Gastric stump MALT lymphoma: a case report and review of the literature

Gastric stump lymphoma is uncommon. We report a case of MALT lymphoma of the gastric stump occurring in a 65 year-old male. This patient had undergone subtotal gastrectomy for a gastric peptic ulcer at age 51. Histologic findings in the initial gastric specimen showed follicular gastritis with Helicobacter Pylori. This previous gastric surgery cured the ulceration but did not remove the Helicobacter Pylori infection that led to the development of gastric lymphoma.     

Gastric MALT lymphoma, clinical features

Gastric mucosa associated lymphoma (MALT) can be regarded as a pathogenetic continuum of reactive B lymphocyte accumulation due to Helicobacter pylori infection, which after a series of mutation may presumably transform into a low grade and later on into a high grade MALT lymphoma. If the lymphoma is confined to the mucosa or strictly to the superficial part of gastric wall, a conventional, regular Helicobacter pylori eradication procedure has a good chance to bring about clinical, histological and less frequently molecular biological remission as well.     

Progress in vaccination against Helicobacter pylori

This review discusses recent progress in the development of a vaccine against Helicobacter pylori. This progress includes demonstration that: effective immunisation is independent of antibodies but dependent upon CD4+ T helper cells, although their role remains unknown; the immunisation regime can be improved to increase efficacy; successful immunisation against H. pylori is possible using a live vector; a strain of H. pylori suitable for experimental infection of humans has been developed. Important issues that remain to be addressed include incomplete protection, non-availability of suitable mucosal adjuvants and post-immunisation gastritis. Significantly, commercial development of products for clinical trial is underway.     

Regression of gastric MALT lymphoma after eradication of Helicobacter pylori infection followed by endoscopic ultrasound

The authors report a case of a 42 year-old female patient, who was admitted with epigastric pain and weight loss to our department. Upper gastrointestinal endoscopy two ulcerated lesions revealed in the stomach at the corpus-antrum border. Histologically the lesion proved to be a low grade, malignant B cell MALT lymphoma. Coexistent Helicobacter pylori infection was detected with modified Giemsa staining. Endoscopic ultrasonography was performed to determine the depth of tumorous infiltration of the gastric wall: the tumor was confined to the mucosa and submucosa. No regional lymph node was observed. As a result of successful Helicobacter pylori eradication the regression of MALT lymphoma occurred. The follow-up examinations showed the regression of the tumour and the patient became asymptomatic. A control ultrasonographic examinations demonstrated the normal five layers structure of the gastric wall without any alteration. In our patient Helicobacter pylori eradication was an effective therapy for gastric MALT lymphoma as well. Our results similar as are published in the literature. Endoscopic ultrasonography is very useful in the assessment of the tumours involvement of the gastric wall. In the proper follow-up examinations of the patient endoscopy, histology and endoscopic ultrasound together are the methods to apply including Helicobacter pylori control.     

Serum-derived IgG1-mediated immune exclusion as a mechanism of protection against H. pylori infection

The induction of protective immunity against Helicobacter challenge in a murine model was found to correlate with the magnitude of IgG (serum and gastric lavage) responsiveness to intra-nasal (i.n.) immunisation. IgG1-secreting hybridoma backpacks in Helicobacter pylori (H. pylori)-infected mice revealed serum transudation into the stomach. A Lpp20-specific monoclonal antibody was associated with significantly reduced H. pylori colonisation. Histology revealed aggregates of the remaining H. pylori in these mice, suggesting a role for IgG1-mediated immune exclusion of the bacteria. In vitro immunogold electron microscopy supported this hypothesis, but also suggested that a threshold of H. pylori-specific antibody needs to be maintained if immune exclusion by the host is to overcome immune evasion by the bacteria.     

