Possible association of interleukin 1B C-31T polymorphism among Helicobacter pylori seropositive Japanese Brazilians with susceptibility to atrophic gastritis

Associations between anti-Helicobacter pylori seropositivity (HP+) and interleukin 1B (IL-1B) C-31T polymorphism have been reported and little is known about the host factors involved in the development of atrophic gastritis (AG) among infected individuals. This study aimed to examine the IL-1B C-31T polymorphism among anti-HP antibody seropositive Japanese descendants with AG in Brazil and to investigate the interactions with lifestyle factors. Subjects were 455 seropositive from four cities in Brazil, aged 33-69 years. Sex-age-adjusted odds ratio (OR) of AG for 61 current smokers was 1.29, 95% confidence interval (CI): 0.18-9.26 for T/T, while that for 325 never smokers was 0.52, 95% CI: 0.27-0.98. A negative association for AG and never alcohol drinking, every day fruit consumption and milk drinking, and less frequently coffee drinking in individuals with C/T or T/T genotype was observed. This study suggested that host genetic constitution and lifestyle factors may influence the protective effect for AG development.     

Helicobacter pylori infection and gastric carcinoma among Japanese Americans in Hawaii

BACKGROUND. Helicobacter pylori are gram-negative spiral bacteria that are associated with chronic gastritis, a known precursor of gastric carcinoma. Persons at high risk for gastric carcinoma have been shown to have a high prevalence of H. pylori infection. METHODS. We studied the relation of H. pylori infection and gastric carcinoma in a cohort of Japanese American men living in Hawaii. The 5908 men were enrolled and examined from 1967 to 1970. By 1989, 109 cases of pathologically confirmed gastric carcinoma had been identified. The store serum of each patient with gastric carcinoma and of each matched control subject were tested for the presence of serum IgG antibody to H. pylori. RESULTS. Ninety-four percent of the men with gastric carcinoma and 76 percent of the matched control subjects had a positive test for H. pylori antibodies, for an odds ratio of 6.0 (95 percent confidence interval, 2.1 to 17.3). As the level of antibody to H. pylori increased, there was a progressive increase in the risk of gastric carcinoma (P for trend = 0.0009). The association was strong even for men in whom the diagnosis was made 10 or more years after the serum sample was obtained (odds ratio, 10.5; 95 percent confidence interval, 2.5 to 44.8). CONCLUSIONS. Infection with H. pylori is strongly associated with an increased risk of gastric carcinoma. However, most persons infected with H. pylori will never have gastric carcinoma. Therefore, other factors that increase the risk of gastric carcinoma among persons infected with H. pylori need to be identified.     

IL-1B基因多态性和H.pylori感染与汉族人胃癌的相关性研究

目的：通过比较胃癌患者与匹配人群的幽门螺旋杆菌（Helicobacter pylori，H.pylori）感染率和IL-1B基因多态性，探讨IL-1B基因多态性是否增加H．pylori感染后胃癌发生的危险性。方法：采用聚合酶链反应-限制性片段长度多态性（Restriction fragment length polymorphism，RFLP）分析法检测胃癌低发区84例胃癌患者和84例与之性别、年龄匹配的普通人群的1L-1B基因多态性。采用酶联免疫吸附法（Enzyme—linked immunosorbent assay，ELISA）检测上述人群中的H.pylori感染率。结果：①胃癌患者IL-1B-511T／T基因型频率显著高于性别、年龄匹配的对照人群（P〈0．05），IL-1B-31T／T基因型频率在两组间无显著差异（P〉0．05）。84例胃癌患者的H.pylori感染率显著高于对照人群（P〈0．01）。胃癌患者H.pylori阳性感染者IL-1B-511 T／T基因型个体显著多于对照人群。结论：H.pylori感染者胃癌组织中IL-1B-511 T／T基因型为主，提示IL-1B-511 T／T基因型可能增加H.pylori感染后中国汉族人群发生胃癌的危险性，而IL-1B-31基因型与H.pylori感染后中国汉族人群胃癌发生无显著相关性。     

Association between TNF-alpha promoter polymorphism and Helicobacter pylori cagA subtype infection

