Immunogenetic analysis of gastric MALT lymphoma-like lesions induced by Helicobacter pylori infection in neonatally thymectomized mice

Abstract

Most gastric mucosa-associated lymphoid tissue (MALT) lymphomas are caused by Helicobacter pylori (H. pylori) infection. We previously reported that acquired lymphoid follicles with germinal centers were induced by H. pylori infection in neonatally thymectomized (nTx) mice. 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. At 6 weeks of age, mice were orally infected with 10 8 H. pylori and serially killed 2, 4, 6, and 12 months later. Normal BALB/c and noninfected nTx mice served as controls. 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 the cases at 12 months. Thus, H. pylori infection is involved in the development of gastric MALT lymphoma-like lesions in nTx mice. Our mouse model is useful for clarifying the pathogenetic mechanism of gastric MALT lymphoma by H. pylori infection.

“ Candidatus Helicobacter heilmannii” from a Cynomolgus Monkey Induces Gastric Mucosa-Associated Lymphoid Tissue Lymphomas in C57BL/6 Mice

“…Enno et al reported observing H. felis-associated gastric MALT lymphomas in normal BALB/c mice, and they found lymphoepithelial lesions in 88% of the animals and lymph follicles in 38% of the animals 22 months after infection (6). Fukui and colleagues reported observing H. pylori-associated gastric MALT lymphomas in neonatally thymectomized BALB/c mice, and they found lymph follicles and lymphoepithelial lesions in 60% of the mice in the absence of Bcl-X immunoreactivity (9). In addition, Bcl-X-immunoreactive cells were found in these mice 6 and 12 months later.…”

“…In animal models, MALT lymphomas have been reported following infection with Helicobacter mustelae in ferrets (7), following infection with Helicobacter felis in normal BALB/c mice (6), following infection with H. pylori in neonatally thymectomized BALB/c mice (9), and following infection with "Candidatus Helicobacter heilmannii" in normal BALB/c mice (19,21). In this study, we used the "Candidatus Helicobacter heilmannii" previously obtained from a cynomolgus monkey to infect C57BL/6 mice for up to 24 months.…”

Helicobacter felis-induced gastritis was suppressed in mice overexpressing thioredoxin-1

“…Sections were stained with hematoxylineosin for histopathology and May-Giemsa for assessment of H. felis colonization. 18 The degree of gastritis was determined using the scoring system as described previously. 19 Chronic inflammation, characterized by infiltration of mononuclear cells, was graded from 0 to 3, where 0 ¼ no increase in the number of inflammatory cells, 1 ¼ slight infiltration of the lamina propria by lymphocytes and plasma cells, 2 ¼ moderately dense infiltration of the lamina propria by lymphocytes and plasma cells, 3 ¼ very dense lymphoplasma-cell infiltration in the lamina propria.…”

Host factors are important in determining clinical outcomes of Helicobacter pylori infection

“…Indeed, C57/ black mice, a representative Th1-predominant strain, develop severe corpus gastritis, 34 whereas Balb/c mice, a Th2-predominant strain, never develop gastritis although of the mouse strains examined, they have the highest level of H. pylori colonization in their gastric mucosa. 35 Moreover, when we perform neonatal thymectomy in these mice to inhibit the development of CD25-positive inhibitory T cells, the development of gastritis in C57/black mice is greatly reduced, whereas most Balb/c mice develop MALT lymphoma [35][36][37][38] (Fig. 4).…”

“…Indeed, among various mouse strains, only Balb/c mice thymectomized 3 days after birth developed MALT lymphoma following H. pylori infection. [35][36][37][38]59 In the gastric mucosa of those mice, in addition to IFN-γ expression, IL4 expression, which has never been observed in H. pylori-induced gastritis, was detected. 35,38 The Balb/c mouse is a typical Th2-predominant strain, and thymectomy enhances the autoimmune reaction by inhibiting the development of CD25 inhibitory CD4 T cells.…”