炎症細胞因子產生。

中大醫學院眼科及視覺科學學系研究助理教授朱偉傑博士表示：「我們的研究結果顯示，由Th17細胞引發的眼部和神經炎症中，GHRH受體是致病細胞Th17分化的重要調節因子。通過利用GHRH抑制劑抑制該路徑的訊息傳遞，可以減少Th17細胞的數量，從而抑制自身免疫性葡萄膜炎。然而，GHRH受體抑制劑有機會抑制正常生長和發育，在臨床應用上存在困難，但團隊已經鎖定一條名為JAK-STAT3的下游信號通路，並發現有已批藥物可以抑制該通路，進一步開發新治療。」

中大醫學院眼科及視覺科學學系博士後研究員杜林博士表示：「Th17細胞可能引起其它自身免疫疾病，包括類風濕性關節炎和多發性硬化症。我們發現T細胞上的GHRH受體促進Th17細胞在自身免疫系統中的分化。根據相同的理論，GHRH受體抑制劑有潛力同時抑制自身免疫性神經炎症。」

附錄 – 有關「淋巴細胞」、「Th17細胞分化」及「炎症細胞因子」

淋巴細胞
淋巴細胞是一種白血球，是適應性免疫反應的關鍵組成部分，在識別和消除病原體以及維持免疫記憶方面發揮關鍵作用。

Th17細胞分化
Th17細胞分化是指免疫細胞原始T細胞演變成輔助性T細胞（Th17細胞）的過程。這個分化過程由特定的細胞因子和信號分子驅動。

炎症細胞因子
炎症細胞因子是體內促進炎症的信號分子。面對感染、損傷或受到其他免疫刺激，體內免疫系統的多種細胞，如巨噬細胞和T細胞，就會產生炎症細胞因子。

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