Malignant lymphoma and Helicobacter pylori infection

Lymphoid tissue is acquired in the stomach in response to antigenic stimulation, so called mucosa-associated lymphoid tissue(MALT). In 1983, Isaacson had named a type of malignant B-cell lymphoma "MALT lymphoma" which grow in the marginal zone of lymphoid foliclies in the gastric mucosa. MALT lymphoma has lately attracted attention because of the relation of Helicobacter pylori(H. pylori). There are several studies that H. pylori can be detected in more than 90% of patients with MALT lymphoma and cure of H. pylori infection is followed by a complete regression of these tumors in most patient. This paper reviews the current knowledge about MALT lymphoma, and immunological and molecular aspects in the pathogenesis of the disease.     

VacA and HP-NAP, Ying and Yang of Helicobacter pylori-associated gastric inflammation

Helicobacter pylori is a Gram-negative bacterium which infects almost half of the population worldwide and represents the major cause of gastroduodenal pathologies, such as duodenal and gastric ulcer, gastric cancer, B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) and autoimmune gastritis. H. pylori colonization is followed by infiltration of the gastric mucosa by polymorphonuclear cells, macrophages and lymphocytes. Two of the major H. pylori virulence factors are the vacuolating cytotoxin (VacA) and the H. pylori neutrophil-activating protein (HP-NAP). VacA has been proposed as a modulator of immune cell function because of its capacity to interfere with antigen presentation and to inhibit T-cell activation. HP-NAP was designated as neutrophil-activating protein because it stimulates high production of oxygen radicals from neutrophils. We have recently demonstrated that HP-NAP is able to recruit leukocytes in vivo and to stimulate either neutrophils or monocytes to release IL-12, a key cytokine for the differentiation of naive Th cells into the Th1 phenotype. Altogether these evidences indicate that both VacA and HP-NAP play a major role in generating and maintaining the gastric inflammatory response associated with the H. pylori infection.     

胃黏膜相关淋巴组织淋巴瘤幽门螺杆菌分离株与胃炎分离株的转录组比较

目的本研究对胃黏膜相关淋巴组织淋巴瘤（MALT淋巴瘤）幽门螺杆菌分离株与胃炎分离株的转录组进行比较，以阐述胃MALT淋巴瘤幽门螺杆菌分离株的转录组特征。方法对2株分离自胃MALT淋巴瘤的菌株与胃炎菌株26695的转录组进行比较。结果胃MALT淋巴瘤幽门螺杆菌分离株之间转录组非常相似，而与胃炎菌株26695之间差异较大。 对差异表达基因进行GO功能富集分析，结果显示富集基因数前5位的为催化活性、代谢进程、细胞进程、结合、单组织进程。 Pathway显著性富集分析表明差异基因的功能主要参与氨基酸和核苷酸糖代谢、卟啉和叶绿素代谢以及乙醛和二羧酸代谢。结论胃MALT淋巴瘤幽门螺杆菌相关菌株可能通过代谢调控菌体生长和侵染宿主，从而在胃MALT淋巴瘤形成过程中发挥着重要作用。     

Helicobacter pylori: why it still matters in 2005

Despite falling prevalence rates in the developed world, H pylori is still present in the United States and is particularly prevalent among racial minorities and recent immigrants. H pylori infection is clearly associated with an increased risk of peptic ulcer disease, gastric cancer, and MALT lymphoma, and it is associated with some cases of uninvestigated dyspepsia. Identification and eradication of H pylori improves outcomes in patients with peptic ulcer disease and causes tumor regression in patients with MALT lymphoma. It is uncertain whether H pylori eradication will improve outcomes in patients with gastric cancer. Decision analytic models suggest that a test-and-treat strategy for H pylori is rational and cost-effective for patients with uninvestigated dyspepsia.     

Involvement of the CD95 (APO-1/Fas) receptor and ligand system in Helicobacter pylori-induced gastric epithelial apoptosis.

