干眼的免疫学研究现状及进展

干眼,是指由于泪液量或质的异常引起的泪膜不稳定和眼表面损害而致眼部不适的一类疾病。依照干眼发病与泪膜的关系,干眼可分为五类[1]:水液缺乏型干眼,脂质缺乏型干眼,粘蛋白缺乏型干眼,泪液动力学异常型干眼,混合型干眼。随着近年来研究的深入,干眼发病过程中免疫机制越来越受到重视,本文拟对部分干眼的免疫发病机帛研究及干眼的免疫调控治疗作一综述。一、和泪腺的免疫环境眼表面由角膜,结膜和角结膜缘三部分组成,是经常发生炎症和免疫反应的潜在部位。睑结膜和球结膜具有独特的细胞群体,包括杯状细胞,肥大细胞和附属泪腺。出生时正常的眼…     

干眼的免疫机制研究进展

干眼是一种由多因素所致,发病机制众多的常见眼表疾病。随着我国干眼发病率逐年升高,干眼逐渐引起人们的重视。干眼的发病机制较为复杂,其中炎症、角结膜上皮细胞改变、泪膜成分改变、角膜神经改变、睑板腺功能异常改变等均为重要因素。泪膜高渗导致眼表上皮细胞高渗,刺激炎症发生级联反应,眼表炎症反应为干眼发病机制中最为关键的环节。该过程中有多种炎症介质和免疫细胞参与,越来越多的人认为干眼是一种抗原特异性自身免疫性炎症疾病且二者存在联系。临床治疗中,各类抗炎药物及促进泪液分泌药物在一定程度上标志着干眼药物治疗的快速发展,但干眼治疗并非仅仅为了改善症状,而要根据具体病因展开治疗。近年关于干眼免疫机制的研究日益增多,据此本文就干眼的免疫机制研究进展进行综述,希望系统性了解免疫在干眼发生发展过程中的作用及临床意义。     

干眼病理损害中的炎症机制

干眼是一种泪液和眼表的多因素性疾病,可引起眼部不适、视觉障碍、泪膜不稳定和眼表损害,并伴有泪膜渗透性升高和眼表炎症。目前研究表明,炎症在干眼的发病和病理损害中起着重要作用。本文从炎症与泪液渗透压、眼表黏蛋白表达、角结膜上皮结构及功能、泪腺及睑板腺结构和功能等方面对炎症造成干眼眼表和泪液功能损害的可能机制进行综述。     

P2Y2受体激动剂治疗干眼的研究进展

干眼是一类累及眼表和泪膜的多因素疾病.临床上治疗干眼的传统方法主要是被动性增加泪液,如人工泪液点眼、泪小点栓塞等,但新的关于干眼发病机制的研究表明,理想的干眼治疗方法是促进泪腺分泌泪液.研究已经证实,P2Y2受体激动剂具有促进水分及黏蛋白分泌的作用,可以促进泪腺主动分泌泪液.目前研制了多种人工合成的P2Y2受体激动剂并用于干眼的治疗,临床研究证实,P2Y2受体激动剂能够明显增加水性泪液的分泌和黏蛋白的分泌,改善临床症状,且Ⅰ期临床试验证实其具有较好的安全性.就近年来P2Y2受体激动剂在干眼治疗方面的作用机制、临床疗效和研究进展进行综述.     

基于泪液功能单位的干眼治疗

干眼发病原因多,其主要特征是泪膜稳态失衡.泪膜稳态的维持得益于泪液功能单位各组成部分的正常运转.泪液功能单位由角膜、结膜、泪腺、睑板腺、泪腺以及连接它们的神经网络组成,通过调节方式控制泪液分泌.一个或多个组成部分功能失常会直接影响泪膜稳态而导致干眼.针对角膜的干眼治疗包括自体血清、神经生长因子、接触镜及抗炎治疗;针对结...     

