Ocular Surface最新文献_第2页

Meibomian gland tortuosity, truncation, and dilation in paediatric dry eye disease: A multi-centre, investigator-masked, cross-sectional study 研究通讯标题：小儿干眼症中的睑板腺迂曲、截断和扩张：一项多中心、研究者掩蔽的横断面研究

IF 5.9 1区医学 Q1 OPHTHALMOLOGY

Ocular Surface

Pub Date : 2024-10-01 DOI: 10.1016/j.jtos.2024.09.009

Michael T.M. Wang, James S. Wolffsohn, Ji Soo Kim, Sophie Speakman, Edward Pritchard, Barry Power, Jennifer P. Craig

引用次数: 0

“En bloc” combined 270-degree keratolimbal allograft with central lamellar keratoplasty for severe limbal stem cell deficiency secondary to mustard gas exposure "整体 "联合 270 度角膜同种异体移植术和中央板层角膜移植术，用于治疗芥子气暴露导致的严重角膜干细胞缺乏症。

IF 5.9 1区医学 Q1 OPHTHALMOLOGY

Ocular Surface

Pub Date : 2024-10-01 DOI: 10.1016/j.jtos.2024.10.006

Farid Karimian , Kiana Hassanpour , Mohammadreza Arzaghi , Zahra Karjou

Background

Severe limbal stem cell deficiency (LSCD) resulting from chronic and delayed-onset mustard gas keratopathy (MGK) presents substantial management challenges. This article introduces an “en bloc” surgical procedure combining a 270-degree keratolimbal allograft (KLAL) with central lamellar keratoplasty (CLK) as a novel approach to treat this condition.

Methods

A retrospective case series was conducted at Labbafinejad Medical Center in Tehran, Iran, from 2002 to 2019, including 13 eyes from 13 male patients diagnosed with chronic and delayed-onset MGK. Each patient underwent the combined 270-degree KLAL and central LK procedure. A 270-degree peritomy, sparing the superior quadrant, was performed. A lamellar dissection using a crescent blade and a blunt Melles dissector was carried out, extending 2 mm from the limbus. Fresh donor tissue with intact 270-degree limbo-conjunctiva, obtained from a whole globe, was prepared to match the recipient bed and sutured into place. Postoperative outcomes and success including ocular surface integrity, graft longevity, and best-corrected visual acuity (BCVA), were evaluated.

Results

The average follow-up period was 87.6 ± 49.8 months. Surgical success was achieved in 12 of 13 patients (92.3 %). Preoperative BCVA improved from 1.07 ± 0.24 (approximately 20/250) logMAR to 0.63 ± 0.30 (approximately 20/80) logMAR postoperatively. One patient experienced immune rejection of the KLAL graft, while two patients had episodes of corneal rejection, all successfully managed with aggressive immunosuppressive therapy.

Conclusions

The “en bloc KLAL + CLK” procedure demonstrates promising long-term outcomes in managing chronic and delayed-onset MGK associated with severe LSCD. This approach offers advantages, including reduced surgical complexity, minimized antigenic load, and better anatomical alignment, leading to successful ocular surface restoration and improved visual acuity.

背景：慢性和迟发性芥子气角膜病（MGK）导致的严重角膜缘干细胞缺乏症（LSCD）给治疗带来了巨大挑战。本文介绍了一种结合270度角膜同种异体移植术（KLAL）和中央板层角膜移植术（CLK）的 "整体 "手术方法，作为治疗这种疾病的新方法：2002年至2019年，伊朗德黑兰拉巴菲内贾德医疗中心开展了一项回顾性病例系列研究，其中包括13名被诊断为慢性和迟发性MGK的男性患者的13只眼睛。每位患者都接受了 270 度 KLAL 和中央 LK 联合手术。手术进行了 270 度周边切除术，并保留了上象限。使用新月形刀片和钝性梅勒斯剥离器进行板层剥离，剥离范围为距角膜缘 2 毫米处。从一个完整的球体上获取带有完整的270度边缘结膜的新鲜供体组织，准备好与受体床相匹配的组织并缝合到位。对术后效果和成功率进行了评估，包括眼表完整性、移植物寿命和最佳矫正视力（BCVA）：平均随访时间为 87.6 ± 49.8 个月。13 位患者中有 12 位（92.3%）手术成功。术前 BCVA 从 1.07 ± 0.24（约 20/250）logMAR 提高到术后的 0.63 ± 0.30（约 20/80）logMAR。一名患者出现了 KLAL 移植免疫排斥反应，两名患者出现了角膜排斥反应，但都通过积极的免疫抑制治疗得到了成功控制：结论："en bloc KLAL + CLK "手术在治疗与重度LSCD相关的慢性和迟发性MGK方面具有良好的长期疗效。这种方法的优势包括降低手术复杂性、最大限度地减少抗原负荷以及更好的解剖对位，从而成功恢复眼表并提高视力。