Helicobacter pylori infection is associated with chronic gastritis, peptic ulceration, and gastric carcinoma. The potential role of CD95-mediated apoptosis was investigated in a panel of gastric biopsies obtained from patients with H. pylori-associated chronic gastritis (n = 29) and with noninfected normal mucosa (n = 10). Immunohistochemistry revealed increased CD95 receptor expression in epithelial and lamina propria cells in chronic gastritis. By in situ hybridization, CD95 ligand mRNA was absent or low in normal mucosa but expressed at high levels in lamina propria lymphocytes and, unexpectedly, in epithelial cells in chronic gastritis. Apoptotic cells were rare in normal mucosa but were observed regularly in chronic gastritis in close proximity to CD95 ligand mRNA expression throughout the epithelial and lamina propria cells. In a functional analysis gastric epithelial cell lines were incubated with supernatants of H. pylori. Treatment with the cytotoxic isolate H. pylori 60190 but not with the noncytotoxic isolate Tx30a upregulated CD95 in up to 50% of gastric epithelial cells and induced apoptosis in these cells. H. pylori-induced apoptosis was partially prevented by blocking CD95, demonstrating the functional role of the CD95 system. These findings suggest that H. pylori-associated chronic gastritis involves apoptosis of gastric epithelial cells by activation of the CD95 receptor and ligand system.     

Helicobacter pylori strikes again: gastric mucosa-associated lymphoid tissue (MALT) lymphoma.

Infection with Helicobacter pylori is common. Over 50% of the world's population is estimated to be colonized with the bacteria. The association between Helicobacter pylori and gastric mucosa-associated lymphoid tissue (MALT) lymphoma is well documented. Anti-Helicobacter pylori treatment and the successful eradication of the bacteria can potentially cure patients who test positive for the bacteria and who are diagnosed with low-grade gastric MALT lymphoma. The purpose of this article is to review the evidence implicating Helicobacter pylori as a causal pathogen for the development of gastric MALT lymphoma and to determine that anti-Helicobacter pylori therapy is an effective first-line treatment. The clinical presentation, endoscopic findings, diagnosis, staging, treatment, and follow-up of patients with gastric MALT lymphoma who are treated with anti-Helicobacter pylori therapy are also discussed.     

Gastric malignant lymphoma

Primary gastric lymphoma is a rare tumor and the frequency is less than 5% of gastric neoplasms. Although the histological diagnosis is diverse, the majority is MALT lymphoma and diffuses large B-cell lymphoma. MALT lymphoma is derived from marginal B-cell of lymphoid follicle, which is induced by Helicobacter pylori infection. The 60-80% of them is regressed by the eradication treatment. A part of MALT lymphoma is characterized by chromosomal translocations, t(11;18), t(1;14) or t(14;18) that is poor response factors to the eradication. Interestingly, all chimeric proteins produced by the translocations have activated NF-kappaB in the cells. The phenotype of diffuse large B-cell lymphoma is heterogeneous. However, the combination treatment of rituximab plus CHOP is effective and it is capable to preserve the stomach. A non-surgical treatment is recommended to gastric lymphoma.     

Virulence gene of H. pylori

H. pylori is a well-recognized pathogen that infects up to 50% of humans in the world. H. pylori lives for decades in the hostile environment of the human stomach. H. pylori is closely associated with histologic gastritis, gastric ulceration, duodenal ulceration, gastric cancer and MALT lymphoma. These various clinical outcomes are considered by 1) different virulence, 2) host response, 3) other environmental factors, and their interactions. Since the whole genome was sequenced in 1997, the virulence genes have been investigated in molecular genetic aspects. The cag pathogenicity island (cagPAI) is a complex of virulence genes, which code approximately 30 proteins. The cagPAI acquired by horizontal transfer and is coding for type 4 secretion machinery system. Via this system, many virulence gene products or other interactive proteins are transferred into the host cells.     