关注0.1%CsA阳离子乳剂在眼表免疫性疾病中的合理选择及应用

眼表免疫性疾病(OSID)是由全身免疫性疾病引起, 或是有局部免疫系统参与的慢性炎性眼部疾病, 通过在眼及其附属器产生持续性炎症而引起泪液高渗环境和眼表上皮损伤, 从而导致或加重干眼。常见的免疫炎性相关眼表疾病包括春季角结膜炎(VKC)、干燥综合征、移植物抗宿主病、干眼、免疫性角膜疾病等, 严重影响患者的视觉功能和生活质量。目前, OSID主要采用人工泪液和糖皮质激素滴眼液进行治疗, 但治疗效果欠佳且不良反应风险较大, 因此OSID的有效治疗一直面临很大挑战。环孢素A(CsA)是一种临床常用的免疫抑制剂, 具有很强的免疫调节作用, 但由于其既有眼用剂型的通透性低, 在临床上的应用受到一定限制。CsA眼用制剂的研发改变了OSID的治疗策略, 近来研发的0.1%CsA阳离子乳剂显著提高了CsA局部应用的作用效果及安全性, 值得临床医生关注。眼科医生应该充分认识各种OSID的免疫相关病理机制, 充分了解0.1%CsA阳离子乳剂对OSID的疗效、适应证、眼表局部应用方法、不良反应等, 进而在各种OSID的治疗中进行合理选择。     

糖尿病相关干眼发病机制的研究进展

糖尿病(DM)已成为世界范围内最严重的健康问题之一。糖尿病在眼部会引起角膜神经损伤、泪液成分改变、泪膜稳定性差、泪液渗透压升高、免疫炎症反应和细胞凋亡等,这增加了眼表疾病的风险。其中,眼表疾病又以干眼发病率高为著。本文就糖尿病相关干眼的患病相关因素、患病率及发病机制进行综述,以期对临床治疗提供思路。     

催泪蛋白（Lacritin）与干眼的关系

干眼已经成为眼科最常见的眼表疾病,其致病因素多样化,近年来临床和基础研究证实,泪液成份的改变在干眼发病和临床症状中起到至关重要的作用,其中之一为催泪蛋白（Lacritin）,在干眼患者泪液中其含量的减低与干眼的发病和临床表现密切相关.     

干眼的诊治及其在眼科手术中的影响

干眼是指由于泪液的量或质的异常引起的泪膜不稳定和眼表面损害而致眼部不适的一类疾病。本文综述干眼的病因、发病机理、分类、检查、诊断和治疗,及其在眼科手术中的影响作了简要的介绍。     

干眼的泪道栓塞治疗

干眼(dry eye)是指多因素所致的一种泪液和眼表疾病,包括眼表不适症状、视觉障碍及泪膜不稳定并具有潜在眼表损害,可伴有泪液渗透压升高及眼表炎症反应.干眼是最常见的眼表疾病,严重者可致盲,是近年来眼科研究重点、热点及难点问题[1].     

The role of the lacrimal functional unit in the pathophysiology of dry eye

The majority of dry eye symptoms are due to a chronic inflammation of the lacrimal functional unit resulting in a loss of tear film integrity and normal function. This leads to a reduction in the ability of the ocular surface to respond to environmental challenges. The underlying cause of tear film dysfunction is the alteration of tear aqueous, mucin, and lipid components. This may result from a systemic autoimmune disease or a local autoimmune event. A lack of systemic androgen support to the lacrimal gland has been shown to be a facilitative factor in the initiation of this type of pathophysiology. Tear secretion is controlled by the lacrimal functional unit consisting of the ocular surface (cornea, conjunctiva, accessory lacrimal glands, and meibomian glands), the main lacrimal gland and the interconnecting innervation. If any portion of this functional unit is compromised, lacrimal gland support to the ocular surface is impeded. Factors such as neurogenic inflammation and T cell involvement in the disease pathogenesis as well as newly developed animal models of ocular surface inflammation are discussed.     

Preservation of tear film integrity and inhibition of corneal injury by dexamethasone in a rabbit model of lacrimal gland inflammation-induced dry eye.