不同职业和地区人群幽门螺杆菌感染的调查情况

幽门螺杆菌（helicobacter pylori,Hp）是上消化道疾病常见的致病因素,与慢性胃炎、消化性溃疡、胃黏膜相关淋巴组织淋巴瘤及胃癌有密切关联。Hp感染已经成为一个重要的公共卫生问题,也是近年来国内外消化病的热点研究内容。Hp感染多与职业因素、地区环境、生活饮食习惯、经济条件等方面有关,在不同国家、地区、人群中感染率存在明显差异。总结Hp感染的职业、地区分布特点,加强健康宣教,有针对性地开展Hp检测,并对Hp感染者进行合理的治疗干预,可以减少消化系统疾病的发病率,降低医疗成本,减少医疗费用,促进全民健康,对个人、家庭、社会都是很有意义的。作者就近年来不同职业、不同地区Hp的感染情况作一综述。     

Diagnostic methods for Helicobacter pylori infection in children

A Helicobacter pylori infection is usually acquired during early childhood. Poor socioeconomic circumstances form an important risk factor for this. An untreated infection may lead to peptic ulceration and, particularly in adults, to gastric cancer and mucosa associated lymphoid tissue (MALT) lymphoma. The gold standard for the diagnosis of H. pylori infection is gastroscopy with histology and culture of biopsy specimens. Non-invasive tests are serology, 13C-urea breath test and stool antigen test. The sensitivity and specificity of serology tests are low in children, but for both the 13C-urea breath test and the stool antigen test the sensitivity and specificity are high. A 'test and treat' approach is advised with due consideration for possible symptoms and the risk for peptic ulcers and gastric cancer at a more advanced age. The treatment results must be evaluated. If necessary, young children can be treated at a later age.     

Immunization with a recombinant fusion protein protects mice against Helicobacter pylori infection

More than 50% of the world's population is infected with the bacterium Helicobacter pylori. If left untreated, infection with H. pylori can cause chronic gastritis and peptic ulcer disease, which may progress into gastric cancer. Owing to the limited efficacy of anti-H. pylori antibiotic therapy in clinical practice, the development of a protective vaccine to combat this pathogen has been a tempting goal for several years. In this study, a chimeric gene coding for the antigenic parts of H. pylori FliD, UreB, VacA, and CagL was generated and expressed in bacteria and the potential of the resulting fusion protein (rFUVL) to induce humoral and cellular immune responses and to provide protection against H. pylori infection was evaluated in mice. Three different immunization adjuvants were tested along with rFUVL: CpG oligodeoxynucleotides (CpG ODN), Addavax, and Cholera toxin subunit B. Compared to the control group that had received PBS, vaccinated mice showed significantly higher cellular recall responses and antigen-specific IgG2a, IgG1, and gastric IgA antibody titers. Importantly, rFUVL immunized mice exhibited a reduction of about three orders of magnitude in their stomach bacterial loads. Thus, adjuvanted rFUVL might be considered as a promising vaccine candidate for the control of H. pylori infection.     

Heat shock protein complex vaccination induces protection against Helicobacter pylori without exogenous adjuvant

Background

The development of a vaccine against the human gastric pathogen Helicobacter pylori, the main causative agent of gastric adenocarcinoma, has been hampered by a number of issues, including the lack of a mucosal adjuvant for use in humans. Heat shock proteins (Hsp), highly conserved molecules expressed by both bacteria and mammalian species, possess a range of functions, including acting as chaperones for cellular proteins and the ability to activate innate immune receptors. Hsp complex (HspC) vaccines, containing Hsp derived from pathogenic bacteria, are immunostimulatory without addition of an exogenous adjuvant and can induce immunity against their chaperoned proteins. In this study we explored in mice the potential utility of a H. pylori HspC vaccine.

Results

Vaccination with H. pylori HspC, by either the subcutaneous or respiratory mucosal route, induced a strong antibody response, elevated gastric cytokine levels and significant protection against subsequent live challenge with this pathogen. The level of protection induced by non-adjuvanted HspC vaccine was equivalent to that which resulted from vaccination with adjuvanted vaccines. While protection induced by immunisation with adjuvanted vaccines was associated with the development of a moderate to severe atrophic gastritis, that induced by H. pylori HspC only resulted in a mild inflammatory response, despite an increase in pro-inflammatory gastric cytokines. This reduced gastritis correlated with an increase in IL-10 and IL-13 levels in the gastric tissues of HspC vaccinated, H. pylori challenged mice.

Conclusions

H. pylori HspC vaccines have the potential to overcome some of the issues preventing the development of a human vaccine against this pathogen: HspC induced protective immunity against H. pylori without addition of an adjuvant and without the induction of a severe inflammatory response. However, complete protection was not obtained so further optimisation of this technology is needed if a human vaccine is to become a reality.     