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引用次数: 0

Meibomian gland lipid alterations and ocular surface sequela in Awat2 knockout murine model of meibomian gland dysfunction and evaporative dry eye disease Awat2基因敲除小鼠睑板腺功能障碍和蒸发性干眼症模型的睑板腺脂质改变和眼表后遗症。

IF 5.9 1区医学 Q1 OPHTHALMOLOGY

Ocular Surface

Pub Date : 2024-10-01 DOI: 10.1016/j.jtos.2024.10.003

Erin A. Hisey , Sydni Wong , Sangwan Park , Kevin Aguirre Gamarra , Sara A. Adelman , Kelly E. Knickelbein , Melinda Quan , Michelle H. Ferneding , Michelle McCorkell , Nicole Daley , Vanessa Ureno , Sophie Le , Monica Ardon , Liana Williams , Bryan Puentes , Morgan Bowman , Monica J. Motta , Hoang Quoc Hai Pham , Amber Wilkerson , Seher Yuksel , Brian C. Leonard

Purpose

There is an urgent need for animal models of meibomian gland dysfunction (MGD) and evaporative dry eye disease (EDED) to understand their pathophysiology and investigate novel therapeutics. This study sought to further define the acyl-CoA: wax alcohol acyltransferase 2 knockout (Awat2 KO) mouse as a model of EDED using a combination of novel clinical, biochemical, and biophysical endpoints.

Methods

Wildtype and Awat2 KO mice between 1 and 18 months of age were used. Ocular examinations and advanced imaging were performed. The lipidomic composition and in situ melting temperature of meibum were determined. qPCR was performed to define ocular surface gene and pro-inflammatory transcript expression. Dynamic contact angle goniometry was performed to assess the adherence capability of the ocular surface.

Results

Awat2 KO mice have mild, white, hyperreflective corneal opacities of the anterior stroma and significantly enlarged apical epithelial cells (P = 0.0004). In Awat2 KO meibum, wax esters were 9–10 times lower than in wildtype meibum. Additionally, meibum melting temperature increased from 32° to 47 °C (P < 0.0001), leading to impaired meibum secretion and dilation of the central duct. Awat2 KO corneal epithelia had significantly decreased mucin expression (Muc1 and Muc4, P = 0.0043) and increased interferon-γ production (P = 0.0303). Awat2 KO globes have a significantly shortened time of droplet adherence to their ocular surface (P = 0.0053), indicating a decreased tear film adherence capacity. Wildtype corneal epithelia does not express Awat2, indicating that the EDED phenotype is secondary to the loss of Awat2 from the meibomian glands.

Conclusions

Awat2 KO mice recapitulate many of features of human MGD and EDED, representing a model to test novel therapeutics.

目的：目前急需建立睑板腺功能障碍（MGD）和蒸发性干眼症（EDED）的动物模型，以了解其病理生理学并研究新型疗法。本研究试图结合新的临床、生化和生物物理终点，进一步确定酰基-CoA：蜡醇酰基转移酶 2 基因敲除（Awat2 KO）小鼠作为干眼症的模型：方法：使用 1 到 18 个月大的野生型和 Awat2 KO 小鼠。进行了眼部检查和高级成像。通过 qPCR 确定眼表基因和促炎转录物的表达。采用动态接触角测角法评估眼表的粘附能力：结果：Awat2 KO小鼠的前基质有轻度、白色、高反射性角膜不透明，角膜顶端上皮细胞明显增大（P=0.0004）。Awat2 KO 卵膜中的蜡酯含量比野生型卵膜低 9-10 倍。此外，咀嚼液的熔化温度从32°升至47°C（PConclusions：Awat2 KO小鼠再现了人类MGD和EDED的许多特征，是一种测试新型疗法的模型。

