Pathology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt.
Pathology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt; Al Maarefa University, Riyadh, Saudi Arabia.
Pathol Res Pract. 2020 Oct;216(10):153102. doi: 10.1016/j.prp.2020.153102. Epub 2020 Jul 8.
Neutrophil extracellular traps (NETs) are incriminated in several immune and inflammatory diseases including ulcerative colitis (UC). Analysis of colonic tissues for NETs-related markers in UC carries prognostic and therapeutic implications. This work aims to evaluate the immunohistochemical (IHC) expression of NETs-associated-protein arginine deaminase 4 (PAD4) in colonic biopsies from UC patients in comparison to normal colon (NC). Association between PAD4 expression level and histopathologic grade, patient's therapeutic response and other clinicopathological prognostic predictors in UC are determined. This cohort study included biopsies from 42 UC patients and 11 NC controls. Clinicopathological data including patient's age at diagnosis, gender, presenting symptoms, anatomical disease extent, extra-intestinal manifestations, type and response to therapy and surgical interventions were recorded and tabulated. Histopathological grading of disease activity and associated epithelial changes were assessed. PAD4 immunostaining was conducted using Horseradish Peroxidase technique and scored semiquantitatively considering intensity and percentage of nuclear staining of lamina propria inflammatory cells. Appropriate statistical tests were applied. Anti-PAD4 was localized mainly in the nuclei of lamina propria infiltrating neutrophils. It was expressed more significantly in UC (95.2 %) compared to NC (p 0.001). Increased PAD4 expression level was significantly associated with increasing histopathologic grade, anatomical disease extent, lacking response to therapy and subjection to radical surgery (p:0.001, = 0.038, 0.046, 0.046 respectively). Age, gender, presenting symptoms, extra-intestinal manifestations and epithelial changes showed insignificant associations. This study characterizes a subset of UC patients with high histopathological grade of activity, pancolonic involvement, strong/moderate PAD4 expression levels and who are unresponsive to routine medical therapeutic regimens rendering them candidates for radical surgery. In conjunction with histopathological grading, IHC evaluation of PAD4 in UC is recommended to guide patient's selection for targeted therapy using the novel-discovered selective PAD4 inhibitors.
中性粒细胞胞外诱捕网（NETs）与几种免疫和炎症性疾病有关，包括溃疡性结肠炎（UC）。分析 UC 患者结肠组织中的 NETs 相关标志物具有预后和治疗意义。本研究旨在评估 UC 患者结肠活检组织中 NETs 相关蛋白精氨酸脱氨酶 4（PAD4）的免疫组织化学（IHC）表达，并与正常结肠（NC）进行比较。确定 PAD4 表达水平与 UC 患者的组织病理学分级、患者的治疗反应以及其他临床病理预后预测因素之间的关系。这项队列研究包括 42 例 UC 患者和 11 例 NC 对照的活检组织。记录并列出了包括患者诊断时的年龄、性别、首发症状、解剖疾病范围、肠外表现、治疗类型和反应以及手术干预等临床病理数据。评估了疾病活动和相关上皮变化的组织病理学分级。使用辣根过氧化物酶技术进行 PAD4 免疫染色，并根据固有层炎症细胞的核染色强度和百分比进行半定量评分。应用了适当的统计检验。抗 PAD4 主要定位于固有层浸润中性粒细胞的核内。与 NC 相比，UC 中表达更为显著（p<0.001）。PAD4 表达水平增加与组织病理学分级增加、解剖疾病范围增加、对治疗无反应和接受根治性手术显著相关（p=0.001，=0.038，0.046，0.046 分别）。年龄、性别、首发症状、肠外表现和上皮变化与 PAD4 表达水平无关。本研究描述了一组 UC 患者，其具有高组织病理学活动分级、全结肠受累、强/中度 PAD4 表达水平且对常规医学治疗方案无反应，使其成为根治性手术的候选者。结合组织病理学分级，建议在 UC 中使用 IHC 评估 PAD4，以指导使用新发现的选择性 PAD4 抑制剂进行靶向治疗的患者选择。
