Gastric Mucosa-associated Lymphoid Tissue Research Articles

Mouse Models for Assessing the Protective Efficacy of Lactobacillus gasseri SBT2055 against Helicobacter suis Infection Associated with the Development of Gastric Mucosa-Associated Lymphoid Tissue Lymphoma.

Helicobacter suis strain TKY infection has been strongly associated with the development of gastric mucosa-associated lymphoid tissue (MALT) lymphoma in a C57BL/6J mouse model. 1. C57BL/6J mice were intragastrically administered Lactobacillus strains once daily with 10(8)-10(9) colony-forming units (CFU), starting 2 days before intragastric infection with H. suis TKY (approximately 1 × 10(4) copies of 16S rRNA genes) or H. pylori Sydney strain 1 (SS1; 3 × 10(8) CFU) and continuing for 14 days after infection. 2. C57BL/6J mice were given powdered feed mixed with lyophilized L. gasseri SBT2055 (LG2055) cells (5 × 10(8) CFU/g), starting 2 weeks before intragastric infection with H. suis TKY and continuing 12 months after infection. 1. Among the 5 Lactobacillus strains that we examined, only LG2055 exhibited significantly preventive efficacy against both H. suis TKY and H. pylori SS1 at day 15 after infection. 2. Dietary supplementation with LG2055 protected mice from the formation of round protrusive lesions in the gastric fundus 12 months after infection with H. suis TKY, whereas such lesions had developed in the gastric fundus of nonsupplemented mice 12 months after infection. In addition, the formation of lymphoid follicles in gastric mucus layers was suppressed by dietary LG2055 at 3 months after infection. LG2055 administration is effective for suppressing the progression of gastric MALT lymphoma by reducing H. suis colonization.

Corrigendum: Immunoglobulin Gene Repertoire Diversification and Selection in the Stomach – From Gastritis to Gastric Lymphomas

Chronic gastritis is characterized by gastric mucosal inflammation due to autoimmune responses or infection, frequently with Helicobacter pylori. Gastritis with H. pylori background can cause gastric mucosa-associated lymphoid tissue lymphoma (MALT-L), which sometimes further transforms into diffuse large B-cell lymphoma (DLBCL). However, gastric DLBCL can also be initiated de novo. The mechanisms underlying transformation into DLBCL are not completely understood. We analyzed immunoglobulin repertoires and clonal trees to investigate whether and how immunoglobulin gene repertoires, clonal diversification, and selection in gastritis, gastric MALT-L, and DLBCL differ from each other and from normal responses. The two gastritis types (positive or negative for H. pylori) had similarly diverse repertoires. MALT-L dominant clones (defined as the largest clones in each sample) presented higher diversification and longer mutational histories compared with all other conditions. DLBCL dominant clones displayed lower clonal diversification, suggesting the transforming events are triggered by similar responses in different patients. These results are surprising, as we expected to find similarities between the dominant clones of gastritis and MALT-L and between those of MALT-L and DLBCL.

A Case of Simultaneous Primary Gastric and Duodenal Mucosa-Associated Lymphoid Tissue Lymphoma after Therapeutic Endoscopy

원발성 위 MALT 림프종은 흔하지만 원발성 십이지장 MALT 림프종은 드물며, 위와 십이지장을 동시에 침범한 MALT 림 프종은 매우 드물다. 위와 십이지장의 MALT 림프종의 보고 는 국내와 국외의 증례를 합하여 총 5예에 불과하다. 지금까 지 보고된 증례가 많지 않아 위와 십이지장 MALT 림프종을 동시에 효과적으로 치료할 수 있는 명확한 치료 방침이 없 지만, 저등급 MALT 림프종의 경우에는 첫 치료로 H. pylori 제균을 시도해 볼 수 있고, 추가적으로 항암화학요법 및 방 사선 치료를 고려해 볼 수 있겠다.

Helicobacter pylori-negative gastric mucosa-associated lymphoid tissue lymphomas: A review.

