Descamps F J, Kangave D, Cauwe B, Martens E, Geboes K, Abu El-Asrar A, Opdenakker G
Department of Microbiology and Immunology, Rega Institute for Medical Research, University of Leuven, Leuven, Belgium.
J Cell Mol Med. 2008 Dec;12(6A):2449-56. doi: 10.1111/j.1582-4934.2008.00264.x. Epub 2008 Feb 4.
Autoimmune diseases of the eye, exemplified by Beh cet disease and Vogt-Koyanagi-Harada disease, are a major cause of blindness. We studied interphotoreceptor retinoid-binding protein (IRBP), a dominant autoimmune antigen in the eye. Aqueous humour samples from 28 patients with active uveitis were analysed for immunoglobulin G (IgG) content as a marker for blood-ocular barrier breakdown and by gelatinase B zymography for the detection of inflammation. The data were correlated with the presence of intact IRBP (approximately 140 kD) as determined by Western blot analysis and with the clinical disease activity. Aqueous humour samples from control eyes and eyes with low disease activity showed positive immunoreactivity for intact IRBP. The IRBP signal weakened or disappeared with higher disease activity. Significant positive correlations were observed between disease activity and levels of gelatinase B/matrix metalloproteinase-9 (MMP-9) (rs=0.713; P<0.001) and IgG (rs=0.580; P=0.001). Significant negative correlations were found between levels of IRBP and disease activity (rs=-0.520; P=0.005) and levels of MMP-9 (rs=-0.727; P<0.001) and of IgG (rs=-0.834; P<0.001). Whereas neutrophil elastase converted intact IRBP into an immunoreactive 55 kD peptide in vitro, the conversion by neutrophil degranulates resembled more the in vivo context with a complete degradation of IRBP. Reversal of inflammation with immunosuppressive therapy was accompanied with reappearance of intact IRBP and disappearance of IgG and MMP-9. The analysis of IRBP proteolysis is useful as a biomarker for uveitis and suggests that inhibition of proteinases might become a therapeutic strategy in an inflammatory context of a damaged blood-ocular barrier.
以白塞病和伏格特-小柳-原田病为代表的眼部自身免疫性疾病是失明的主要原因。我们研究了光感受器间类视黄醇结合蛋白（IRBP），它是眼部主要的自身免疫抗原。对28例活动性葡萄膜炎患者的房水样本进行免疫球蛋白G（IgG）含量分析，作为血眼屏障破坏的标志物，并通过明胶酶B酶谱法检测炎症。这些数据与通过蛋白质印迹分析确定的完整IRBP（约140 kD）的存在以及临床疾病活动度相关。对照眼和疾病活动度低的眼的房水样本对完整IRBP显示出阳性免疫反应性。随着疾病活动度升高，IRBP信号减弱或消失。在疾病活动度与明胶酶B/基质金属蛋白酶-9（MMP-9）水平（rs = 0.713；P < 0.001）和IgG水平（rs = 0.580；P = 0.001）之间观察到显著的正相关。在IRBP水平与疾病活动度（rs = -0.520；P = 0.005）、MMP-9水平（rs = -0.727；P < 0.001）和IgG水平（rs = -0.834；P < 0.001）之间发现显著的负相关。虽然中性粒细胞弹性蛋白酶在体外将完整的IRBP转化为具有免疫反应性的55 kD肽，但中性粒细胞脱颗粒的转化在体内更类似于IRBP的完全降解。免疫抑制治疗使炎症逆转伴随着完整IRBP的重新出现以及IgG和MMP-9的消失。IRBP蛋白水解分析作为葡萄膜炎的生物标志物很有用，并表明在血眼屏障受损的炎症背景下抑制蛋白酶可能成为一种治疗策略。