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引用次数: 0

Mineralocorticoid receptor expression and the effects of the mineralocorticoid receptor antagonist spironolactone in a murine model of graft-versus-host disease 在小鼠移植物抗宿主病模型中矿质皮质激素受体的表达和矿质皮质激素受体拮抗剂螺内酯的作用。

IF 5.9 1区医学 Q1 OPHTHALMOLOGY

Ocular Surface

Pub Date : 2024-10-01 DOI: 10.1016/j.jtos.2024.10.004

Shinri Sato , Yoko Ogawa , Calvin W. Wong , Harrison L. Le , Richard W. Yee , Dan S. Gombos , Kazuno Negishi , Masatoshi Hirayama

Purpose

The topical administration of spironolactone, a mineralocorticoid receptor antagonist (MRA) improves dry eye symptoms in patients with ocular graft-versus-host disease (GVHD); however, the detailed mechanism remains unclear. This study aimed to investigate the effects of spironolactone eyedrops on the ocular surface using a chronic GVHD (cGVHD) mouse model and to determine the expression of the mineralocorticoid receptor (MR).

Methods

A cGVHD mouse model was established by allogeneic bone marrow transplantation (BMT) from B10.D2 mice to BALB/c mice. Subsequently, cGVHD mice were treated with either 0.005 % spironolactone or vehicle eyedrops. The eyelids, cornea and conjunctiva of the recipients were analyzed at 4-week intervals post-BMT in both groups.

Results

Signs of ocular GVHD, such as corneal epithelial damage, depletion of meibomian glands, and inflammatory cell infiltration onto the ocular surface, were significantly decreased in cGVHD mice treated with spironolactone eyedrops. The expression of the MR NR3C2 in the corneal and conjunctival epithelia was significantly increased in cGVHD mice. HSP47⁺NR3C2⁺ MR-expressing fibroblasts, CD45⁺NR3C2⁺ MR-expressing leukocytes, and CD4⁺NR3C2⁺ MR-expressing T cells infiltrated the ocular surface tissue of cGVHD mice significantly more than that of syngeneic controls.

Conclusions

MR expression is increased in epithelial cells, fibroblasts, and T cells in a murine cGVHD model, whereas MRA and spironolactone eyedrops could attenuate the severity of ocular GVHD. These findings suggest that MR signaling partially contributes to the development of ocular GVHD in this mouse model.

目的：局部使用螺内酯（一种矿物质皮质激素受体拮抗剂（MRA））可改善眼部移植物抗宿主病（GVHD）患者的干眼症状，但其具体机制仍不清楚。本研究旨在利用慢性移植物抗宿主病（cGVHD）小鼠模型研究螺内酯眼药水对眼表的影响，并确定矿皮质激素受体（MR）的表达：方法：通过将 B10.D2 小鼠的异体骨髓移植（BMT）至 BALB/c 小鼠，建立了 cGVHD 小鼠模型。随后，用 0.005% 螺内酯或载体眼药水治疗 cGVHD 小鼠。在 BMT 术后每隔 4 周对两组受者的眼睑、角膜和结膜进行分析：结果：使用螺内酯眼药水治疗的 cGVHD 小鼠的眼部 GVHD 症状，如角膜上皮损伤、睑板腺枯竭和眼表面炎性细胞浸润，均明显减少。cGVHD 小鼠角膜和结膜上皮中 MR NR3C2 的表达明显增加。HSP47+NR3C2+MR表达的成纤维细胞、CD45+NR3C2+MR表达的白细胞和CD4+NR3C2+MR表达的T细胞浸润cGVHD小鼠眼表组织的程度明显高于合成对照组：结论：在小鼠 cGVHD 模型中，上皮细胞、成纤维细胞和 T 细胞中的 MR 表达增加，而 MRA 和螺内酯眼药水可减轻眼部 GVHD 的严重程度。这些研究结果表明，在这种小鼠模型中，MR 信号传导部分导致了眼部 GVHD 的发生。

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引用次数: 0

BMAL1 deficiency provokes dry mouth and eyes by down-regulating ITPR2/3 缺乏 BMAL1 会通过下调 ITPR2/3 导致口干和眼干。