AIMS: To assess the importance of tumour necrosis factor alpha (TNF-alpha) promoter polymorphism in relation to infection with the cytotoxin associated gene A (cagA) subtype of Helicobacter pylori within a dyspeptic Korean population. METHODS: Eighty three patients with gastric disease and 113 healthy controls were studied. The DNA from gastric biopsy specimens was analysed by H pylori specific and cagA specific polymerase chain reaction (PCR). To characterise TNF-alpha polymorphism at positions -308 and -238, PCR based restriction fragment length polymorphism analysis was performed. RESULTS: Helicobacter pylori infection was closely correlated with G to A transition at position -308 of the TNF-alpha promoter when compared with healthy controls (odds ratio (OR), 2.912; 95% confidence interval (CI), 1.082 to 7.836; p = 0.034). Although TNF-alpha -308 polymorphism in patients with H pylori was not significantly different from that in patients without H pylori, the -308A polymorphism was strongly associated with H pylori cagA subtype infection when compared with the polymorphism in cagA negative H pylori infection (OR, 8.757; 95% CI, 1.413 to 54.262; p = 0.019) and healthy controls (OR, 3.683; 95% CI, 1.343 to 10.101; p = 0.011). G to A genetic change at position -238 of the TNF-alpha gene was not significantly associated with H pylori cagA subtype infection. In addition, genetic polymorphisms at both sites of the TNF-alpha promoter in patients with H pylori infection did not correlate with the severity of disease. CONCLUSION: TNF-alpha -308A polymorphism was significantly related to infection with the H pylori cagA subtype in Korean patients with gastric disease.     

HLA—DQB1＊0301与胃腺癌及幽门螺杆菌感染的关系

为探讨HLA－DQB1等位基因与胃腺癌临床特征及其幽门螺杆菌（Hp)感染的关联性，运用序列特异性引物聚合酶链反应技术，检测无亲缘关系湖北汉族健康人136例，胃癌组63例患者的HLA－DQB1基因，内镜活检，Giemsa染色和（或）外周血ELISA检查胃粘膜Hp感染情况，SAS软件编译处理，结果表明HLA－DQB1基因，内镜活检，Giemsa染色和（或）外周血ELISA检查胃粘膜Hp感染情况，SAS软件统计处理。结果表明HLA－DQB1*0301与湖北汉族人胃腺癌呈正关闻。携带与非带该等位基因患者，。其临床特征包括患者平均患病年龄，性别比，肿瘤原发部位，肿瘤TNM分期，肿瘤细胞分化程度，以及Hp感染率等情况比较，均无显著差别，HLA－DQB＊0301等位基因并不是通过增加Hp感染危险性，而影响胃腺癌的遗传易感性。     

Sublingual Immunization Protects against Helicobacter pylori Infection and Induces T and B Cell Responses in the Stomach

