幽门螺杆菌泛表位的HLA-DR限制性优势应答谱学特征及其与疾病转归相关性研究

Helicobacter pylori infects more than half of the world's population. The infection is causally linked to chronic gastritis, peptic ulcer, gastric adenocarcinoma, and gastric mucosa-associated lymphoid tissue lymphoma. Antigen-specific CD4+ T lymphocytes play a important role in the development of different H. pylori infection-associated gastrointestinal diseases. Studies in humans, rhesus macaques and mice have shown increased gastric T-cell infiltration in situ with a typical T-helper (Th)1 phenotype during H pylori infection. Immunodominance is a phenomenon in which cellular immune responses reproducibly focus on one or a few epitopes, even during immune responses to complex microorganisms or antigens. The immunodominant T cells are believed to be more effective and play a central role in the host adaptive immunity against pathogens. In our previous studies, we identified and characterized several immunodominant CD4+ T-cell epitopes derived from H. pylori HpaA. The immunodominant CD4+ T-cell responses specific to HpaA88-100 were observed in most H pylori-infected individuals who expressed HLA-DRB1*1501 and were significantly more abundant in patients with less severe diseases. Furthermore, we found that epitope HpaA88-100 was Pan HLA-DR- binding T-helper epitope (PADRE), which could be processed and presented by combination with other HLA-DR molecules beside HLA-DR*1501. So basing this found, we will investigate HLA-DR restriction map and repetoire of immunodominant CD4+ T-cell responses to promiscuous epitopes (HpaA88-100) in H. pylori-infected patients. According to HLA-DR restriction map, the correlationship between PADRE-specific CD4 T cell responses and different gastrointestinal diseases will be studied. This research will be helpful to understand the pathogenetic mechanism of chronic H. pylori infection and be useful in epitope-based vaccine design.

幽门螺杆菌（Hp）慢性感染可导致胃炎、胃溃疡等不同胃肠疾病，而特异性CD4+ T细胞应答在疾病转归中发挥重要作用。本课题前期研究发现：在HLA-DR*1501基因型慢性胃炎患者中，Hp粘附素（HpaA）抗原中显性表位HpaA88-100特异性CD4+ T细胞应答较其他类型胃肠疾病患者更为优势，可能与疾病发生密切相关。此外，表位HpaA88-100不仅具有HLA-DR*1501限制性特征，还可通过其他HLA-DR分子进行抗原递呈，由此判定HpaA88-100是一个泛HLA-DR限制性表位（PADRE）。本项目将围绕泛表位HpaA88-100，以Hp慢性感染患者为对象，开展泛表位HLA-DR限制性谱系及其特异性CD4+ T细胞优势应答谱学特征与作用机制研究，并揭示其优势应答谱学特征与疾病转归的相关性，为深入认识Hp慢性感染的致病机制提供新的解析，对抗Hp感染的免疫防治具有重要的指导意义。

幽门螺杆菌（Hp）慢性感染可导致胃炎、胃溃疡等不同胃肠疾病，而特异性CD4+ T细胞应答在疾病转归中发挥重要作用。本项目针对Hp慢性感染人群，描绘出泛表位（PADRE）的HLA-DR限制性谱系及其特异性CD4+ T淋巴细胞优势应答谱，结果显示：HpaA88-100特异性CD4+ T细胞阳性应答均为HLA-DR限制性，分别为HLA-DRB1*1501、HLA-DRB1*1305、HLA-DRB1*1202、HLA-DRB1*0101、HLA-DRB1*0901、HLA-DRB1*0301。在HLA-DRB1*1501基因型的感染人群分析中发现，泛表位HpaA88-100特异性CD4+ T细胞优势应答频率为35.3%，总体优势应答频率为41.2%。在非HLA-DRB1*1501的Hp感染人群中，泛表位HpaA88-100特异性CD4+ T细胞出现优势应答频率为9.52%，亚优势应答频率为3.57%，总体优势应答频率为13.1%。综合分析，在101例Hp感染人群中，泛表位HpaA88-100的优势应答频率约为10%，总体优势应答频率为26.7%。泛表位HpaA88-100特异性CD4+ T细胞均具有免疫记忆表型特征，分泌高水平IFN-r，且高表达归巢受体L选择素和α4β7整合素。针对泛表位HpaA88-100的优势应答谱学特征与不同类型胃肠疾病发生的相关性分析结果显示：HpaA88-100特异性CD4+ T细胞应答在不同类型胃肠疾病中存在显著差异。慢性胃炎患者的应答水平显著高于消化性溃疡和胃癌患者；慢性胃炎患者中非萎缩性胃炎患者的特异性应答显著高于萎缩性胃炎，胃窦炎患者显著高于全胃胃炎；消化性溃疡患者中十二指肠溃疡患者的特异性应答显著高于胃溃疡。上述结果提示HpaA88-100特异性CD4+ T细胞应答水平与Hp感染相关性胃肠疾病的严重程度呈负相关关系，可能发挥一定的免疫保护作用。上述研究结果为深入认识Hp慢性感染的致病机制提供新的解析，对抗Hp感染的免疫防治具有重要的指导意义。