Since Isaacson and Wright first reported on the extra-nodal marginal zone B-cell lymphoma of the stomach in 1983, following studies have clarified many aspects of this disease. We now know that the stomach is the most affected organ by this disease, and approximately 90% of gastric mucosa-associated lymphoid tissue (MALT) lymphomas are related to Helicobacter pylori (H. pylori) infection. This implies that approximately 10% of gastric MALT lymphomas occur independent of H. pylori infection. The pathogenesis of these H. pylori-negative gastric MALT lymphomas remains unclear. To date, there have been several speculations. One possibility is that genetic alterations result in nuclear factor-kappa B (NF-κB) activation. Among these alterations, t(11;18)(q21;q21) is more frequently observed in H. pylori-negative gastric MALT lymphomas, and such translocation results in the synthesis of fusion protein API2-MALT1, which causes canonical and noncanonical NF-κB activation. Another possibility is infection with bacteria other than H. pylori. This could explain why H. pylori eradication therapy can cure some proportions of H. pylori-negative gastric MALT lymphoma patients, although the bacteria responsible for MALT lymphomagenesis are yet to be defined. Recent advances in endoscopy suggest magnifying endoscopy with narrow band imaging as a useful tool for both detecting gastric MALT lymphoma lesions and judging the response to treatment. A certain proportion of H. pylori-negative gastric MALT lymphoma patients respond to eradication therapy; hence, H. pylori eradication therapy could be considered as a first-line treatment for gastric MALT lymphomas regardless of their H. pylori infection status.

Endoscopic Appearances with a High Probability of Positive Biopsy in Follow-up Endoscopy of Gastric Mucosa-associated Lymphoid Tissue Lymphoma

served in 50 cases (21.0%). Tumor positivity was high in ulcerated lesions (2/3, 66.7%), erosion (1/5, 20.0%), discoloration (32/89, 36.0%), mucosal thickening (10/41, 24.4%) and ulcer scars (3/21, 14.3%). Conversely, lesions appearing normal showed low pos- itivity (1/68, 1.5%) and was significantly lower compared with the aforementioned lesions (P<0.001). Conclusions: Endoscopic appearances of depression, discoloration, mucosal thickening and ulcer scars were more likely to have tu- mor cells and should be targeted during follow up for gastric MALT lymphoma. (Korean J Helicobacter Up Gastrointest Res 2015;15:117-123)

Alteration of angiogenesis in Helicobacter heilmannii‐induced mucosa‐associated lymphoid tissue lymphoma: Interaction with c‐Met and hepatocyte growth factor

The hepatocyte growth factor (HGF)/c-Met pathway has attracted attention in the formation of malignant tumors, as HGF secreted from the microcirculatory components as well as residing macrophages has been suggested to act on the c-Met receptors of cancer cells to decrease apoptosis and increase proliferation, invasion, and metastasis. The present study was undertaken to elucidate the interaction of the gastric, hepatic, and pulmonary mucosa-associated lymphoid tissue (MALT) lymphoma induced by Helicobacter heilmannii infection with c-Met and HGF. C57BL/6 female mice, infected with H. heilmannii for 3 months were used. The localization of the HGF, c-Met, and HGF activator immunoreactivities was observed by the indirect immunohistochemical methods. In addition, the effect of c-Met antibody and c-Met inhibitor, PHA-665752, was also investigated. c-Met immunoreactivity was found in the lymphocytes composing the MALT lymphoma, and HGF immunoreactivity was recognized mostly in the endothelial cells and macrophages in the MALT lymphoma. HGFA was localized on mesenchymal cells other than the lymphocytes. The administration of the antibody against c-Met or the c-Met inhibitor to the infected mice induced the significant suppression of hepatic and pulmonary MALT lymphoma, while the gastric MALT lymphoma showed only a tendency to decrease in size, while the active caspase 3 positive cells markedly decreased in the gastric, hepatic, and pulmonary MALT lymphoma after the treatment with the c-Met antibody or the c-Met antagonist. HGF and c-Met pathway were suggested to contribute to the lymphomagenesis in the MALT lymphoma after H. heilmannii infection.