PURPOSE: The aim of this study was to establish a clinically relevant short-term animal model of dry eye with utility in identifying compounds with potential therapeutic efficacy. METHODS: Rabbit lacrimal glands were injected with the T-cell mitogen Concanavalin A (Con A) and inflammation, tear function, and corneal epithelial cell integrity were subsequently assessed. The inflammatory response was characterized by quantifying biochemical markers of inflammation ex vivo and by confirming inflammatory cell influx by histology. Matrix metalloproteinase-9 (MMP-9) and proinflammatory cytokines IL-1beta, IL-8, and TGF-beta1 were quantified in tissue extracts. Tear function was monitored by measuring tear fluorescein clearance and tear breakup time (TBUT). Corneal epithelial cell integrity was determined by quantifying the uptake of methylene blue dye following the exposure of rabbits to a low-humidity environment. The anti-inflammatory corticosteroid, dexamethasone, was administered topically as indicated for each study. RESULTS: Histopathologic evaluation of lacrimal glands injected with Con A revealed a pronounced inflammatory process characterized by lymphocytic infiltration, multifocal necrosis, and fibroplasia. Elevated levels of MMP-9 and cytokines IL-1beta, IL-8, and TGF-beta1 were detected in the lacrimal gland and cornea. Inflammation of the rabbit lacrimal gland following an injection of Con A significantly reduced tear clearance and TBUT and increased susceptibility to desiccation-induced corneal damage. Dexamethasone was prophylactically and therapeutically effective in this inflammation model of dry eye, restoring tear function and inhibiting corneal injury following topical ocular application. CONCLUSIONS: Characteristics of this rabbit lacrimal gland inflammation model of dry eye are consistent with the current understanding of dry eye as a local ocular surface inflammatory response to abnormal tear volume and composition. These results suggest that this rabbit model of dry eye may be employed to assess the therapeutic efficacy of mechanistically diverse agents on clinically relevant signs of ocular surface disease. These methods were strategically developed to be applicable for advancing drug discovery for a broad spectrum of dry eye patients.     

Antiinflammatory therapy for dry eye

PURPOSE: To present evidence establishing the relationship between inflammation and dry eye and supporting the use of antiinflammatory therapy for dry eye. DESIGN: Analysis of literature. METHODS: Research studies that evaluated inflammation in dry eye pathogenesis and clinical trials of antiinflammatory therapies for dry eye were reviewed. RESULTS: There is increasing evidence that decreased tear secretion, decreased tear turnover, and desiccation promote inflammation on the ocular surface. An increase in soluble mediators (cytokines and proteases) in the tear fluid, adhesion molecule expression by the conjunctival epithelium, and T-cell infiltration of the conjunctiva have been observed in dry eye patients. This inflammation appears to have a role in the pathogenesis of the ocular surface epithelial disease, termed keratoconjunctivitis sicca (KCS), that develops in dry eye. Clinical improvement of KCS has been observed after therapy with antiinflammatory agents including corticosteroids, cyclosporin and doxycycline. Cyclosporin A emulsion was approved by the Food and Drug Administration as therapy for dry eye. Randomized placebo-controlled FDA clinical trials showed that cyclosporine A was superior to vehicle in stimulating aqueous tear production, decreasing corneal punctuate fluorescein staining, reducing symptoms of blurred vision, and decreasing artificial tear use in patients with KCS. No ocular or systemic toxicity was observed from this medication. CONCLUSIONS: Ocular surface and lacrimal gland inflammation has been identified in dry eye that plays a role in the pathogenesis of KCS. Antiinflammatory therapy has efficacy for treating KCS. Cyclosporin A is the first FDA approved therapy for this indication. It improved signs and symptoms of KCS, and it is safe for long-term use.     