Chimeric flagellin as the self-adjuvanting antigen for the activation of immune response against Helicobacter pylori

Helicobacter pylori infection can cause gastritis, peptic ulcer and can lead to gastric cancer. Lengthy antibiotic therapy does not protect the host against reinfection. H. pylori evolved to evade the recognition of the immune response by modifying several of its components whose orthologous proteins from other bacteria activate the innate immune response. Flagella are essential for the H. pylori effective colonization of human duodenum and stomach. TLR5, a member of the Toll-like receptor family, recognizes flagellin of most bacteria, such as Escherichia coli, but does not recognize the flagellin FlaA of H. pylori. We restored the ability of FlaA for the recognition by TLR5 by engineering a chimeric flagellin, in which both terminal segments of H. pylori flagellin were replaced by the corresponding segments from TLR5-activating E. coli flagellin. Recombinant chimeric flagellin folded correctly and was able to activate TLR5. Significantly increased serum IgG and IgA antibody responses were determined in mice vaccinated with chimeric flagellin in comparison to mice vaccinated with a control protein (FlaA) or negative control. Antibody titers remained high even 8 months after the last immunization. Antibodies were able to bind native flagellin from H. pylori lysate. Vaccination with chimeric flagellin provided mice with significant protection against H. pylori. The approach of chimeric flagellin can therefore generate effective immunogens that enable activation of innate and adaptive immune response and can be used to construct efficient vaccines against H. pylori or other flagellated bacteria that evade TLR5 recognition.     

Oral immunization with recombinant Helicobacter pylori urease confers long-lasting immunity against Helicobacter felis infection

Recombinant Helicobacter pylori urease (rUre) has been shown to confer protection against challenge with Helicobacter felis in mice. The purpose of the present study was to examine duration of the immune response and long-term protective efficacy of immunization with rUre. Swiss Webster mice were orally immunized four times at weekly intervals with 100 microg rUre plus 5 microg heat-labile enterotoxin of Escherichia coli (LT) adjuvant, or with LT only. At 4, 10, 20 or 40 weeks post immunization, 25 rUre-immunized mice and control mice were challenged with H. felis and sacrificed at 2 or 10 weeks post-challenge. H. felis infection was assessed by gastric urease assay and by histology. Anti-H. pylori urease specific antibody levels were measured in serum and saliva both pre- and post-challenge. Over the 40 week time period, the infection rates in rUre-immunized mice were significantly lower than those in controls (p < 0.05) as assessed by gastric urease activity. Protection ranged from 79 100% at 2 weeks post-challenge and 63-78% at 10 weeks post-challenge. Gastric bacterial density in rUre-immunized mice was significantly lower than that of controls (p < 0.03) as determined by histologic assessment. Anti-urease antibody levels remained elevated in the serum and mucosal compartments at 39 weeks following immunization. This study shows that immunization with rUre plus LT results in long-lasting protective immunity against challenge with H. felis.     

Further development of the Helicobacter pylori mouse vaccination model

Immunisation against Helicobacter infection in mouse models has thus far produced neither complete protection against the bacteria, nor a complete prevention of the associated gastritis. This study aimed firstly to compare the sensitivities of the various methods used to assess H. pylori infection in the mouse model, and secondly to develop the experimental design to induce a more effective immunity, aimed at further reducing bacterial burden in the gastric tissue. Various mouse strains were prophylactically immunised with whole bacterial sonicate and cholera toxin before challenge with H. pylori-SS1. The relative sensitivities of the urease assay, histological assessment and the colony forming assay to detect levels of H. pylori colonisation were compared. Comparisons of different antigen doses and different timecourses of immunisation were performed. The colony forming assay was found to be far more sensitive than either the urease assay or histological assessment for determining the protective efficacies of immunisation. Mice which had 10(5) H. pylori per gram of stomach by colony assay were negative by histology and urease. Lower doses of whole cell sonicate were more protective than high doses and more effective immunisation was achieved by leaving at least 3 weeks between immunisation instead of weekly immunisations. In conclusion, for assessment of H. pylori colonisation in the mouse model, the colony forming assay should be used. The experimental protocol for immunisation has been altered to produce a significant improvement in protection. However, full protection has still not yet been achieved and more work is still required.     