幽门螺杆菌感染对胃粘膜细胞动力学的影响

应用流式细胞技术对Ｈｐ阳性和阴性患者胃粘膜细胞动力学进行对比研究，并以体外培养Ｈｐ所制备的Ｈｐ提取液灌喂大鼠，观察其对大鼠胃粘膜细胞周期的影响。结果表明，Ｈｐ阳性胃粘膜Ｓ期细胞和增殖指数均显著高于Ｈｐ阴性胃粘膜。Ｈｐ提取液可刺激大鼠胃粘膜细胞增殖指数和Ｓ期细胞显著增加。提示Ｈｐ可能通过刺激胃粘膜细胞增殖加速，更新加快，增加ＤＮＡ受损的机会，从而增加患胃癌的危险性。     

Gastric MALT lymphoma in the absence of Helicobacter pylori infection presenting as an upper gastrointestinal hemorrhage

Gastric MALT lymphoma is almost exclusively a sequelae of Helicobacter pylori infection and rarely presents with profuse bleeding. Gastric mucosa is not normally thought to contain lymphoid tissue, yet in the presence of H pylori reactive lymphoid follicles form which are possibly throught to predispose the patient to developing lymphoma. GI bleeding from these tumors is common during treatment as a consequence of tumor regression or necrosis. We present the case of a MALT Lymphoma in a 59 year-old woman manifesting as a brisk upper GI bleed without serologic or microbiologic evidence of an H pylori infection.     

Reactions of humoral and cellular immunity in peptic ulcer in relation to the condition of the gastric mucosa

A total of 160 persons including 50 patients with duodenal ulcer (DU) and 38 with gastric ulcer (GU) were examined for antibodies to the parietal cells of the stomach (PCA) and cell cellular immunity responses to autologous antigen from the gastric mucosa. It was shown that both PCA of the stomach and cell immunity responses in patients with GU and DU occurred in an insignificant number of cases. No differences were revealed in the humoral and cellular immunity in GU and DU persons with and without concomitant gastritis or in the stage of exacerbation and ulcer cicatrization.     

The possible involvement of micro-organisms other than Helicobacter pylori in the development of rectal MALT lymphoma in H. pylori-negative patients

It remains unclear whether lymphoma of the mucosa-associated lymphoid tissue (MALT) in the extragastric organs is related to Helicobacter pylori infection or not. This report describes three patients with rectal MALT lymphoma negative for H. pylori infection, all of whom showed disease regression after being treated with antibiotics. One patient had MALT lymphoma in both the descending colon and the rectum; the other two patients had rectal disease only. None of the patients had chronic gastritis which was detectable either endoscopically or histologically and H. pylori infection was completely ruled out by various methods, including a urease breath test. These patients received antibiotic therapy. In all the patients, regression of MALT lymphoma was observed endoscopically and histologically, and polymerase chain reaction revealed that a previously observed rearranged band of immunoglobulin heavy chain had also disappeared after antibiotic treatment. These cases therefore suggest involvement of micro-organisms other than H. pylori in the development of rectal MALT lymphoma.     

Molecular mimicry between Helicobacter pylori antigens and H+, K+ --adenosine triphosphatase in human gastric autoimmunity

Autoimmune gastritis and Helicobacter pylori-associated gastric atrophy develop through similar mechanisms involving the proton pump H+,K+-adenosine triphosphatase as autoantigen. Here, we report that H. pylori-infected patients with gastric autoimmunity harbor in vivo-activated gastric CD4+ T cells that recognize both H+, K+-adenosine triphosphatase and H. pylori antigens. We characterized the submolecular specificity of such gastric T cells and identified cross-reactive epitopes from nine H. pylori proteins. Cross-reactive H. pylori peptides induced T cell proliferation and expression of T helper type 1 functions. We suggest that in genetically susceptible individuals, H. pylori infection can activate cross-reactive gastric T cells leading to gastric autoimmunity via molecular mimicry.     

Mucosa-associated lymphoid tissue (MALT) lymphoma

OBJECTIVES: To review the pathogenesis of MALT lymphoma, and the associations with antigenic stimulation, presentation, and unique treatment. DATA SOURCES: Research and review articles and textbooks. CONCLUSION: MALT lymphoma is a heterogeneous but unique pathologic form of extranodal B-cell non-Hodgkin's lymphoma. The gastrointestinal tract is the most common site of disease, but involvement of multiple other organ systems has been reported. In the case of gastric MALT lymphomas, H. pylori has been highly implicated as the stimulating agent. Treatment strategies for early disease involve eradication of H. pylori when it is involved and/or radiotherapy, which alone may result in cure of this lymphoma. Chemotherapy is used in more advanced or resistant disease. IMPLICATIONS FOR NURSING PRACTICE: Nurses play a significant role in the education of patients about this unique malignancy and follow-up regarding compliance with therapy. Attention to social needs of the patients is critical.     