IF 5.9 1区医学 Q1 OPHTHALMOLOGY

Ocular Surface

Pub Date : 2024-10-01 DOI: 10.1016/j.jtos.2024.09.008

Xiaozhao Zhang , Guangjin Chen , Yan He , Qingming Tang , Ying Yin , Ying Jie

Secretory glands, responsible for tears and saliva production, play essential roles in maintaining ocular and oral well-being. Disruptions in gland secretion can arise from various factors, including rhythm disturbances associated with sleep disorders. However, the underlying mechanisms governing these disruptions remain largely unexplored. We demonstrate that BMAL1, a core component of the circadian system, plays a critical role in regulating secretory gland secretion. Loss of BMAL1 induces vacuolation and atrophy phenotypes in acinar cells, subsequently leading to cell apoptosis and gland hypofunction, but does not cause Sjogren's syndrome, which is characterized by localized inflammatory cell infiltration. Mechanically, BMAL1 directly modulates the transcription of ITPR2 and ITPR3, thereby altering the secretion of Lactoferrin and Lysozyme. Restoration of ITPR2 and ITPR3 expression in Bmal1-deficient rats effectively alleviated the symptoms of lacrimal and parotid glands secretory dysfunction and significantly reduced dry mouth and dry eye conditions in rhythm-disordered rats. These findings highlight the essential role of BMAL1 in regulating salivary and lacrimal gland secretion and suggest a novel therapeutic approach for treating dry mouth and dry eyes associated with rhythm disorders.

分泌腺负责泪液和唾液的分泌，在维持眼部和口腔健康方面发挥着至关重要的作用。腺体分泌紊乱可由多种因素引起，包括与睡眠障碍有关的节律紊乱。然而，这些干扰的潜在机制在很大程度上仍未得到探索。我们证明，昼夜节律系统的核心成分 BMAL1 在调节分泌腺分泌方面起着关键作用。BMAL1 的缺失会诱导尖腺细胞出现空泡化和萎缩表型，随后导致细胞凋亡和腺体功能低下，但不会引起以局部炎性细胞浸润为特征的 Sjogren's 综合征。在机制上，BMAL1 直接调节 ITPR2 和 ITPR3 的转录，从而改变乳铁蛋白和溶菌酶的分泌。恢复 Bmal1 基因缺陷大鼠 ITPR2 和 ITPR3 的表达可有效缓解泪腺和腮腺分泌功能障碍的症状，并显著减轻节律紊乱大鼠的口干和眼干症状。这些发现强调了 BMAL1 在调节唾液腺和泪腺分泌中的重要作用，并为治疗与节律紊乱相关的口干和眼干提出了一种新的治疗方法。

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引用次数: 0

Development of human amniotic epithelial cell-derived extracellular vesicles as cell-free therapy for dry eye disease 开发人羊膜上皮细胞衍生细胞外囊泡，作为干眼症的无细胞疗法。

IF 5.9 1区医学 Q1 OPHTHALMOLOGY

Ocular Surface

Pub Date : 2024-10-01 DOI: 10.1016/j.jtos.2024.09.006

Soojin Yi , Jeongho Kim , Mi Ju Kim , Che Gyem Yae , Ki Hean Kim , Hong Kyun Kim

Purpose

This study aimed to investigate the therapeutic potential of extracellular vesicles (EVs) derived from human amniotic epithelial cells (hAEC-EVs) for Dry Eye Disease (DED) treatment.

Methods

Highly purified EVs were isolated from the culture supernatants of hAECs, which obtained from term placenta and characterized. Proteomic contents were analyzed for assessing its biological function related to the therapeutic potentials for DED. Subsequently, we examined the therapeutic efficacy of hAEC-EVs on human corneal epithelial cells exposed to hyperosmotic stress and in an experimental DED mouse model induced by desiccation stress.

Results

Proteomic analysis of hAEC-EVs revealed proteins linked to cell proliferation and anti-inflammatory responses. We demonstrated efficient uptake of hAEC-EVs by ocular surface cells. Under DED conditions, EV treatment increased corneal epithelial cell proliferation and migration, and concurrently reducing inflammatory cytokines. In the DED mouse model, hAEC-EVs showed significant improvements in corneal staining score, tear secretion, corneal irregularity, and conjunctival goblet cell density. Additionally, hAEC-EVs exhibited a mitigating effect on ocular surface inflammation induced by desiccation.

Conclusions

These findings suggest that hAEC-EVs hold potential as a cell-free therapy for corneal epithelial defects and ocular surface diseases, presenting a promising treatment option for DED.