Therapeutic vaccination against HSV-2: influence of vaccine formulation on immune responses and protection in mice

Therapeutic immunisation may represent a means of influencing viral infections that persist in the host by modulating the nature or level of host immunity. To assess the influence of the form of the antigenic stimulus on immunity to type-2 herpes simplex virus (HSV-2), mice pre-infected with sublethal doses of HSV-2 were immunised with various HSV-2 vaccine formulations prior to challenge infection with heterologous HSV-1. Measurements of interleukin-2 (IL-2), interleukin-4 (IL-4) and interferon-gamma (IFN-gamma) levels in mouse spleen cell cultures restimulated in vitro with HSV-2 antigens showed that, depending on the form of HSV-2 antigen preparation used in this therapeutic context, changes in the levels of these cytokines could be effected. Measurement of HSV-specific antibody by serological tests support the contention that immunisation of HSV-2-infected mice can either enhance the existing Th1-like immune response elicited following HSV-2 infection, or modulate this response towards a more Th2-like profile, and this is dependent on the form of the antigenic stimulus. The degree of protection against subsequent lethal, heterologous HSV-1 challenge infection varied according to the nature of the infection and the immunisation history of the animals.     

Transcutaneous immunization with novel lipid-based adjuvants induces protection against gastric Helicobacter pylori infection

The development of vaccines to combat pathogens that infect across mucosal surfaces has been a major goal of vaccine research. Successful mucosal vaccination requires the co-administration of adjuvants that can overcome the state of immune tolerance normally associated with mucosal application of proteins. In the case of oral immunization, delivery systems are also required to protect vaccine antigens against destruction by gastric pH and digestive enzymes. Furthermore, adjuvants used for mucosal delivery must be free of neurotoxic effects like those induced by the commonly used experimental mucosal adjuvant cholera toxin. Maintenance of the “cold chain” is also essential for the effectiveness of any vaccine and adjuvants/delivery systems that enhance the stability of a vaccine would offer a significant advantage. Needle-free methods of vaccination that induce protective immunity at multiple mucosal surfaces are also desirable for rapid vaccination of large populations. In the present study we show that transcutaneous immunization (TCI) using Lipid C, a novel lipid-based matrix originally developed for oral immunization, containing soluble Helicobacter sonicate significantly reduces the gastric bacterial burden in mice following gastric challenge with live Helicobacter pylori. Protection is associated with the production of splenic gamma interferon and gastric IgA and was achieved without the co-administration of potent and potentially toxic adjuvants, although protection was further enhanced by inclusion of CpG-ODN and cholera toxin in the lipid delivery system.     

Protection against bubonic and pneumonic plague with a single dose microencapsulated sub-unit vaccine

Protection against virulent plague challenge by the parenteral and aerosol routes was afforded by a single administration of microencapsulated Caf1 and LcrV antigens from Yersinia pestis in BALB/c mice. Recombinant Caf1 and LcrV were individually encapsulated in polymeric microspheres, to the surface of which additional antigen was adsorbed. The microspheres containing either Caf1 or LcrV were blended and used to immunise mice on a single occasion, by either the intra-nasal or intra-muscular route. Both routes of immunisation induced systemic and local immune responses, with high levels of serum IgG being developed in response to both vaccine antigens. In Elispot assays, secretion of cytokines by spleen and draining lymph node cells was demonstrated, revealing activation of both Th1 and Th2 associated cytokines; and spleen cells from animals immunised by either route were found to proliferate in vitro in response to both vaccine antigens. Virulent challenge experiments demonstrated that non-invasive immunisation by intra-nasal instillation can provide strong systemic and local immune responses and protect against high level challenge. Microencapsulation of these vaccine antigens has the added advantage that controlled release of the antigens occurs in vivo, so that protective immunity can be induced after only a single immunising dose.     

Intranasal vaccination with SfbI or M protein-derived peptides conjugated to diphtheria toxoid confers protective immunity against a lethal challenge with Streptococcus pyogenes

We investigated whether intranasal immunisation with diphtheria toxoid (DT) conjugated polypeptides encompassing T and B cell epitopes of the SfbI protein (FNBR) or a conformational-constrained B cell epitope of the M1 protein (J8) was able to confer protection against lethal mucosal challenge with a heterologous Streptococcus pyogenes strain. To this end, BALB/c mice were immunised with the conjugates. Strong antigen-specific antibody responses were observed in both serum and mucosal secretions. Vaccinated mice were challenged 10 days after the last boost by the intranasal route. Animals receiving FNBR-DT co-administered with either the cholera toxin B subunit (CTB) or the TLR 2/6 agonist MALP-2 were efficiently protected against the virulent S. pyogenes strain (90% and 70% survival, respectively), whereas those immunised with J8-DT plus either CTB or MALP-2 showed intermediate levels of protection (60% and 40%, respectively). The obtained results indicate that in our experimental animal model peptide-based conjugate vaccines represent a valid alternative to protect against streptococcal infection.     

