FAM26F protein: Innate regulator of Type 3 immune responses

对无害共生细菌的耐受性和对病原体的保护之间平衡的破坏会导致肠道炎症和炎症性肠病(IBD)的发展，IBD是溃疡性结肠炎(UC)和克罗恩病(CD)的常见名称。在英国，大约每250人中就有1人感染IBD。目前的治疗方法(手术或免疫抑制/免疫调节)并不总是有效的，可能会引起严重的副作用。因此，需要新的治疗方法，但这种治疗方法的合理开发需要新的靶点识别和验证。最近的全基因组关联研究将几个基因的多态与UC联系起来。其中一个位于新描述的基因FAM26F(具有序列相似性的家族26，成员F)的调控区。活动期UC患者黏膜组织中FAM26F的表达较正常对照组明显增加。FAM26F还预测类风湿性关节炎(RA)的皮质类固醇疗法的结果，这种疗法也用于治疗UC患者。为了了解FAM26F的功能，我们建立了FAM26F缺陷小鼠，发现FAM26F控制与UC疾病进展相关的炎性细胞因子的诱导，以及T辅助(Th17)T细胞反应的指令。我们现在寻求支持，以UC为模型，阐明FAM26F的作用机制及其临床意义。我们还发现了FAM26F缺陷的人类，这将使我们能够将在老鼠身上的发现直接转化为人类。实现这些目标将产生更好地管理和治疗UC或其他Th17相关疾病所需的新的治疗靶点和/或生物标记物。

Breakdown in the balance between tolerance to harmless commensal bacteria and protection against pathogens leads to intestinal inflammation and development of inflammatory bowel disease (IBD), which is the common name for ulcerative colitis (UC) and Crohn's disease (CD). IBD affects approximately 1 in every 250 people in the UK. Current treatments (surgery or immunosuppression/immunomodulation) are not always effective and may cause serious side effects. Thus, new therapies are needed, but rational development of such therapies requires new target identification and validation. Recent genome-wide association studies (GWAS) have linked several gene polymorphisms with UC. Amongst these is one in the regulatory region of a newly described gene called FAM26F (Family with sequence similarity 26, member F). FAM26F expression is increased in the mucosa of patients with active UC compared to healthy controls. FAM26F also predicts the outcome of corticosteroid therapy in rheumatoid arthritis (RA), the therapy that is also used to treat UC patients. To understand FAM26F function, we have generated FAM26F-deficient mice and found that FAM26F controls the induction of inflammatory cytokines, which are associated with UC disease progression, and instruction of T helper (Th17) T cell responses. We now seek support to elucidate the mechanism of FAM26F function and its clinical significance, using UC as a model. We have also identified FAM26F-deficient humans, which will allow us to directly translate findings made in mice to humans. Achieving these objectives will generate new therapeutic targets and/or biomarkers needed to better manage and treat UC or other Th17-linked diseases.