目的：本研究旨在探讨从人羊膜上皮细胞（hAEC-EVs）中提取的细胞外囊泡（EVs）治疗干眼症（DED）的潜力。方法：从足月胎盘中获得的 hAECs 培养上清液中分离出高度纯化的 EVs，并对其进行了表征，分析了其蛋白质组含量，以评估其与 DED 治疗潜力相关的生物功能。随后，我们研究了 hAEC-EVs 对暴露于高渗透压下的人角膜上皮细胞和干燥应激诱导的实验性 DED 小鼠模型的治疗效果：hAEC-EVs的蛋白质组分析显示了与细胞增殖和抗炎反应相关的蛋白质。我们证明了眼表细胞对 hAEC-EVs 的高效吸收。在 DED 条件下，EV 处理增加了角膜上皮细胞的增殖和迁移，同时减少了炎症细胞因子。在 DED 小鼠模型中，hAEC-EVs 能显著改善角膜染色评分、泪液分泌、角膜不规则性和结膜上皮细胞密度。此外，hAEC-EVs 对干燥引起的眼表炎症也有缓解作用：这些研究结果表明，hAEC-EVs 具有作为角膜上皮缺陷和眼表疾病无细胞疗法的潜力，为 DED 的治疗提供了一种前景广阔的选择。

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引用次数: 0

Recent advances in NLRP3 inflammasome in corneal diseases: Preclinical insights and therapeutic implications 角膜疾病中 NLRP3 炎症体的最新研究进展：临床前见解和治疗意义。

IF 5.9 1区医学 Q1 OPHTHALMOLOGY

Ocular Surface

Pub Date : 2024-10-01 DOI: 10.1016/j.jtos.2024.09.007

Jiayun Ge , Xiang Li , Yutong Xia , Zhitong Chen , Chen Xie , Yuan Zhao , Kuangqi Chen , Ye Shen , Jianping Tong

NLRP3 inflammasome is a cytosolic multiprotein complex formed in response to exogenous environmental stress and cellular damage. The three major components of the NLRP3 inflammasome are the innate immunoreceptor protein NLRP3, the adapter protein apoptosis-associated speck-like protein containing a C-terminal caspase activation and recruitment domain, and the inflammatory protease enzyme caspase-1. The integrated NLRP3 inflammasome triggers the activation of caspase-1, leading to GSDMD-dependent pyroptosis and facilitating the maturation and release of inflammatory cytokines, namely interleukin (IL)-18 and IL-1β. However, the inflammatory responses mediated by the NLRP3 inflammasome exhibit dual functions in innate immune defense and cellular homeostasis. Aberrant activation of the NLRP3 inflammasome matters in the etiology and pathophysiology of various corneal diseases. Corneal alkali burn can induce pyroptosis, neutrophil infiltration, and corneal angiogenesis via the activation of NLRP3 inflammasome. When various pathogens invade the cornea, NLRP3 inflammasome recognizes pathogen-associated molecular patterns or damage-associated molecular patterns to engage in pro-inflammatory and anti-inflammatory mechanisms. Moreover, chronic inflammation and proinflammatory cascades mediated by the NLRP3 inflammasome contribute to the pathogenesis of diabetic keratopathy. Furthermore, overproduction of reactive oxygen species, mitochondrial dysfunction, and toll-like receptor-mediated activation of nuclear factor kappa B drive the stimulation of NLRP3 inflammasome and participate in the progression of dry eye disease. However, there still exist controversies regarding the regulatory pathways of the NLRP3 inflammasome. In this review, we provide a comprehensive overview of recent advancements in the function of NLRP3 inflammasome in corneal diseases and its regulatory pathways primarily through studies using animal models. Furthermore, we explore prospects for pharmacologically targeting pathways associated with NLRP3.

