Biomarkers for Inflammatory Bowel Disease Behavior and Treatment Response

项目摘要：IBD可能有几种免疫遗传形式，CD和UC代表 最广泛的临床分类。虽然治疗方法在过去十年中有所增加，但我们的能力 针对特定患者亚群的更新的生物疗法已经落后。我们最近的研究 已经表明，GM-CSF自身抗体(GM-CSF Ab)升高的CD患者患 进行性疾病需要手术，中性粒细胞抗菌功能在这一亚型中降低 病人。我们假设：1)升高的GM-CSF抗体将预示着复杂疾病风险的增加 2)GM-CSF Ab水平是一个家族特征；3)GM-CSF Ab通过以下途径抑制中性粒细胞功能 抑制GM-CSF生物活性。我们将在以下目标中检验这些假设：目标1.验证GM- 脑脊液抗体对CD行为的预测作用中和性GM-CSF抗体的血清浓度将为 在CD患者的前瞻性队列中确定，并与疾病行为有关。这些数据将决定 中和GM-CSF抗体是否会增加需要手术的复杂CD行为的风险 目前的血清标志物和治疗方法。目的2.测定血清GM-CSF抗体水平的遗传度。 受累和未受累的一级亲属血清GM-CSF抗体浓度测定 CD患者与GM-CSF的类内相关系数及家族聚集性估计 AB将被确定。这些数据将决定中和GM-CSF抗体是否作为一种 受CARD15和IRGM基因多态影响的数量性状。目的3.检测GM-CSF抗体 中性粒细胞功能的调节。将测定血清GM-CSF抗体浓度并与之相关 基础和GM-CSF依赖的中性粒细胞STAT3/5激活、细胞存活和抗菌功能 包括CD11b的激活、黏附、吞噬、微生物杀伤和氧化爆发。这些数据将 确定GM-CSF抗体是否抑制中性粒细胞STAT5的激活和抗菌功能，而 促进STAT3活化和细胞存活。

Project Summary: It is likely that there are several immunogenetic forms of IBD, with CD and UC representing the broadest clinical classifications. While therapeutic options have increased over the past decade, our ability to target newer biologic therapies to specific subgroups of patients has lagged behind. Our recent studies have shown that CD patients with elevated GM-CSF auto-antibodies (GM-CSF Ab) are at high risk for progressive disease requiring surgery, and that neutrophil antimicrobial functions are reduced in this subset of patients. We hypothesize that: 1) elevated GM-CSF Ab will predict increased risk for complicated disease and surgery; 2) GM-CSF Ab level is a familial trait; and 3) GM-CSF Ab suppress neutrophil function by inhibiting GM-CSF bioactivity. We will test these hypotheses in the following Aims: Aim 1. Validate GM- CSF Ab antibody prediction of CD behavior. The serum concentration of neutralizing GM-CSF Ab will be determined in a prospective cohort of CD patients and related to disease behavior. These data will determine whether neutralizing GM-CSF Ab increase risk for complicated CD behavior requiring surgery, relative to current serologic markers and therapies. Aim 2. Determine the heritability of serum GM-CSF Ab levels. The serum concentration of GM-CSF Ab will be determined in affected and unaffected first degree relatives of index CD patients and the intra-class correlation coefficient and estimate of familial aggregation for GM-CSF Ab will be determined. These data will determine whether neutralizing GM-CSF Ab are inherited as a quantitative trait influenced by CARD15 and IRGM genetic polymorphisms. Aim 3. Examine GM-CSF Ab regulation of neutrophil function. The serum concentration of GM-CSF Ab will be determined and related to basal and GM-CSF dependent neutrophil STAT3/5 activation, cell survival, and antimicrobial functions including CD11B activation, adhesion, phagocytosis, microbial killing, and oxidative burst. These data will determine whether GM-CSF Ab suppress neutrophil STAT5 activation and antimicrobial function, while promoting STAT3 activation and cell survival.