Helicobacter pylori infection and cancer of the stomach

Although the incidence of gastric cancer has declined in the past few decades in developed countries, it has remained one of the most frequent malignomas with high mortality. Epidemiological, clinical and basic research studies confirm the role of Helicobacter pylori in the pathogenesis of the tumors of the distal stomach and low-grade MALT lymphomas. On the contrary more and more data suggest a possible protective role of the infection in the gastro-oesophageal reflux disease, tumors of the cardia and adenocarcinoma of the distal oesophagus. The intensive research being done in the past few years prove our previous concept, that the pathogenesis of gastric cancer is a multifactorial process, which is affected by Helicobacter pylori ("a major environmental factor") together with distinct environmental, social and genetic factors. The interaction of these factors and the importance of them urge further investigations, which may differ in different populations.     

Expression of Helicobacter pylori urease subunit B gene in Lactococcus lactis MG1363 and its use as a vaccine delivery system against H. pylori infection in mice

The use of Lactococcus lactis as an antigen delivery vehicle for mucosal immunisation has been proposed. To determine whether L. lactis could effectively deliver Helicobacter pylori antigens to the immune system, a recombinant L. lactis expressing H. pylori urease subunit B (UreB) was constructed. Constitutive expression of UreB by a pTREX1 vector resulted in the intracellular accumulation of UreB to approximately 6.25% of soluble cellular protein. Five different oral regimens were used to vaccinate C57BL/6 mice and the immune response measured. One regimen, which consisted of four weekly doses of 10(10) bacteria, followed after an interval of approximately 4 weeks by three successive daily doses, was able to elicit a systemic antibody response to UreB in the mice, although subsequently, a similar regimen produced a significant antibody response in only one out of six mice. The other three regimes, in which mice were vaccinated with two or three sets of three consecutive daily doses of recombinant bacteria over 30 days, failed to elicit significant anti-UreB serum antibody responses. In three regimens, the immunised mice were then challenged by H. pylori strain SS1 and no protective effect was observed. These findings suggest that any adjuvant effects of L. lactis are unlikely to be sufficient to produce an effective immune response and to protect against H. pylori challenge, when used to deliver a weak immunogen, such as UreB.     

Spontaneous regression and recurrence of primary low-grade B-cell gastric lymphoma on the gastric stump 15 and 20 years after gastroresection

The recurrence of primary gastric lymphoma (PGL) on the gastric stump after gastroresection is rare. We describe the case of an 84-year-old man who had recurrences 15 and 20 years after a Billroth I gastrectomy. The concordance of the three gastric biopsies showing a low grade B-cell lymphocytic lymphoma of the mucosa-associated tissue, demonstrated the recurrence of the disease. The patient has serological evidence of Helicobacter pylori infection but the eradication therapy had no effect on the evolution of the disease. The case suggests that PGL is really a particular entity in the non-Hodgkin's lymphoma group, characterized by a long spontaneous natural history, with long lasting spontaneous remissions and recurrences.     

Intranasal immunization with immunodominant epitope peptides derived from HpaA conjugated with CpG adjuvant protected mice against Helicobacter pylori infection

HpaA is considered to be an effective protective antigen for vaccination against Helicobacter pylori (H. pylori) infection. Oral immunization with HpaA significantly decreases bacterial colonization in H. pylori infected mice. In this study, we investigated whether subcutaneous or intranasal immunization with HpaA could protect against H. pylori infection. Mice immunized subcutaneously with HpaA in Complete Freund’s adjuvant, but not mice intranasally immunized with HpaA in CpG adjuvant acquired protection against H. pylori infection. However, intranasal immunization with immunodominant epitope peptides in CpG adjuvant protected mice against H. pylori infection, and immunodominant epitope peptides stimulated stronger Th1 responses and mediated more robust protection against H. pylori infection than subdominant ones. Our results suggest that the length of a candidate antigen is critical for particular vaccination routes, and that immunodominant epitope peptides are promising candidates for protection against H. pylori infection through nasal vaccination.