NLRP3 炎症小体是一种细胞膜多蛋白复合物，在外源性环境压力和细胞损伤时形成。NLRP3 炎症体的三个主要成分是先天免疫受体蛋白 NLRP3、含有 C 端树突酶激活和招募结构域的适配蛋白凋亡相关斑点样蛋白和炎症蛋白酶树突酶-1。整合后的 NLRP3 炎性体触发了 caspase-1 的活化，导致依赖于 GSDMD 的热凋亡，并促进炎性细胞因子（即白细胞介素（IL）-18 和 IL-1β）的成熟和释放。然而，NLRP3 炎性体介导的炎症反应在先天性免疫防御和细胞稳态中表现出双重功能。NLRP3 炎性体的异常激活与各种角膜疾病的病因和病理生理学有关。角膜碱灼伤可通过激活 NLRP3 炎性体诱发角膜热变态反应、中性粒细胞浸润和角膜血管生成。当各种病原体侵入角膜时，NLRP3 炎症小体识别病原体相关分子模式或损伤相关分子模式，参与促炎和抗炎机制。此外，NLRP3 炎性体介导的慢性炎症和促炎级联也是糖尿病角膜病的发病机制之一。此外，活性氧的过度产生、线粒体功能障碍以及收费样受体介导的核因子卡巴B的活化，都会刺激NLRP3炎性体，并参与干眼症的进展。然而，关于 NLRP3 炎症小体的调控途径仍存在争议。在这篇综述中，我们主要通过对动物模型的研究，全面概述了 NLRP3 炎症小体在角膜疾病中的功能及其调控途径的最新进展。此外，我们还探讨了以 NLRP3 相关途径为药物靶点的前景。

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引用次数: 0

Changes in conjunctival mononuclear phagocytes and suppressive activity of regulatory macrophages in desiccation induced dry eye 干燥引起的干眼症中结膜单核吞噬细胞的变化和调节性巨噬细胞的抑制活性。

IF 5.9 1区医学 Q1 OPHTHALMOLOGY

Ocular Surface

Pub Date : 2024-09-19 DOI: 10.1016/j.jtos.2024.09.003

Jehan Alam , Ebru Yaman , Cintia S. de Paiva , De-Quan Li , Gerda Cristal Villalba Silva , Zhen Zuo , Stephen C. Pflugfelder

Purpose

To evaluate the effects of dry eye on conjunctival immune cell number and transcriptional profiles with attention to mononuclear phagocytes.

Methods

Expression profiling was performed by single-cell RNA sequencing on sorted conjunctival immune cells from non-stressed and C57BL/6 mice subjected to desiccating stress (DS). Monocle 3 modeled cell trajectory, scATAC-seq assessed chromatin accessibility and IPA identified canonical pathways. Inflammation and goblet cells were measured after depletion of MRC1⁺ MΦs with mannosylated clodronate liposomes.

Results

Mononuclear phagocytes (monocytes, MΦs, DCs) comprised 72 % of immune cells and showed the greatest changes with DS. Distinct DS induced gene expression patterns were seen in phagocytes classified by expression of Ccr2 and [Timd4, Lyve1, Folr2 (TLR)]. Expression of phagocytosis/efferocytosis genes increased in TLF⁺CCR2^- MΦs. Monocytes showed the highest expression of Ace, Cx3cr1, Vegfa, Ifngr1,2, and Stat1 and TLF⁻CCR2⁺ cells expressed higher levels of inflammatory mediators (Il1a, Il1b, Il1rn, Nfkb1, Ccl5, MHCII, Cd80, Cxcl10, Icam1). A trajectory from monocyte precursors branched to terminate in regulatory MΦs or in mDCs via transitional MΦ and cDC clusters. Activated pathways in TLF⁺ cells include phagocytosis, PPAR/RXRα activation, IL-10 signaling, alternate MΦ activation, while inflammatory pathways were suppressed. Depletion of MRC1⁺ MΦs increased IL-17 and IFN-γ expression and cytokine-expressing T cells, reduced IL-10 and worsened goblet loss.

Conclusions

Dryness stimulates distinct gene expression patterns in conjunctival phagocytes, increasing expression of regulatory genes in TLF⁺ cells regulated in part by RXRα, and inflammatory genes in CCR2⁺ cells. Regulatory MΦs depletion worsens DS induced inflammation and goblet cell loss.

