Relation of Helicobacter heilmannii infection to gastric MALT lymphoma formation in human and mouse

1.建立小鼠MALT淋巴瘤模型，电子显微镜下可见MALT淋巴瘤组织中有丰富的微血管网络，由未成熟的毛细血管和小静脉组成。免疫组织化学分析显示，在整个MALT淋巴瘤组织中，VEGF-A免疫反应明显增强，而VEGF-C免疫反应仅见于淋巴瘤的边缘区域。Flt-1和Flk-1在淋巴瘤组织中均有表达。Flk-1主要表达于未成熟的内皮细胞，而Flt-1主要表达于积聚的淋巴细胞。经血管内皮生长因子受体单抗治疗后，隆起性病变明显缩小。综上所述，血管内皮生长因子介导的机制在HH感染诱导的C57BL/6小鼠MALT淋巴瘤组织的生长中起重要作用。12例MALT淋巴瘤中4例Hp阳性，5例HHLO阳性，其中4例HHLO和Hp双阳性。经Fisher‘s精确检验，HHLO感染及Hp和HHLO混合感染与MALT淋巴瘤显著相关。对9例HHLO阳性患者进行尿素酶基因分析，发现4例为HS感染，另1例未检出HH、HS或HF。原位杂交法在HH的表面上皮细胞和胃底腺细胞包括壁细胞附近识别出HH，这与我们以前用C57BL/6小鼠进行的感染研究结果一致。另一方面，在221例非MALT淋巴瘤患者中，129例Hp阳性，仅4例HHLO阳性。

1. Mouse Modelthe MALT lymphoma tissue was shown to have rich microvascular network consisting of the immature capillaries and venules, revealed by electron microscopy. By the immunohistochemical analysis, very much enhanced VEGF-A immunoreactivity was observed in the whole MALT lymphoma tissue, while VEGF-C immunoreactivity was observed only in the marginal area of the lymphoma. Both Flt-1 and Flk-1 were expressed in the lymphoma tissues. Flk-1 were mainly expressed in the immature endothelial cells, while Flt-1 were observed in the accumulated lymphocytes. The treatment with VEGF receptor monoclonal antibody significantly decreased the size of the protrusive lesion. In conclusion, VEGF-mediated mechanism was shown to play an important role in the expansion of the MALT lymphoma tissue induced by Hh infection in C57BL/6 mice.2. Human Casesout of 12 MALT lymphoma cases 4 cases were positive to Hp, 5 positive to HHLO and among them 4 cases were doubly positive to HHLO and Hp. By Fisher's exact test, HHLO infection as well as Hp and HHLO co-nfection was significantly related to the MALT lymphoma. By the analysis of urease gene, 4 cases were found to belong to Hs 'infection among 9 HHLO positive patients, while other cases were not identified to either Hh, Hs or Hf. By the in situ hybridization method, the Hh was recognized near the surface epithelial cells and fundic glandular cells including parietal cells, which coincided well with our previous infection study using C57BL/6 mice. On the other hand, 129 cases were positive to Hp and only 4 cases were positive to HHLO out of 221 non-MALT lymphoma cases. In conclusion, HHLO and Hp coinfection has shown to be closely related to MALT lymphoma in Japanese cases.