Efficacy of standard triple therapy versus bismuth-based quadruple therapy for eradication of Helicobacter Pylori infection

Helicobacter Pylori is the main cause of gastric ulcer, adenocarcinoma and mucosa-associated lymphoid tissue (MALT) lymphoma. Up to now, different regimens have been used for Helicobacter pylori (H.pylori) eradication to find the most potent and cost-effective regimen with less side effects. The aim of this study was to investigate the efficacy of standard triple therapy versus quadruple therapy for eradication of H. pylori. In a randomized clinical trial, 110 patients with H.pylori infection were randomly assigned into two groups of triple or quadruple therapy. The first group received standard triple therapy regimen with clarithromycin, amoxicillin and omeprazole and the second group received bismuth-based quadruple therapy regimen. At the end of study, stool antigen assay was used to confirm H.pylori eradication. The mean age of patients was 41.58 ± 11.98 years and 50.9% of them were male. Side effects of treatment with triple therapy were observed in 49.1% of cases. H.pylori eradication rate with triple and quadruple therapy regimen was 54.5% and 72.7% respectively but the difference was not statistically significant.Results showed that the efficacy of triple therapy was comparable to that of bismuth-based quadruple therapy regimen. However, due to the better compliance of triple therapy regimen, it is recommended for the first line treatment. Quadruple therapy could be used as an alternative treatment when triple therapy fails.

Limited role of bone marrow aspiration and biopsy in the initial staging work-up of gastric mucosa-associated lymphoid tissue lymphoma in Korea.

Background/AimsThe aim of this study was to investigate the frequency of disseminated gastric mucosa-associated lymphoid tissue (MALT) lymphoma and the role of bone marrow study in the initial staging work-up.MethodsA total of 194 patients with gastric MALT lymphoma was enrolled. The incidence of disseminated disease was evaluated in the initial staging work-up. The demographic data and tumor characteristics were compared according to Helicobacter pylori infection status.ResultsLocalized disease of Lugano stage I accounted for 97.4% of the enrolled cases. Abdominal computed tomography revealed abdominal lymph node metastasis in five patients (2.6%). Bone marrow (BM) involvement was found in only one patient without H. pylori infection (0.5%). No patient showed positive findings on chest computed tomography or positron emission tomography. H. pylori-negative cases showed a significantly higher frequency of advanced-stage disease than H. pylori-positive cases (10.0% vs 0.6%). In patients achieving complete remission, no extragastric recurrence occurred during follow-up.ConclusionsThe incidence of disseminated disease, including BM involvement, was very low in Korean gastric MALT lymphoma patients. It might be beneficial to perform BM aspiration and biopsy as a part of staging work-up only in patients with risk factors for advanced disease such as H. pylori negativity.

The emerging role of dendritic cells in the host immune response against Helicobacter pylori.

The emerging role of dendritic cells in the host immune response against Helicobacter pylori.

Gastric Mucosa-Associated Lymphoid Tissue (MALT Lymphoma) and Immunoglobulin IgM Kappa Gammopathy: Is There an Association?