目的：评估干眼症对结膜免疫细胞数量和转录谱的影响，并关注单核吞噬细胞：方法：通过单细胞 RNA 测序，对未受应激和受干燥应激 (DS) 的 C57BL/6 小鼠的分选结膜免疫细胞进行表达谱分析。Monocle 3对细胞轨迹进行了建模，scATAC-seq评估了染色质可及性，IPA确定了典型通路。用甘露聚糖化的克洛膦酸脂质体耗竭 MRC1+ MΦs 后，对炎症和鹅口疮细胞进行了测量：结果：单核吞噬细胞（单核细胞、MΦs、DCs）占免疫细胞的 72%，在 DS 的作用下变化最大。根据 Ccr2 和[Timd4、Lyve1、Folr2 (TLR)]的表达分类，在吞噬细胞中发现了不同的 DS 诱导基因表达模式。在 TLF+CCR2- MΦs 中，吞噬/排泄基因的表达增加。单核细胞的 Ace、Cx3cr1、Vegfa、Ifngr1,2 和 Stat1 表达量最高，TLF-CCR2+ 细胞的炎症介质（Il1a、Il1b、Il1rn、Nfkb1、Ccl5、MHCII、Cd80、Cxcl10、Icam1）表达量较高。单核细胞前体的轨迹经由过渡性 MΦ 和 cDC 簇，最终形成调节性 MΦ 或 mDC。TLF+细胞中的激活途径包括吞噬、PPAR/RXRα激活、IL-10信号传导、MΦ交替激活，而炎症途径则受到抑制。MRC1+MΦ的耗竭增加了IL-17和IFN-γ的表达以及表达细胞因子的T细胞，降低了IL-10，并加剧了上皮细胞脱落：结论：干燥会刺激结膜吞噬细胞中不同基因的表达模式，增加TLF+细胞中部分由RXRα调节的调节基因的表达，以及CCR2+细胞中炎症基因的表达。调节性 MΦs 的耗竭会加剧 DS 诱导的炎症和上皮细胞脱落。

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引用次数: 0

Epidemiology and risk factors for the development of cicatrizing conjunctivitis in chronic ocular graft-versus-host disease 慢性眼部移植物抗宿主疾病卡他性结膜炎的流行病学和发病风险因素

IF 5.9 1区医学 Q1 OPHTHALMOLOGY

Ocular Surface

Pub Date : 2024-09-12 DOI: 10.1016/j.jtos.2024.09.002

Nicole B. Kantor , Paula A. Sepulveda-Beltran , David Valdés-Arias , Elyana V.T. Locatelli , Lakshman Mulpuri , Araliya N. Gunawardene , Guillermo Amescua , Victor L. Perez , Rahul Tonk , Trent Wang , Anat Galor

Purpose

To evaluate the incidence of chronic cicatrizing conjunctivitis (CCC) and its associated risk factors in the context of chronic ocular graft-vs-host disease (coGVHD).

Methods

A retrospective chart review of individuals diagnosed with coGVHD following hematopoietic stem cell transplantation (HSCT) who were seen at the Bascom Palmer Eye Institute between May 2010 and November 2021 was performed. Data regarding baseline demographic characteristics, systemic co-morbidities, lid margin abnormalities, ocular cicatricial changes, transplant information, immunosuppressive therapy, and GVHD severity assessments were collected. The incidence of cicatricial conjunctivitis was estimated with Kaplan-Meier survival analysis. A Cox regression model was used to assess the contribution of demographic and systemic variables to the development of CCC.

Results

167 individuals were included (53.9 ± 14.7 years old; 60.5 % male). 65 individuals presented with features suggestive of CCC an average of 60.9 ± 53.8 months after HSCT, with 60-month and 120-month incidences of 29.3 % and 48.9 %, respectively. Multivariable analysis demonstrated that age younger than 50 at the time of the first eye visit was associated with a higher chance of CCC development (Hazard Ratio (HR): 2.14, 95 % Confidence Interval (CI): 1.16–3.97, p = 0.02).

Conclusion

Clinically detected cicatrizing conjunctivitis is an ocular manifestation of coGVHD, with an incidence that increases over time. Younger individuals may be at higher risk for CCC development.

目的评估慢性卡他性结膜炎（CCC）的发病率及其与慢性眼移植物抗宿主病（coGVHD）相关的风险因素。方法对2010年5月至2021年11月期间在巴斯康帕尔默眼科研究所就诊的造血干细胞移植（HSCT）后确诊为coGVHD的患者进行回顾性病历审查。研究人员收集了有关基线人口统计学特征、全身合并疾病、睑缘异常、眼部卡他性变化、移植信息、免疫抑制疗法和GVHD严重程度评估的数据。卡他性结膜炎的发病率通过卡普兰-梅耶生存分析法进行估算。结果167人（53.9 ± 14.7岁；60.5%为男性）被纳入研究。65人在造血干细胞移植后平均（60.9 ± 53.8）个月出现提示CCC的特征，60个月和120个月的发病率分别为29.3%和48.9%。多变量分析表明，首次眼科就诊时年龄小于 50 岁的患者发生 CCC 的几率更高（危险比 (HR)：2.14，95% 置信区间 (CI)：1.16-3.97，P = 0.02）。年轻患者发生卡他性结膜炎的风险更高。