Sublingual (SL) immunization has been described as an effective novel way to induce mucosal immune responses in the respiratory and genital tracts. We examined the potential of SL immunization against Helicobacter pylori to stimulate immune responses in the gastrointestinal mucosa and protect against H. pylori infection. Mice received two SL immunizations with H. pylori lysate antigens and cholera toxin as an adjuvant, and after challenge with live H. pylori bacteria, their immune responses and protection were evaluated, as were immune responses prior to challenge. SL immunization induced enhanced proliferative responses to H. pylori antigens in cervicomandibular lymph nodes and provided at least the same level of immune responses and protection as corresponding intragastric immunization. Protection in SL-immunized mice was associated with strong H. pylori-specific serum IgG and IgA antibody responses in the stomach and intestine, with strong proliferation and gamma interferon (IFN-γ) and interleukin-17 (IL-17) production by spleen and mesenteric lymph node T cells stimulated with H. pylori antigens in vitro, and with increased IFN-γ and IL-17 gene expression in the stomach compared to levels in infected unimmunized mice. Immunohistochemical studies showed enhanced infiltration of CD4⁺ T cells and CD19⁺ B cells into the H. pylori-infected stomach mucosa of SL-immunized but not unimmunized H. pylori-infected mice, which coincided with increased expression of the mucosal addressin cell adhesion molecule (MAdCAM-1) and T and B cell-attracting chemokines CXCL10 and CCL28. We conclude that, in mice, SL immunization can effectively induce protection against H. pylori infection in association with strong T and B cell infiltration into the stomach.At least half of the world''s population is infected with Helicobacter pylori, one of the few microorganisms known to be able to colonize the human stomach. In 10 to 15% of infected individuals, chronic H. pylori infection causes duodenal ulcers, and infection with H. pylori has been shown to be a strong risk factor for the development of gastric adenocarcinoma and malignant mucosa-associated lymphomas (3, 17, 20). Although treatment with a combination of antibiotics and a proton pump inhibitor is usually effective in individual cases, limited treatment compliance, rapidly emerging antibiotic resistance, and frequent reinfection with H. pylori in countries where it is highly endemic make vaccination an increasingly attractive alternative or complement to standard therapy.Vaccination, given either preventively or therapeutically, is especially needed in countries with a high incidence of gastric cancer (20), reinfection (22), or antibiotic resistance. However, clinical trials of various oral or parenteral H. pylori vaccine candidates have not shown much promise to date, pointing to the need for identifying improved antigen-adjuvant formulations and/or alternative routes of immunization in the quest for an effective vaccine against H. pylori (33).The importance of cell-mediated mucosal immunity in protection against experimental H. pylori infection after vaccination is well established (1, 9, 10, 23, 35). In most studies, intragastric (IG) immunization has been used to achieve efficient stimulation of the gastrointestinal immune response. However, this route usually requires large amounts of antigen for efficient immunization, and the environment in the stomach and intestine may have adverse effects on the antigens and adjuvants used. Intranasal immunization against H. pylori has also been used in mice, but studies in humans have indicated that the nasal route of immunization is ineffective in stimulating immune responses in the intestine or stomach (12). In addition, intranasal immunization is associated with a risk of translocation of some types of antigens or adjuvants to the olfactory bulb of the brain, restricting its applicability in humans (31, 34).Sublingual (SL) immunization has recently emerged as an attractive novel approach for mucosal vaccination against pathogens (7, 8, 31). In a model of influenza virus infection, SL immunization with live or adjuvanted killed virus induced immune responses and protection against aerosol challenge with live virus. In contrast to intranasal immunization, SL immunization had no evidence of vaccine or adjuvant entering the brain (31). In another study, SL immunization was found to induce vaccine-specific antibody and T cell responses in the genital tract and, after SL immunization with human papillomavirus (HPV)-like particles, protection against genital HPV infection, indicating the potential of SL immunization to stimulate immune responses also in nonrespiratory mucosal tissues (7).In the present study, we examined whether SL immunization in mice can induce a mucosal immune response in the gastrointestinal tract. More specifically, we addressed the potential of SL immunization with H. pylori antigen and cholera toxin (CT) adjuvant to stimulate T and B cell responses in the stomach and protect against H. pylori infection. Our findings demonstrate that SL immunization induces strong systemic and stomach mucosal antibody and T cell responses and a high level of protection against H. pylori challenge. After SL immunization and H. pylori challenge, the stomach mucosa showed infiltration of both CD4⁺ T cells and CD19⁺ B cells and increased expression of gamma interferon (IFN-γ) and interleukin-17 (IL-17) compared to unimmunized infected mice. This was associated with increased expression of both the mucosal addressin cell adhesion molecule (MAdCAM-1) integrin and chemokines CXCL10 (10-kDa IFN-γ-induced protein) and CCL28 (mucosa-associated epithelial chemokine) in the immunized mice, which probably facilitated the migration of immunization-induced CD4⁺ T cells and CD19⁺ B cells into the stomach mucosa. Our results indicate that SL immunization against H. pylori effectively induces a strong immune response in the gastrointestinal tract mucosa and protects against infection, providing an attractive novel way of vaccinating against H. pylori infection.     

MTHFR C677T polymorphism and differential methylation status in gastric cancer: an association with Helicobacter pylori infection

MTHFR C677T and Helicobacter pylori infection are believed to play critical roles in the DNA methylation process, an epigenetic feature frequently found in gastric cancer. The aim of this study was to verify the associations between the MTHFR C677T polymorphism and the methylation status of three gastric cancer-related genes. The influence of H. pylori strains was also assessed. DNA extracted from 71 gastric tumor samples was available for MTHFR C677T genotyping by PCR-RFLP, promoter methylation identification by MS-PCR and H. pylori detection and posterior subtyping (cagA and vacA genes) by PCR. In the distal tumors, a positive correlation was found between the methylation of CDKN2A and the allele T carriers (r = 0.357; p = 0.009). Considering the eldest patients (age ≥ 60 years old), this correlation was even higher (r = 0,417; p = 0.014). H. pylori infection by highly pathogenic strains (cagA+/vacAs1m1) was also found correlated to promoter methylation of CDKN2A and the allele T carriers in distal tumors (r = 0.484; p = 0.026). No significant correlation was verified between MTHFR C677T genotype and promoter methylation status when we analyzed the general sample. DNA methylation in CDKN2A associated to the MTHFR 677T carrier is suggested to be a distal tumor characteristic, especially in those 60 years old or older, and it seems to depend on the infection by H. pylori cagA/vacAs1m1 strains.     