Introduction: A 58-year-old man with no significant history presented with progressive dyspnea and weight loss over the past 6 months. He also complained of intermittent nose bleeds and diarrhea for 2 months. On physical exam he was febrile to 38.4 C, tachycardic, tachypneic, and had mild tenderness to palpation in the epigastric region. Significant laboratory work up revealed a normocytic hemoglobin of 11.5 gm/dL, total protein of 9.1, albumin of 2.7, and globulin of 6.4 gm/dL. Further work-up revealed paraprotenemia with elevated IgM levels to 5,880 mg/dL with normal IgA and IgG. Serum protein immunofixation revealed a monoclonal gammopathy of the IgM Kappa type at 895 mg/dl. Urine protein immunofixation found monoclonal-free kappa light chains. Computed tomography of the abdomen demonstrated marked thickening of the stomach with splenomegaly, left adrenal enlargement, and retroperitoneal adenopathy. The patient underwent an endoscopic evaluation and gastric biopsies which confirmed a small B cell lymphoma consistent with gastric MALT lymphoma. Cytogenetic analysis demonstrated a translocation (11:18), confirming the diagnosis. Interestingly, Helicobacter pylori stains were negative. A thorough literature review revealed several studies finding an association between monoclonal gammopathies and ‘extragastric’ MALT lymphoma. As such, up to one-third of patients with extragastric MALT lymphoma also have monoclonal gammopathy, though, IgM gammopathy is not exceedingly rare in extragastric MALT lymphoma, an elevated IgM level is extremely rare in gastric MALT lymphoma with only one Korean case report in the literature. The findings of monoclonal IgM Kappa gammopathy are most often associated with Waldenström’s macroglobulinemia (WM). It is important to distinguish the two as the treatment of WM differs greatly from the treatment of MALT lymphoma. Extensive literature review on this topic found that hypergammopathy is associated with a more difficult to treat extragastric MALT lymphoma as well as distant metastasis. Thus, it has been suggested that paraprotein analysis be done routinely in the staging of MALT lymphoma along with monitoring of IgM levels to monitor therapeutic response. It is not known if this therapeutic response can be found in gastric MALT lymphoma. Our patient will be followed with serial IgM levels to see if the same response to treatment occurs. We highlight in this case report the rare finding of IgM kappa gammopathy and gastric MALT lymphoma, which has not been extensively described in the literature.

Genetic polymorphisms and tissue expression of interleukin-22 associated with risk and therapeutic response of gastric mucosa-associated lymphoid tissue lymphoma.

Chronic Helicobacter pylori-stimulated immune reactions determine the pathogenesis of gastric mucosa-associated lymphoid tissue (MALT) lymphoma. We aimed to explore the genetic predisposition to this lymphoma and its clinical implication. A total of 68 patients and 140 unrelated controls were genotyped for 84 single-nucleotide polymorphisms in genes encoding cytokines, chemokines and related receptors that play important roles in T cell-mediated gastrointestinal immunity. Five genotypes in IL-22, namely CC at rs1179246, CC at rs2227485, AA at rs4913428, AA at rs1026788 and TT at rs7314777, were associated with disease susceptibility. The former four genotypes resided in the same linkage disequilibrium block (r2=0.99) that conferred an approximately threefold higher risk. In vitro experiments demonstrated that co-culturing peripheral mononuclear cells or CD4+ T cells with H. pylori stimulated the secretion of interleukin-22 (IL-22), and that IL-22 induced the expression of antimicrobial proteins, RegIIIα and lipocalin-2, in gastric epithelial cells. Furthermore, patients with gastric tissue expressing IL-22 were more likely to respond to H. pylori eradication (14/22 vs 4/19, P<0.006). We conclude that susceptibility of gastric MALT lymphoma is influenced by genetic polymorphisms in IL-22, the product of which is involved in mucosal immunity against H. pylori and associated with tumor response to H. pylori eradication.

Is a test of cure necessary after completing therapy for Helicobacter pylori?

Evidence-Based Answer A test of cure using a urea breath test is accurate at least 4 weeks after completion of therapy for H pylori infection (SOR: B, cohort studies). However, it is not clear which patients should undergo a test of cure. It may be considered in patients with H pylori-associated ulcer, persistent dyspeptic symptoms after H pylori treatment, current or treated gastric carcinoma or mucosa-associated lymphoid tissue (MALT) lymphoma, and in patients living in areas of high antibiotic resistance (SOR: C, expert opinion).

Interferon-γ-producing B cells induce the formation of gastric lymphoid follicles after Helicobacter suis infection.

