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）是一种潜在的人类致盲疾病，在日本占获得性失明的10-15%。虽然内源性葡萄膜炎涵盖了一系列的临床实体，但所有形式都被认为具有免疫组织学相似性，其特征在于主要是CD 4 T细胞的浸润。众所周知，CD 4 T细胞活化需要至少两种不同信号的整合。信号一由抗原呈递细胞（APC）呈递的MHC 2类结合肽的抗原特异性T细胞受体接合产生。信号二是APC和T细胞表达的共刺激分子相互作用的结果。CD 28同源物诱导型共刺激分子（ICOS）最近被鉴定为CD 28共刺激分子家族的新成员，并在人和小鼠中由活化的T细胞表达。ICOS配体，B7相关蛋白（B7 RP-1），也称为B7同源蛋白（B7 h），由APC组成型表达。作为微阵列分析的结果，与健康对照相比，在具有葡萄膜炎的BD患者中PBMC中的ICOS显示出最大的表达差异。伴葡萄膜炎的BD患者在ConA刺激前后CD 4 T细胞ICOS表达均显著高于健康人。在BD患者中，活动性葡萄膜炎患者CD 4 T细胞上的ICOS表达显著高于缓解性葡萄膜炎患者。在患有活动性葡萄膜炎的BD患者中，当用Con A或IRBP刺激时，抗ICOS mAb阻断ICOS/B7相关蛋白-1相互作用可显著降低PBMC产生IFN-γ和IL-17。总之，我们的数据提供了额外的证据，ICOS表达的CD 4 T细胞作为一个标志物，以确定疾病的活动性和ICOS代表一个有前途的治疗目标，通过抑制Th 1和Th 17细胞因子的眼BD的潜在效用。

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.