Guidelines for the management of Helicobacter pylori--Maastricht III-2005 and Japanese guidelines

The guidelines on the management of Helicobacter pylori were updated at the European Helicobacter study group third Maastricht consensus conference in March 2005. Especially, this conference emphasis on the management of non ulcer dyspepsia, GERD, and the patients who use non steroidal anti-inflammatory drug. Eradication of H. pylori is recommended in patients with peptic ulcer, low grade MALT lymphoma, atrophic gastritis, unexplained iron deficiency anemia, chronic idiopathic thrombocytopenic purpura and first degree relatives of patients with gastric cancer. H. pylori eradication is less effective than proton pomp inhibitor(PPI) treatment in preventing ulcer recurrence in long term NSAIDs users. This meeting also emphasized on the relationship between H. pylori and gastric cancer. The guideline concluded that H. pylori eradication has the potential to reduce the risk of gastric cancer development. Japanese guideline in 2003 does not mention the effect of eradication for prevention of gastric cancer. The H. pylori eradication and new strategy should be desirable for global strategy of gastric cancer prevention.     

Autoantibodies against heat shock protein 60 mediate endothelial cytotoxicity.

Stress or heat shock proteins (hsp) are a family of approximately two dozen proteins with a high degree of amino acid sequence homology between different species, ranging from prokaryotes to humans, and are representative of a generalized response to environmental and metabolic stressors. Our previous studies showed increased expression of human hsp60 on endothelial cells of arterial intima with atherosclerotic lesions, and elevated levels of serum antibodies (Ab) against hsp65/60 in subjects with carotid atherosclerosis. To investigate the possible involvement of anti-hsp65/60 Ab in endothelial injury, specific hsp-Ab were isolated from human high titer sera by affinity chromatography and probed on heat-shock human umbilical vein endothelial cells. Purified human anti-hsp65/60 Ab reacted specifically with mycobacterial hsp65, human hsp60, and a 60-kD protein band of heat-shocked endothelial cells. High levels of hsp60 mRNA expression in endothelial cells were found between 4 and 12 h after 30 min treatment at 42 degrees C. In immunofluorescence tests, positive staining of heat-stressed endothelial cells was observed not only in the cytoplasm but also on the cell surface. Furthermore, only heat-stressed, but not untreated, Cr-labeled endothelial cells were lysed by anti-hsp65/60 Ab in the presence of complement (complement-mediated cytotoxicity) or peripheral blood mononuclear cells (antibody-dependent cellular cytotoxicity). Control Abs, including human anti-hsp65/60 low titer antiserum, human Ig fraction deprived of hsp65/60 Ab, and mAbs to Factor VIII, alpha-actin, hsp70, and CD3 showed no cytotoxic effect. In conclusion, human serum anti-hsp65 antibodies act as autoantibodies reacting with hsp60 on stressed endothelial cells and are able to mediate endothelial cytotoxicity. Thus, a humoral immune reaction to hsp60 may play an important role in the pathogenesis of atherosclerosis.     

Helicobacter pylori CagA protein can be tyrosine phosphorylated in gastric epithelial cells

Attachment of Helicobacter pylori to gastric epithelial cells induces various cellular responses, including the tyrosine phosphorylation of an unknown 145-kD protein and interleukin 8 production. Here we show that this 145-kD protein is the cagA product of H. pylori, an immunodominant, cytotoxin-associated antigen. Epithelial cells infected with various H. pylori clinical isolates resulted in generation of tyrosine-phosphorylated proteins ranging from 130 to 145 kD in size that were also induced in vitro by mixing host cell lysate with bacterial lysate. When epithelial cells were infected with [(35)S]methionine-labeled H. pylori, a radioactive 145-kD protein was detected in the immunoprecipitates with antiphosphotyrosine antibody or anti-CagA (cytotoxin-associated gene A) antibody. Consistently, the 145-kD protein recognized by the anti-CagA and antiphosphotyrosine antibodies was induced in epithelial cells after infection of wild-type H. pylori but not the cagA::Km mutant. Furthermore, the amino acid sequence of the phosphorylated 145-kD protein induced by H. pylori infection was identical to the H. pylori CagA sequence. These results reveal that the tyrosine-phosphorylated 145-kD protein is H. pylori CagA protein, which may be delivered from attached bacteria into the host cytoplasm. The identification of the tyrosine-phosphorylated protein will thus provide further insights into understanding the precise roles of CagA protein in H. pylori pathogenesis.     

