Induction of gastric immune response and development of gastric MALT lymphoma by Helicobacter pylori infection.

幽门螺杆菌感染诱导胃免疫反应和胃 MALT 淋巴瘤的发展。

• 批准号: 14570463
• 负责人: OKAZAKI Kazuichi
• 金额: $ 2.18万
• 依托单位: Kansai Medical University (2003)Kyoto University (2002)
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14570463/
• 关键词: Helicobacter pylori; MALT lymphoma; Th1; Th1 immunity; dendritic cell

In the present study, we developed gastric MALT lymphoma-like lesions in nTx mice by long-term H. pylori infection, and performed immunogenetic analyses. BALB/c mice were thymectomized on the 3rd day after birth. Follicle formation occurred after 2 months of H.pylori infection in the nTx mice. Follicle formation and infiltration of intraepithelial lymphocytes progressed in a time -dependent manner. Lymphoepithelial lesions, a characteristic feature of MALT lymphoma, also occurred in a time-dependent manner(100% at 12 months). Serum immunoelectrophoresis revealed a monoclonal band(M-protein) in 30%(3/10) of mice 6 months after infection. M-protein-positive mice had amplification of one or two IgM and/or IgG heavy-chain genes in the gastric B lymphocytes, as determined with polymerase chain reaction, suggesting mono-or oligoclonality. Overexpression of Bcl-X(L) protein was immunohistologically observed in the infiltrating B lymphocytes and in some follicular B lymphocytes in 80%(8/10) of … More the cases at 12 months. We also investigated the distribution of DC subsets using this model and examined their roles. To identify lymphoid and myeloid DCs, sections were stained with anti-CD11c(pan-DC marker) in combination with anti-CD8alpha(lymphoid DC marker) or anti-CD11ib(myeloid DC marker) and were examined with a con focal microscope. Expression of macrophage inflammatory protein 3alpha(MIP-3alpha), which chemoattracts immature DCs, was analyzed by real-time PCR and immunohistochemistry. Follicular dendritic cells(FDCs) were stained with anti-SKY28 antibodies. In noninfected nTx mice, a few myeloid and lymphoid DCs were observed in the bottom portion of the lamina propria, whereas in H. pylori-infected nTx mice, there was an increased influx of myeloid DCs throughout the lamina propria. FDC staining was also observed in the stomachs of members of the infected group. MIP-3alpha gene expression was upregulated in the infected nTx group, and the immunohistochemistry analysis revealed MIP-3alpha-positive epithelial cells. These data suggest that H. pylori infection upregulates MIP-3alpha gene expression in gastric epithelial cells and induces an influx of myeloid DCs in the lamina propria of the gastric mucosa in nTx mice. Myeloid DCs and FDCs might contribute to the development of gastric secondary lymphoid follicles in H. pylori-infected nTx mice. Most gastric mucosa-associated lymphoid tissue(MALT) lymphomas are caused by Helicobacter pylori(H.pylori) infection. Less

