Role of Immune co-signals in the pathogenesis and development of new treatment of refractory uveoretinitis

内源性葡萄膜炎，如白塞病(BD)，是一种潜在的致盲疾病，是日本10%-15%的获得性失明的原因。虽然内源性葡萄膜炎涵盖了一系列临床实体，但所有类型的葡萄膜炎都被认为具有免疫组织学相似的特征，主要是CD4T细胞的渗透。众所周知，CD4T细胞的激活需要至少两个不同信号的整合。信号1是由抗原提呈细胞(APC)提呈的MHC-2类结合多肽与抗原特异性T细胞受体结合而产生的。信号二是APC和T细胞表达的共刺激分子相互作用的结果。CD28同源可诱导共刺激分子(ICOS)是近年来发现的CD28共刺激分子家族中的一个新成员，在人和小鼠体内均由活化的T细胞表达。ICOS配体B7相关蛋白(B7RP-1)，又称B7同源蛋白(B7h)，由APC组成性表达。基因芯片分析结果显示，BD伴葡萄膜炎患者PBMCs中ICOS的表达与健康对照组相比差异最大。BD伴葡萄膜炎患者在ConA刺激前后CD4T细胞ICOS表达均显著高于正常人。在BD患者中，活动期葡萄膜炎患者的CD4T细胞ICOS表达显著高于缓解期葡萄膜炎患者。用抗ICOS单抗阻断ICOS/B7相关蛋白-1的相互作用，可显著降低活动期葡萄膜炎患者PBMC在ConA或IRBP刺激下产生的干扰素-γ和IL-17。总之，我们的数据为CD4T细胞上ICOS表达作为确定疾病活动性的标志物的潜在用途提供了额外的证据，并且ICOS通过抑制Th1和Th17细胞因子而成为眼部BD的一个有前途的治疗靶点。

Endogenous uveitis such as Behcet's disease (BD) is a potentially blinding disease in humans and is responsible for 10-15% of the acquired blindness in Japan. Although endogenous uveitis covers a spectrum of clinical entities, all forms are believed to share immunohistological similarities characterized by the infiltration of mainly CD4 T cells. It is well known that CD4 T cell activation requires the integration of at least two distinct signals. Signal one results from antigen-specific T cell receptor engagement by MHC class 2-bound peptide presented by antigen presenting cells (APC). Signal two results from engagement of costimulatory molecules expressed by APC and T cell. The CD28 homolog inducible costimulator (ICOS) has recently been identified as a novel member of the CD28 costimulator family, and is expressed by activated T cells in both humans and mice. The ICOS ligand, B7-related protein (B7RP-1), also known as B7 homologous protein (B7h), is constitutively expressed by APC. As the result of microarray analysis, ICOS in PBMCs showed the greatest difference in expression in BD patients with uveitis compared to healthy controls. ICOS expression on CD4 T cells in BD patients with uveitis was significantly higher than that in healthy individuals both before and after Con A stimulation. Among BD patients, ICOS expression on CD4 T cells was significantly higher in those with active uveitis than in those with remitted uveitis. Blockade of ICOS/B7-related protein-1 interaction by anti-ICOS mAb significantly decreased IFN-γ and IL-17 production by PBMCs when stimulated with Con A or IRBP in BD with active uveitis. In conclusion, our data provide additional evidence for the potential utility of ICOS expression on CD4 T cells as a marker to determine disease activity and that ICOS represents a promising therapeutic target for ocular BD by inhibiting Th1 and Th17 cytokines.