ICAM-1 expression predisposes ocular tissues to immune-based inflammation in dry eye patients and Sjogrens syndrome-like MRL/lpr mice
ICAM-1 expression predisposes ocular tissues to immune-based inflammation in dry eye patients and Sjogrens syndrome-like MRL/lpr mice
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DOI：
10.1016/j.exer.2003.10.024
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发表时间：
2004-04-01
影响因子：
3.4
通讯作者：
Stern, ME
中科院分区：
文献类型：
--
作者：
Gao, JP;Morgan, G;Stern, ME
目的。我们以前报道过，免疫炎症发生在人和干燥性角结膜炎(KCS)犬的眼表。细胞间黏附分子-1(ICAM-1)在淋巴细胞和/或血管内皮细胞上表达上调，导致淋巴细胞向泪膜和结膜组织渗出。本研究的目的是阐明ICAM-1在眼部炎症时的驻留上皮细胞反应中的作用，(2)局部和/或外周淋巴细胞在眼组织中的激活或聚集，以及(3)抗ICAM-1是否有效地减轻免疫介导的眼部炎症。应用免疫组织化学和原位杂交技术检测KCS患者和(或)MRL/LPR小鼠不同眼部组织中ICAM-1蛋白和信使RNA(MRNA)的表达。用ELISA法测定MRL/LPR小鼠发病过程中血浆中可溶性ICAM-1的浓度。用溴脱氧尿嘧啶核苷(BrdU)掺入法和免疫组织化学方法检测眼组织内细胞增殖情况。T细胞活化水平由IL-2受体(T细胞活化和增殖标志物CD25)和CD69(T细胞活化标志物)免疫反应性测定。为观察抗ICAM-1/LFA-1对泪腺炎症的抑制作用，给MRL/LPR小鼠(腹腔注射)。在有或没有ICAM-1和LFA-1的单抗的情况下，在3或8周龄。干眼症患者结膜和副泪膜上皮细胞内源性ICAM-1在蛋白和mRNA水平均有较高的表达。16周龄的mrl/lpr小鼠泪腺泡上皮细胞、结膜上皮细胞、炎症细胞和血管内皮细胞均有ICAM-1的表达。与对照组相比，随着疾病的发展，可溶性ICAM-1水平显著升高。发病时，MRL/LPR小鼠泪腺内未检测到明显的淋巴细胞增殖(缺乏BrdU和CD25免疫反应)。然而，大量浸润性T细胞呈CD69阳性，表明T细胞亚群处于激活阶段。用抗小鼠ICAM-1和LFA-1的单抗处理后，MRL/LPR小鼠的炎性浸润物数量减少。我们的发现表明，ICAM-1的局部和系统上调促进了淋巴细胞的激活和向眼表(OS)的迁移。眼部驻留上皮是眼表面的活性成分，在免疫激活和炎症反应中，通过产生ICAM-1与侵袭性淋巴细胞相互作用。上皮细胞合成的ICAM-1可能作为易感眼表炎症的信号分子，促进上皮细胞潜在的抗原提呈。MRL/LPR小鼠泪腺中淋巴细胞的渗入似乎是聚集的结果，而不是从迁移到局部眼组织的血管系统中的循环淋巴细胞的增殖。抗ICAM-1治疗在治疗干眼等免疫性炎症性疾病中的潜在应用值得进一步研究。(C)2004爱思唯尔有限公司。保留所有权利。
Purpose. We previously reported that immune-based inflammation occurs on the ocular surface of humans as well as canines with keratoconjunctivitis sicca (KCS). Intercellular adhesion molecule-1 (ICAM-1) was found to be upregulated on lymphocytes and/or vascular endothelial cells resulting in lymphocytic diapedesis to the lacrimal and conjunctival tissues. The purpose of the current study was to demonstrate the role of ICAM-1 in (1) resident epithelial cell response during ocular inflammation, (2) local and/or peripheral lymphocyte activation or accumulation in the ocular tissues, and (3) whether anti-ICAM-1 is effective to attenuate immune-mediated ocular inflammation.Methods. ICAM-1 levels in various ocular tissues of human with KCS and/or MRL/lpr mouse were evaluated by immunohistochemistry and in situ hybridization for protein and messenger RNA (mRNA) expression, respectively. Soluble ICAM-1 concentrations in MRL/lpr mouse plasma over the course of disease development were measured by ELISA. Cell proliferation within ocular tissues was assessed by bromodeoxyuridine (BrdU) incorporation and immunohistochemical detection. The level of T cell activation was determined by IL-2 receptor (CD25, a marker of T cell activation and proliferation) and CD69 (a marker of T cell activation) immunoreactivity using FACS analysis. To examine the effectiveness of anti-ICAM-1/LFA-1 in elimination of lacrimal gland inflammation, MRL/lpr mice were injected intraperitoneally (i.p.) with or without monoclonal antibodies against ICAM-1 and LFA-1 at three or eight weeks of age.Results. Increased endogenous ICAM-1 expression at the level of protein and mRNA was detected in the epithelial cells present in the conjunctival and accessory lacrimal tissues in dry eye patients. In MRL/lpr mice, ICAM-1 expression by lacrimal acinar epithelial cells and conjunctival epithelial cells were detected in addition to inflammatory infiltrates and vascular endothelial cells at 16 weeks of age. Soluble ICAM-1 levels were markedly increased concomitantly with disease progression over time as compared with the controls. No significant lymphocytic proliferation (a lack of BrdU and CD25 immunoreactivities) was detected within lacrimal glands of MRL/lpr mice at the disease onset. However, a population of the infiltrated T cells were CD69 positive, indicating the activation stage of a T cell subset. Treatment using monoclonal antibodies against murine ICAM-1 and LFA-1 resulted in a decrease in the number of inflammatory infiltrates in MRL/lpr mice.Conclusions. Our findings suggest that ICAM-1 upregulation locally and systemically promote lymphocyte activation and migration to the ocular surface (OS). Ocular resident epithelium is an active component of ocular surface and is capable of interacting with invasive lymphocytes by ICAM-1 production in response to immune activation and inflammation. ICAM-1 synthesized by epithelial cells may serve as a signaling molecule for predisposition of ocular surface inflammation and facilitate potential antigen presentation by epithelial cells. Lymphocytic infiltrates in the lacrimal gland of the MRL/lpr mouse appeared to be the result of the accumulation, but not proliferation of circulating lymphocytes diapodesed from the vasculature that had migrated into the local ocular tissues. The potential use of anti-ICAM-1 therapy in treating immune-based inflammatory diseases such as dry eye deserves further investigation. (C) 2004 Elsevier Ltd. All rights reserved.