在本研究中，我们通过长期幽门螺杆菌感染，在 nTx 小鼠中形成了胃 MALT 淋巴瘤样病变，并进行了免疫遗传学分析。 BALB/c小鼠在出生后第3天进行胸腺切除。 nTx 小鼠感染幽门螺杆菌 2 个月后出现滤泡形成。滤泡形成和上皮内淋巴细胞浸润以时间依赖性方式进行。淋巴上皮病变是 MALT 淋巴瘤的一个特征，其发生也具有时间依赖性（12 个月时为 100%）。感染后6个月，血清免疫电泳显示30%（3/10）的小鼠出现单克隆带（M蛋白）。通过聚合酶链式反应测定，M 蛋白阳性小鼠的胃 B 淋巴细胞中存在 1 或 2 个 IgM 和/或 IgG 重链基因扩增，表明单克隆或寡克隆。 12 个月时，80% (8/10) 的病例在浸润 B 淋巴细胞和一些滤泡 B 淋巴细胞中观察到 Bcl-X(L) 蛋白过度表达。我们还使用该模型研究了 DC 子集的分布并检查了它们的作用。为了鉴定淋巴和髓系 DC，将切片用抗 CD11c（泛 DC 标记）与抗 CD8α（淋巴 DC 标记）或抗 CD11ib（髓系 DC 标记）结合染色，并用共焦显微镜检查。通过实时 PCR 和免疫组织化学分析了巨噬细胞炎症蛋白 3α（MIP-3α）的表达，该蛋白对未成熟的 DC 进行化学吸引。滤泡树突状细胞（FDC）用抗 SKY28 抗体染色。在未感染的 nTx 小鼠中，在固有层的底部观察到一些骨髓和淋巴 DC，而在幽门螺杆菌感染的 nTx 小鼠中，整个固有层的髓系 DC 流入增加。在感染组成员的胃中也观察到 FDC 染色。感染nTx组的MIP-3α基因表达上调，免疫组织化学分析显示MIP-3α阳性上皮细胞。这些数据表明，幽门螺杆菌感染上调胃上皮细胞中的 MIP-3α 基因表达，并诱导 nTx 小鼠胃粘膜固有层中髓样 DC 的流入。骨髓 DC 和 FDC 可能有助于幽门螺杆菌感染的 nTx 小鼠胃次级淋巴滤泡的发育。大多数胃粘膜相关淋巴组织（MALT）淋巴瘤是由幽门螺杆菌（H.pylori）感染引起的。较少的

项目成果

Matsushima y, Kinoshita Y, Fukui H, Maekawa T, Yazumi S, Okada A, Nakase H, Kawanami C, Iwano M, Hashimoto K, Takeda Z, Okazaki K, Chiba T.: "Immunological and molecular analysis of B lymphocytes in low-grade MALT lymphoma of the stomach. -Are there any u

Matsushima y、Kinoshita Y、Fukui H、Maekawa T、Yazumi S、Okada A、Nakase H、Kawanami C、Iwano M、Hashimoto K、Takeda Z、Okazaki K、Chiba T.：“低水平 B 淋巴细胞的免疫学和分子分析

Fukui T, Okazaki K, et al.: "Immunogenetic analysis of gastric MALT lymphoma-like lesions induced by Helicobacter pylori infection in neonatally thymectomized mice."Lab Invest.. 84・4. 485-492 (2004)

Fukui T, Okazaki K, et al.：“新生胸腺切除小鼠中幽门螺杆菌感染诱导的胃 MALT 淋巴瘤样病变的免疫遗传学分析。”Lab Invest.. 84・4 (2004)。

Okazaki K, Chiba T.: "Leadingarticle. Autoimmune related pancreatitis."Gut. 51. 1-4 (2002)

冈崎 K、千叶 T.：“领先文章。自身免疫相关胰腺炎。”肠道。

Nakase H, Okazaki K, Tabata Y, Chiba T: "Biodegradable microspheres targeting mucosal immune-regulating cells : New approach for treatment of inflammatory bowel disease."J Gastroenterol. 59-62 (2003)

Nakase H、Okazaki K、Tabata Y、Chiba T：“针对粘膜免疫调节细胞的可生物降解微球：治疗炎症性肠病的新方法。”J Gastroenterol。

Fukui T, Okazaki K, Tamaki H, Kawasaki K, Matsuura M, Asada M, Nishi T, Uchida K, Iwano M, Ohana M, Hiai H, Chiba T: "Immuno-genetic analysis of gastric MALT lymphoma-like lesions induced by Helicobacter pylori infection in neonatally thymectomized mice."

Fukui T、Okazaki K、Tamaki H、Kawasaki K、Matsuura M、Asada M、Nishi T、Uchida K、Iwano M、Ohana M、Hiai H、Chiba T：“胃 MALT 淋巴瘤样病变的免疫遗传学分析