Biomarkers for Inflammatory Bowel Disease Behavior and Treatment Response

项目总结：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。虽然在过去的十年里，治疗选择增加了，但我们的能力 针对特定亚组患者的新生物疗法已经落后。我们最近的研究 已经表明，具有升高的GM-CSF自身抗体（GM-CSF Ab）的CD患者具有高风险， 进行性疾病，需要手术，和中性粒细胞抗菌功能降低，在这一子集的 患者我们假设：1）GM-CSF抗体升高将预测并发症的风险增加 和手术; 2）GM-CSF Ab水平是一种家族特征; 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。通用电气- CD行为的CSF Ab抗体预测。中和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相关。这些数据将决定 中和GM-CSF Ab是否会增加需要手术的复杂CD行为的风险，相对于 目前的血清学标志物和治疗。目标二。测定血清GM-CSF Ab水平的遗传度。 将在受影响和未受影响的一级亲属中测定GM-CSF Ab的血清浓度。 指标CD患者和GM-CSF的组内相关系数和家族聚集性估计 AB将被确定。这些数据将确定中和GM-CSF抗体是否作为一种遗传因素遗传。 数量性状受CARD 15和IRGM遗传多态性的影响。目标3.检查GM-CSF抗体 调节中性粒细胞功能。将测定GM-CSF Ab的血清浓度，并将其与 基础和GM-CSF依赖性中性粒细胞STAT 3/5活化、细胞存活和抗菌功能 包括CD 11B活化、粘附、吞噬作用、微生物杀灭和氧化爆发。这些数据将 确定GM-CSF Ab是否抑制中性粒细胞STAT 5活化和抗微生物功能， 促进STAT 3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.