Gastric Interleukin-8 and IgA IL-8 Autoantibodies in Helicobacter pylori Infection

Gastric infection with Helicobacter pylori is frequently characterized by neutrophil infiltration. The production of the neutrophil-activating peptide (NAP-1/IL-8) and mucosal IgA autoantibodies to IL-8 by human antral biopsies have been examined during short-term in vitro culture. Detectable IL-8 was secreted by 84% of H. pylori- negative patients with normal antral mucosa (range <0.07–61.5 ng/mg biopsy protein, n =19). Concentrations in 4 patients with reactive gastritis and 10 with inactive gastritis were not significantly different from subjects with normal mucosa. In H. pylori- positive patients with active gastritis and neutrophil infiltration into the epithelium ( n =17) IL-8 secretion was significantly increased relative to subjects with normal mucosa ( p > 0.0001), inactive gastritis ( p <0.001) and reactive gastritis ( P <0.01). IL-8 concentrations in active gastritis were significantly correlated with the extent of epithelial surface degeneration ( r =0.64). IgA autoantibodies were present in 19 patients (13 active, 4 inactive gastritis) and concentrations were significantly correlated with IL-8 production ( p <0.001). Gastric synthesis of IL-8 is likely to be an important factor in regulating mucosal neutrophil infiltration and activation in patients with H. pylori infection. The local production of IgA antibodies to IL-8 may represent a down-regulatory response of the host to limit mucosal damage associated with a chronic bacterial infection.     

Polymorphism of IL-1RA and TNF-alpha genes in patients with Helicobacter pylori associated gastritis and duodenal ulcer

The goal of this work was to determine the frequency of major types of polymorphism in the genes of interleukin-1 receptor antagonist (IL-1RA) and TNF-alpha in patients with Helicobacter pylori-associated gastritis and duodenal ulcer and elucidate its correlation with clinical manifestation of the disease. A total of 126 patients were selected for the study with different gastroduodenal pathologies and H. pylori detected in biopsy material. The obtained data indicate a possible correlation between the risk of developing duodenal ulcer and the presence of the allele A in the TNF-alpha gene at the ?308 position in the patients. Polymorphism analysis of the IL-1RA gene revealed a statistically significant difference in the availability of the 2/L genotype in the studied groups of patients. The conducted research demonstrates that a parallel typing of the H. pylori virulence genes and determination of the cytokine gene polymorphism in the biopsy material taken from the patient is required for characterization of the bacterium-host interaction.     

Association of transforming growth factor-beta1 single nucleotide polymorphism C-509T with allergy and immunological activities

BACKGROUND: A single nucleotide polymorphism (SNP) C-509T within the tumor growth factor beta1 (TGFbeta1) gene has been associated with atopic asthma and asthma severity. To further understand the mechanisms involved, the association of C-509T with allergy, T-lymphocyte proliferation and plasma TGFbeta1 concentration has been explored in a case-control study with allergic and non-allergic subjects. METHODS: The recruited subjects including allergic (n = 38) and nonallergic (n = 25) participants have been genotyped for C-509T using allele discrimination assay. Association of C-509T with allergy status was examined using logistic regression analysis in both dominant and recessive models. Association of C-509T with T-cell proliferation in control and antigen-stimulated peripheral blood mononuclear cells (PBMCs), plasma TGFbeta1 and total IgE level were tested by multiple regression analysis. Results: Individuals with homozygous mutant TT genotype showed a higher risk of allergy (TT: odds ratio = 5.099, 95% confidence limit: 1.355-19.190, p = 0.016) after covariates were adjusted. A trend to increased plasma TGFbeta1 in subjects with T allele has been discovered. In the meantime, the T allele is associated with lower T cell proliferation in controls and maximum response to above antigens. A low T-cell proliferation is correlated with higher plasma TGFbeta1 concentration (p < 0.01). The in vitro studies confirmed the suppressing effect of TGFbeta1 on T-cell proliferation at physiological range. A significant inhibitory effect on IL-4 production was also observed. CONCLUSIONS: A C to T base change in TGFbeta1 SNP C-509T has been associated with a higher risk of allergy. The mechanisms are not clear. Elevated TGFbeta1 levels associated with the C-509T polymorphism might suppress immune activation as well as Th2 cytokine production.     