Helicobacter pylori infection and eradication

H. pylori infection is associated with various gastroduodenal diseases such as gastritis, peptic ulcer, gastric cancer, gastric MALT lymphoma. H. pylori infection is suggested that it plays a role as protective factor not promoting factor for reflux esophagitis and GERD. Epidemiological studies showed lower prevalence of H. pylori infection in reflux esophagitis and Barrett's esophagus comparing the control. Increased occurrence of reflux esophagitis after curing of H. pylori infection was reported. However, the relationship between H. pylori infection and reflux esophagitis has not been actually made clear. Also the mechanism of reflux esophagitis occurrence after H. pylori eradication is not obscure.     

Helicobacter pylori and non-Helicobacter pylori bacterial flora in gastric mucosal and tumour specimens of patients with primary gastric lymphoma

There is an association between Helicobacter pylori (H. pylori) and gastric mucosa-associated lymphoid tissue (MALT) and MALT lymphoma. Histologically, mainly non-specific stains are used to detect H. pylori, such as haematoxylin–eosin (HE) or modified Giemsa (MG). In this study, both a MG and a specific immunohistochemical stain (IMM) for H. pylori (Dako B471) were performed on sequential slides of resected material containing tumour and non-tumorous gastric mucosa from patients with primary gastric lymphoma (n = 52). Special attention was paid to the presence of non-H. pylori bacterial flora diagnosed by a positive MG (according to form and localization) and a subsequently negative IMM. On all slides, bacterial density was scored semiquantitatively (grades 0, 1, 2, 3). In total, 32 (61.5%) patients were H. pylori positive using IMM and 34 (65.4%) were non-H. pylori positive using MG. In 24 out of the 34 patients, the non-H. pylori flora consisted mainly of cocci in combination with rods in 15 patients, mostly in minor quantities; in another 10 patients, high numbers of both cocci and different types of rods were present. Most non-H. pylori bacteria were localized superficially, although in 22 patients minor quantities of non-H. pylori were also seen in the glandular lumina. After all of the patients had been analysed, no differences in the density of H. pylori and of non-H. pylori flora were found. Only when comparing patients who had a small-cell lymphoma with those who had a large-cell lymphoma was a significantly higher density of H. pylori found in the corpus mucosa of large-cell lymphomas and a higher prevalence of non-H. pylori was found in tumours, in antrum or corpus, of patients with large-cell lymphomas. In conclusion, with joint evaluation using MG and a H. pylori-specific immunohistochemical stains, the proportion of H. pylori-positive gastric lymphoma patients was lower than in most previous studies but other bacteria were found in a relatively high proportion. The role of the non-H. pylori intragastric bacterial flora identified in this study has to be further elucidated in the aetiopathogenesis of primary gastric lymphoma.     

Treatment of gastric MALT lymphoma by H. pylori eradication

Strong evidence exists for the efficacy of H. pylori eradication in achieving gastric low-grade MALT lymphoma (L-MALT) regression when the bacteria present. Besides histological evaluation, the appearance of endoscopic finding such as 'discolored mucosa-like atrophy' after treatment may be useful for the prediction of its outcome (endoscopic evaluation). However, a reliable marker for molecular evaluation is not obtained so far. On the other hand, long-term control of L-MALT with H. pylori eradication therapy is uncertain and there still remains a subset of patients with no evidence of H. pylori or who fail H. pylori eradication therapy. Therefore, the optimal non antibiotic therapy for these patients has been studied. According to the recent report, radiation therapy appears to be well tolerated and effective for patients with gastric L-MALT.