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引用次数: 0

Detection of SARS-CoV-2 binding receptors and miscellaneous targets as well as mucosal surface area of the human lacrimal drainage system 检测与 SARS-CoV-2 结合的受体和其他目标，以及人类泪液引流系统的粘膜表面积。

IF 5.9 1区医学 Q1 OPHTHALMOLOGY

Ocular Surface

Pub Date : 2024-08-31 DOI: 10.1016/j.jtos.2024.08.016

Anna-Lena Rau , Martin Schicht , Ingrid Zahn , Mohammad Javed Ali , Minas Theodore Coroneo , Friedrich Paulsen

Purpose

Our aim was to evaluate a potential role for the lacrimal drainage system (LDS) as a portal of entry and conduit for SARS-CoV-2 in human infection. We also investigate the mucosal surface area. The relatively long tear contact time in a closed system raises the possibility that this pathway may contribute to the initiation of systemic infection. We looked for expression of ACE2, the main receptor for SARS-CoV-2, as well as cofactors such as TMPRSS2 and other enzymes such as cathepsinB, CD147, elastase1, furin, neuropilin1, neuropilin2, TMPRSS11D and trypsin which also play a role in SARS-CoV-2 infection, in this system.

Methods

Human tissue samples of the draining tear ducts from body donors were analyzed by RT-PCR, Western blot and immunohistochemistry. It is not known whether the respective body donors were Sars-Cov-2 positive at any time; they were negative when they entered the institute. Besides, the draining LDS of body donors were measured to determine the mucosal surface in the lacrimal system.

Results

The expression of the main receptor studied, ACE2, cofactors such as TMPRSS2 and other enzymes such as cathepsinB, CD147, elastase1, furin, neuropilin1, neuropilin2, TMPRSS11D and trypsin were all detected at the gene and protein level. The average mucosal surface area of the lacrimal sac and nasolacrimal duct was calculated to be 110 mm².

Conclusion

The results show the presence of all analyzed receptors in the efferent LDS. With an average tear passage time of 3 min and a relatively large mucosal surface area, the LDS could therefore be considered as a portal of entry and conduit for SARS-CoV-2. In addition, it represents a surface that should be taken into consideration in the administration of topically applied medication to the ocular surface.

目的：我们的目的是评估泪液引流系统（LDS）在人类感染中作为 SARS-CoV-2 进入门户和通道的潜在作用。我们还对粘膜表面积进行了调查。在一个封闭系统中，泪液接触时间相对较长，这就提出了这一途径可能有助于引发全身感染的可能性。我们研究了 SARS-CoV-2 的主要受体 ACE2 以及辅助因子如 TMPRSS2 和其他酶如 cathepsinB、CD147、弹性蛋白酶 1、呋喃、神经蛋白酶 1、神经蛋白酶 2、TMPRSS11D 和胰蛋白酶的表达情况，这些酶也在 SARS-CoV-2 感染中发挥作用。方法：通过 RT-PCR、Western 印迹和免疫组化对人体捐献者的泪腺引流管组织样本进行分析。目前尚不清楚各人体捐献者是否在任何时候都是 Sars-Cov-2 阳性；他们在进入研究所时都是阴性。此外，还测量了供体的引流LDS，以确定泪腺系统的粘膜表面：结果：所研究的主要受体 ACE2、辅助因子（如 TMPRSS2）和其他酶（如 cathepsinB、CD147、弹性蛋白酶 1、呋喃、神经蛋白酶 1、神经蛋白酶 2、TMPRSS11D 和胰蛋白酶）的表达均在基因和蛋白水平上被检测到。计算得出泪囊和鼻泪管的平均粘膜表面积为 110 平方毫米：结果表明，所有分析的受体都存在于流出的泪腺中。由于泪液通过的平均时间为 3 分钟，且粘膜表面积相对较大，因此可将泪囊视为 SARS-CoV-2 的入口和通道。此外，在对眼表进行局部用药时，也应考虑到这一表面。

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