HIV1 seropositivity and B and D viruses in West Africa

This study was undertaken to investigate relationships between three widespread viruses in West Africa, i.e. HIV1 and viruses B and D, in Ivory Coast. Serologic tests for viruses B and D were carried out in a random sample of black adults of both sexes with asymptomatic HIV1 seropositivity. Coinfection by virus B or viruses B and D was a common finding. Coinfection with both viruses B and D, but not with virus B alone, was found to be significantly more frequent in these HIV1-infected adults than in a control group with acute viral hepatitis. Potential interactions between the HIV1 and viruses B and D as well as other viruses are discussed. These findings suggest that one or several cofactors acting alone or in combination play a major role in the clinical expression of HIV infection. The results of this study, together with the suggestion put forward by several investigators that B virus infection may increase the severity of AIDS, are evidence in support of the value of immunization against the B virus in the management of AIDS.     

Copy number variations in SPAST and ATL1 are rare among Brazilians

Copy number variations (CNV) may represent a significant proportion of SPG4 and SPG3A diagnosis, the most frequent autosomal dominant subtypes of hereditary spastic paraplegias (HSP). We aimed to assess the frequency of CNVs in SPAST and ATL1 and to update the molecular epidemiology of HSP families in southern Brazil. A cohort study that included 95 Brazilian index cases with clinical suspicion of HSP was conducted between April 2011 and September 2022. Multiplex Ligation Dependent Probe Amplification (MLPA) was performed in 41 cases without defined diagnosis by different massive parallel sequencing techniques (MPS). Diagnosis was obtained in 57/95 (60%) index cases, 15/57 (26.3%) being SPG4. Most frequent autosomal recessive HSP subtypes were SPG7 followed by SPG11, SPG76 and cerebrotendinous xanthomatosis. No CNVs in SPAST and ATL1 were found. Copy number variations are rare among SPG4 and SPG3A families in Brazil. Considering the possibility of CNVs detection by specific algorithms with MPS data, we consider that this is likely the most cost-effective approach to investigate CNVs in these genes in low-risk populations, with MLPA being reserved as an orthogonal confirmatory test.     

The nonfunctional allele TCRBV6S1B is strongly associated with Helicobacter pylori infection

To determine genetic susceptibility factors for Helicobacter pylori infection, polymorphic T-cell receptor gene elements were investigated in 203 H. pylori-infected individuals and 180 uninfected individuals (controls). H. pylori infection is highly associated with individuals homozygous for the nonfunctional TCRBV6S1B element (odds ratio = 5.9; chi(2) = 13; P = 0.00032; P value corrected for multiple comparisons [Bonferroni correction] = 0. 00063).     

Interleukin-6 polymorphism and Helicobacter pylori infection in Brazilian adult patients with chronic gastritis

Helicobacter pylori is recognised as the most common cause of chronic active gastritis and this bacterium is also an important pathogenic factor in peptic ulcer disease. The biological factors that influence clinical outcome in H. pylori infection have been extensively studied. In addition to immunological factors in the host, bacterial virulence determinants in H. pylori strains are likely to play a crucial role in gastric cancer development. Singlenucleotide polymorphisms at the 5' flanking region of the interleukin (IL)-6 gene promoter (G or C at -174 base) have been identified and individuals with the G allele at position -174 have been shown to produce higher levels of IL-6 than those with the C/C genotype. The mucosal levels of IL-6 were reported to be increased in H. pylori-associated gastritis. The present study was conducted to examine any relationship between inflammatory cytokine polymorphisms and the inflammatory process in mucosa infected by H. pylori. In our study we did not find any association between the C and G alleles in adult patients with chronic gastritis and inflammatory process in gastric mucosa.     

Single nucleotide polymorphism of interleukin-1β associated with Helicobacter pylori infection in immune thrombocytopenic purpura

To examine the role of genetic factors in development of immune thrombocytopenic purpura (ITP) in association with Helicobacter pylori infection, gene polymorphisms within the loci for human leukocyte antigen class II, interleukin (IL)-1β (−511), tumor necrosis factor-β (+252), immunoglobulin (Ig)G1 heavy chain (+643), and Igκ light chain (+573) were determined in 164 adults with ITP and 75 healthy controls. Of these gene polymorphisms, the IL-1β (−511) T allele was less frequently detected in H.   pylori -infected than in H.   pylori -uninfected (58% vs 81%, P  = 0.01, odds ratio = 0.31) ITP patients diagnosed before age 50. These findings suggest that a single nucleotide polymorphism within the IL-1β (−511) may affect susceptibility to early-onset ITP associated with H.   pylori infection.