DataSheet_1_Experimental and genetic evidence for the impact of CD5 and CD6 expression and variation in inflammatory bowel disease.pdf

Crohn’s disease (CD) and ulcerative colitis (UC) are inflammatory bowel diseases (IBD) resulting from the interaction of multiple environmental, genetic and immunological factors. CD5 and CD6 are paralogs encoding lymphocyte co-receptors involved in fine-tuning intracellular signals delivered upon antigen-specific recognition, microbial pattern recognition and cell adhesion. While CD5 and CD6 expression and variation is known to influence some immune-mediated inflammatory disorders, their role in IBD remains unclear. To this end, Cd5- and Cd6-deficient mice were subjected to dextran sulfate sodium (DSS)-induced colitis, the most widely used experimental animal model of IBD. The two mouse lines showed opposite results regarding body weight loss and disease activity index (DAI) changes following DSS-induced colitis, thus supporting Cd5 and Cd6 expression involvement in the pathophysiology of this experimental IBD model. Furthermore, DNA samples from IBD patients of the ENEIDA registry were used to test association of CD5 (rs2241002 and rs2229177) and CD6 (rs17824933, rs11230563, and rs12360861) single nucleotide polymorphisms with susceptibility and clinical parameters of CD (n=1352) and UC (n=1013). Generalized linear regression analyses showed association of CD5 variation with CD ileal location (rs2241002CC) and requirement of biological therapies (rs2241002C-rs2229177T haplotype), and with poor UC prognosis (rs2241002T-rs2229177T haplotype). Regarding CD6, association was observed with CD ileal location (rs17824933G) and poor prognosis (rs12360861G), and with left-sided or extensive UC, and absence of ankylosing spondylitis in IBD (rs17824933G). The present experimental and genetic evidence support a role for CD5 and CD6 expression and variation in IBD’s clinical manifestations and therapeutic requirements, providing insight into its pathophysiology and broadening the relevance of both immunomodulatory receptors in immune-mediated disorders.

克罗恩病（CD）和溃疡性结肠炎（UC）系由多种环境、遗传和免疫因素相互作用所引起的炎症性肠病（IBD）。CD5和CD6为编码淋巴细胞共受体的同源物，这些共受体参与对特定抗原识别、微生物模式识别和细胞粘附过程中传递的细胞内信号的精细调节。尽管已知CD5和CD6的表达和变异会影响某些免疫介导的炎症性疾病，但它们在IBD中的作用尚不明确。为此，Cd5-和Cd6缺陷小鼠被用于接受乳糖硫酸钠（DSS）诱导的结肠炎，这是最广泛使用的IBD实验动物模型。这两株小鼠在DSS诱导的结肠炎后表现出相反的结果，即体重减轻和疾病活动指数（DAI）的变化，从而支持Cd5和Cd6表达与该实验IBD模型的病理生理学相关。此外，来自ENEIDA登记处IBD患者的DNA样本被用于测试CD5（rs2241002和rs2229177）和CD6（rs17824933、rs11230563和rs12360861）单核苷酸多态性与CD（n=1352）和UC（n=1013）的易感性和临床参数的相关性。广义线性回归分析显示CD5变异与CD回肠部位（rs2241002CC）和生物治疗需求（rs2241002C-rs2229177T杂合子）以及UC不良预后（rs2241002T-rs2229177T杂合子）相关。至于CD6，观察到其与CD回肠部位（rs17824933G）和不良预后（rs12360861G）相关，以及与UC左侧或广泛受累以及IBD中强直性脊柱炎的缺失（rs17824933G）相关。目前的实验和遗传证据支持CD5和CD6表达和变异在IBD的临床表现和治疗需求中的作用，为该疾病的病理生理学提供了见解，并扩大了免疫调节受体在免疫介导疾病中的相关性。