Elucidation of pathophysiology for various digestive diseases

本研究试图阐明幽门螺杆菌引起的胃炎、自身免疫性胰腺炎(AIP)和炎症性肠病(IBD)的病理生理机制，并获得以下结果。(1)在人类中，胃溃疡患者具有Th1为主的免疫应答，而十二指肠溃疡患者更倾向于Th2应答。此外，在MALT淋巴瘤患者中，Th2反应显著。(2)在小鼠中，Hp感染引起的典型Th1型菌株C57Black小鼠出现严重胃炎，而典型Th2型菌株Balb/c小鼠未见胃炎。另一方面，通过胸腺切除，C57黑鼠的严重胃炎消失，Balb/c小鼠出现MALT淋巴瘤。此外，对于MALT淋巴瘤B细胞的体外生长，除了幽门螺杆菌的存在外，幽门螺杆菌特异性T细胞和外周血树突状细胞是必不可少的。(3)利用自身免疫性胰腺炎患者血清中抗CAII抗体或抗乳铁蛋白抗体阴性但血清免疫球蛋白滴度较高的患者的血清，确定胰酶抑制物可作为自身免疫性胰腺炎患者自身抗体的候选靶点。(4)IBD患者血清抗分枝杆菌抗体滴度明显高于正常人，提示副结核分枝杆菌感染参与了IBD的病理生理过程。(5)CMV和EBV感染均参与IBD的病理生理过程，对IBD患者结肠病变部位和非病变部位的CMV基因拷贝数进行检测和比较，对诊断IBD患者CMV感染具有重要意义。(6)IBD的发生与上皮屏障通透性异常和上皮再生异常有关。因此，给予生长因子，如碱性成纤维细胞生长因子，以促进上皮细胞的修复，似乎是治疗IBD的有效方法。

In this study, we tried to elucidate pathophysiology of H.pylori-induced gastyritis, autoimmune pancreatitis (AIP) and inflammatory bowel disease (IBD) all of which involve immunological responses, and the following results were obtained. (1)In human, patients with gastric ulcer had Th1-predominant immunological response, whereas patients with duodenal ulcer were more polarized to Th2 response. Moreover, in patients with MALT lymphoma, Th2 reaction was remarkable. (2)In mice, severe gastritis developed by HP infection in C57black mice, a typical Th1-type strain, whereas no gastritis could be observed in Balb/c mice, a typical Th2-type strain. On the other hand, by thymectomy, severe gastritis seen in C57black mice disappeared and MALT lymphoma developed in Balb/c mice. Moreover, for MALT lymphoma B cell growth in vitro, in addition to HP presence of HP specific T cells and peripheral blood DC were essential. (3)By using serum of the patient who was negative for anti CAII antibody or anti-lactoferin but with high serum IgG titer, we identified pancreatic trypsin inhibitor as a candidate target for autoantibody in patients with autoimmune pancreatitis. (4)In patients with IBD, serum titiers for anti-Mycobacterium antibody was significantly higher than normal subjects, and involvement of Mycobacterium paratuberculosis infection in pathophysiology of human IBD was suggested. (5)Moreover, involvement of CMV as well as EBV infection in the pathophysiology of IBD was also suggested, and importance of measurement of and comparison of copy numbers of CMV gene in both affected and non-affected colonic site for diagnosis of CMV infection in patients with IBD was indicated. (6)For development of IBD, abnormality of permeability of epithelial barrier and that of regeneration of the epithelium were found to be involved. Accordingly, administration of growth factors such as bFGF, that enhances repair of epithelial cells appeared to be effective for the treatment of IBD.