Effect of inflammation on lacrimal gland function

The lacrimal gland is the main contributor to the aqueous layer of the tear film. It secretes proteins, electrolytes and water, which helps to nourish and protect the ocular surface. Lacrimal gland secretion is primarily under neural control, which is achieved through a neural reflex arc. Stimuli to the ocular surface activate afferent sensory nerves in the cornea and conjunctiva. This in turn activates efferent parasympathetic and sympathetic nerves in the lacrimal gland to stimulate secretion. Sex steroid hormones are also important regulators of lacrimal gland functions. A decrease or lack of lacrimal gland secretion is the leading cause of aqueous tear deficient dry eye syndrome (DES). It has been suggested that DES is an inflammatory disorder that affects the ocular surface and the lacrimal gland. In several pathological instances, the lacrimal gland can become a target of the immune system and show signs of inflammation. This can result from autoimmune diseases (Sj?gren's syndrome), organ transplantation (graft versus host disease), or simply as a result of aging. The hallmarks of lacrimal gland inflammation are the presence of focal lymphocytic infiltrates and increased production of proinflammatory cytokines. The mechanisms leading to lacrimal gland dysfunction are still poorly understood. Apoptosis, production of autoantibodies, hormonal imbalance, alterations in signaling molecules, neural dysfunction, and increased levels of proinflammatory cytokines have been proposed as possible mediators of lacrimal gland insufficiency in disease states.     

Mechanisms Involved in Injury and Repair of the Murine lacrimal Gland: Role of Programmed Cell Death and Mesenchymal Stem Cells

The non-keratinized epithelia of the ocular surface are constantly challenged by environmental insults, such as smoke, dust, and airborne pathogens. Tears are the sole physical protective barrier for the ocular surface. Production of tears in inadequate quantity or of inadequate quality results in constant irritation of the ocular surface, leading to dry eye disease, also referred to as keratoconjunctivitis sicca (KCS). Inflammation of the lacrimal gland, such as occurs in Sjogren syndrome, sarcoidosis, chronic graft-versus-host disease, and other pathological conditions, results in inadequate secretion of the aqueous layer of the tear film and is a leading cause of dry eye disease. The hallmarks of lacrimal gland inflammation are the presence of immune cell infiltrates, loss of acinar epithelial cells (the secreting cells), and increased production of proinflammatory cytokines. To date, the mechanisms leading to acinar cell loss and the associated decline in lacrimal gland secretion are still poorly understood. It is also not understood why the remaining lacrimal gland cells are unable to proliferate in order to regenerate a functioning lacrimal gland. This article reviews recent advances in exocrine tissue injury and repair, with emphasis on the roles of programmed cell death and stem/progenitor cells.     

The evolving treatment of dry eye

Palliative treatments that historically have been the mainstay of therapy for dry eye continue to improve and are still appropriate therapy while we await new advances to control the underlying cause of dry eye disease. The approach of tear supplementation and tear preservation continues to be useful. The goal of tear stimulation or enhancement is elusive, but it may be nearer with the advent of P2Y2 agonists. The recognized importance of inflammation in producing dry eye through lacrimal gland and ocular surface damage is leading us to novel strategies to immunomodulate the disease and to restore hormonal balance to the ocular surface-lacrimal gland homeostatic cycle. It has taken 20 years of investigation to reach this threshold. The next 3 years should see promising treatments approved for dry eye disease.     

Th细胞及其相关因子参与干眼发病机制的研究进展

干眼是眼表免疫稳态失衡所致的炎症性疾病.由泪膜、角结膜上皮、睑板腺、泪腺以及联络它们的神经通路共同组成的泪腺功能单位(lacrimal functional unit,LFU)是维持眼表生理稳态的完整系统,任何影响这一系统的因素都可以干扰眼表免疫平衡机制引发炎症反应,并最终导致干眼的发生.研究发现,Th细胞及其相关因子在干眼炎症过程中发挥了重要作用,影响Th细胞分化或Th细胞相关因子的异常表达可以控制眼表炎症反应,有助于恢复眼表免疫稳态,有效抑制干眼病理改变和缓解临床症状.