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

在本研究中，我们在长期幽门螺杆菌感染的nTx小鼠中发生胃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。感染幽门螺杆菌2个月后，nTx小鼠出现卵泡形成。卵泡的形成和上皮内淋巴细胞的浸润以时间依赖性的方式进行。淋巴上皮病变是MALT淋巴瘤的一个特征性特征，也以时间依赖性的方式发生（12个月时100%）。感染6个月后，血清免疫电泳显示30%（3/10）小鼠出现单克隆带（m蛋白）。经聚合酶链反应测定，m蛋白阳性小鼠胃B淋巴细胞中有一个或两个IgM和/或IgG重链基因扩增，提示单克隆或寡克隆。在浸润性B淋巴细胞和部分滤泡性B淋巴细胞中，80%（8/10）的患者免疫组织学观察到Bcl-X(L)蛋白过表达。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。为了鉴定淋巴细胞和髓细胞DC，切片采用抗cd11c（泛DC标记）联合抗cd8alpha（淋巴细胞DC标记）或抗cd11ib（髓细胞DC标记）染色，并在共焦显微镜下检查。通过实时荧光定量PCR和免疫组织化学分析巨噬细胞炎性蛋白3α (mip - 3α)的表达。用抗sky28抗体染色滤泡树突状细胞（FDCs）。在未感染的nTx小鼠中，在固有层底部观察到少量髓系和淋巴系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。感染组成员的胃也观察到FDC染色。感染nTx组MIP-3alpha基因表达上调，免疫组化分析显示MIP-3alpha阳性上皮细胞。这些数据表明，幽门螺杆菌感染可上调胃上皮细胞中mip -3 α基因的表达，并诱导nTx小鼠胃黏膜固有层内涌入髓系dc。髓系dc和fdc可能促进幽门螺杆菌感染的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。螺杆菌感染)。少

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