Helicobacter (H.) suis is capable of infecting various animals including humans, and H. suis infections can lead to gastric mucosa-associated lymphoid tissue (MALT) lymphoma. Recently, we reported that interferon-γ (IFN-γ) was highly expressed in the stomachs of H. suis-infected mice, but the direct relationship between the upregulation of IFN-γ expression and the formation of gastric lymphoid follicles after H. suis infection remains unclear. Here, we demonstrated that the IFN-γ produced by B cells plays an important role in the formation of gastric lymphoid follicles after H. suis infection. In addition, IFN-γ-producing B cells evoked gastric lymphoid follicle formation independent of T-cell help, suggesting that they are crucial for the development of gastric MALT induced by Helicobacter infection.

Helicobacter pylori: A Brief History of a Still Lacking Vaccine

Helicobacter pylori colonizes the gastric mucosa of more than half of the human population worldwide. Soon after its discovery, the causative relationships between H. pylori infection and chronic atrophic gastritis, peptic ulcer and gastric mucosa-associated lymphoid tissue lymphoma were evidenced. Then, a significantly increased risk of developing gastric cancer was found to be associated with H. pylori infection. The efficacy of the treatment for H. pylori, based on a proton pump inhibitor plus antibiotics, has dropped below 80%, mainly due to antibiotic resistance. Vaccination would overcome antibiotic resistance and would lead to the eradication of this pathogen; however, in spite of almost twenty-five years of investigation on H. pylori vaccine candidates and good protective results obtained in animal models, no vaccine is currently licensed. This review focuses on the studies on the efficacy of those H. pylori vaccine candidates that underwent clinical trials. Efficacy trials have given unsatisfactory results, so far, with bacterial colonization remaining unaffected by vaccination. However, a vaccine able to counteract H. pylori-induced diseases, such as gastric cancer, even without providing sterilizing immunity, could be considered valuable.

Late-onset sarcoidosis in a patient with gastric mucosa-associated lymphoid tissue non-Hodgkin lymphoma: A case report.

The simultaneous presence of hematological malignancies and sarcoidosis, defined as sarcoidosis-lymphoma syndrome, has been reported in 79 patients in the literature to date. The majority of these patients were affected by sarcoidosis and developed non-Hodgkin lymphoma or acute leukemia after 1–2 years; however, in <20 cases the malignancy developed first. This report presents the case of an 83-year-old male with a clinical history of Helicobacter pylori-positive gastric mucosa-associated lymphoid tissue lymphoma. The patient developed sarcoidosis 10 years after the first diagnosis, which caused the diagnostic work-up and differential diagnosis between a lymphoma relapse and de novo sarcoidosis to be challenging.

Neonatal Thymectomy Favors Helicobacter pylori–Promoted Gastric Mucosa-Associated Lymphoid Tissue Lymphoma Lesions in BALB/c Mice

Neonatal thymectomy in BALB/c mice has been described as a model of gastric mucosa-associated lymphoid tissue (MALT) lymphoma (GML). By using this experimental system, we screened, for the first time to our knowledge, Helicobacter pylori GML-associated strains for their capacity to promote disease. A cohort of BALB/c mice underwent thymectomy at day 3 after birth (d3Tx). Successful thymic ablation was evaluated by the degree of lymphopenia in blood samples collected at 4 weeks of age. d3Tx and non-thymectomized controls were infected with either GML strains (B38 or B47) or control strains (SS1 or TN2GF4). Gastric samples collected at 6, 12, and 18 months after infection were studied for bacteria content, and submitted to histological, immunochemical, molecular, and immunological analyses. Severe gastric inflammation was only observed in d3Tx mice. In these animals, the gastric lamina propria was infiltrated with lymphoid cells organized in follicles composed of B cells with few infiltrating T cells. PCR of D/J IgH gene segments proved the monoclonality of infiltrating B cells, which strongly correlated withthe presence of lymphoepithelial lesions. B-cell infiltrates were particularly prominent in mice infected with the B47-GML strain. No pathological changes were detected in noninfected d3Tx mice. We identified new H. pylori isolates adapted to the mouse stomach with high potential of GML development, which is only revealed in hosts rendered lymphopenic by neonatal thymic ablation.

Immunoglobulin gene repertoire diversification and selection in the stomach - from gastritis to gastric lymphomas.

Chronic gastritis is characterized by gastric mucosal inflammation due to autoimmune responses or infection, frequently with Helicobacter pylori. Gastritis with H. pylori background can cause gastric mucosa-associated lymphoid tissue lymphoma (MALT-L), which sometimes further transforms into diffuse large B-cell lymphoma (DLBCL). However, gastric DLBCL can also be initiated de novo. The mechanisms underlying transformation into DLBCL are not completely understood. We analyzed immunoglobulin repertoires and clonal trees to investigate whether and how immunoglobulin gene repertoires, clonal diversification, and selection in gastritis, gastric MALT-L, and DLBCL differ from each other and from normal responses. The two gastritis types (positive or negative for H. pylori) had similarly diverse repertoires. MALT-L dominant clones (defined as the largest clones in each sample) presented higher diversification and longer mutational histories compared with all other conditions. DLBCL dominant clones displayed lower clonal diversification, suggesting the transforming events are triggered by similar responses in different patients. These results are surprising, as we expected to find similarities between the dominant clones of gastritis and MALT-L and between those of MALT-L and DLBCL.

Helicobacter pylori and t(11;18)(q21;q21) translocation in gastric malt lymphoma.

Gastric mucosa-associated lymphoid tissue (MALT) lymphoma is clearly associated with Helicobacter pylori gastritis and can be cured with anti- H pylori therapy alone. The presence of t(11;18)(q21;q21) translocation is thought to predict a lower response rate to anti- H pylori treatment. To study the presence of t(11;18)(q21;q21) genetic translocation and its clinical impact in low-grade gastric MALT lymphoma Brazilian patients. A consecutive series of eight patients with gastric MALT lymphoma were submitted to gastroscopy, endoscopic ultrasound, histopathological examination, H pylori search and RT-PCR-based methodology. All patients received anti-H pylori treatment. Eradicated patients were followed-up every 3-6 months for 2 years. Eight patients were studied. All patients had tumor involvement restricted to the mucosa or submucosa and seven patients had low-grade gastric MALT lymphoma. All infected patients achieved H pylori eradication. Histological tumor regression was observed in 5/7 (71%) of the low-grade gastric MALT lymphoma patients. The presence of t(11;18)(q21;q21) translocation was found in 4 (57%) of these patients; among them only two had histological tumor regression following H pylori eradication. RT-PCR is a feasible and efficient method to detect t(11;18)(q21;q21) translocation, being carried out in routine molecular biology laboratories. The early detection of such translocation can be very helpful for better targeting the therapy to be applied to gastric MALT lymphoma patients.

Association of helicobacter pylori CagA translocation with the expression of CagA-signaling transduction molecules in gastric mucosa-associated lymphoid tissue lymphoma.

8571 Background: We previously reported that a direct contact of Helicobacter pylori (HP) with B cells results in CagA translocation into the latter, and the translocated CagA regulates intracellul...

Animal models for the study of Helicobacter pylori infection

The Gram-negative bacillus Helicobacter pylori is widely recognized as a major etiologic agent responsible for chronic active gastritis, peptic ulcers, the development of gastric cancer and mucosa-associated lymphoid tissue (MALT lymphoma). Still, little is known about the natural history of H. pylori infection, since patients usually after many years of not suffering from symptoms of the infection are simply asymptomatic. Since the research investigators carried out on human models has many limitations, there is an urgent need for the development of an animal model optimal and suitable for the monitoring of H. pylori infections. This review summarizes the recent findings on the suitability of animal models used in H. pylori research. Several animal models are useful for the assessment of pathological, microbiological and immunological consequences of infection, which makes it possible to monitor the natural history of H. pylori infection. Preclinical investigations on animal models are an essential stage of research which enrich the knowledge on treatment and prevention strategies.