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Background: Helicobacter pylori (H. pylori) infection is ubiquitous in sub-Saharan Africa, but paradoxically gastric cancer is rare. Methods: Sera collected during a household-based survey in rural Tanzania in 1985 were tested for anti-H. pylori IgG and IgG subclass antibodies by enzyme immunoassay. Odds ratios (OR) and confidence intervals (CI) of association of seropositivity with demographic variables were computed by logistic regression models. Results: Of 788 participants, 513 were aged ≤17 years. H. pylori seropositivity increased from 76% at 0–4 years to 99% by ≥18 years of age. Seropositivity was associated with age (OR 11.5, 95% CI rd st 4.2–31.4 for 10–17 vs. 0–4 years), higher birth-order (11.1; 3.6–34.1 for ≥3 vs. 1 born), and having a seropositive next-older sibling (2.7; 0.9–8.3). Median values of IgG subclass were 7.2 for IgG1 and 2.0 for IgG2. The median IgG1/IgG2 ratio was 3.1 (IQR: 1.7–5.6), consistent with a Th2- dominant immune profile. Th2-dominant response was more frequent in children than adults (OR 2.4, 95% CI 1.3–4.4). Conclusion: H. pylori seropositivity was highly prevalent in Tanzania and the immunological response was Th2-dominant. Th2-dominant immune response, possibly caused by concurrent bacterial or parasitic infections, could explain, in part, the lower risk of H. pylori-associated gastric cancer in Africa. Background populations of low socioeconomic status, poor hygiene, In sub-Saharan Africa, Helicobacter pylori (H. pylori) infec- and limited access to clean water [2-4]. The most severe tion is ubiquitous, with seroprevalence reaching 90% or consequence of chronic H. pylori infection is gastric aden- higher in many populations . H. pylori is transmitted ocarcinoma . However, gastric cancer rates vary widely from person-to-person, and transmission risk is high in worldwide and correlate imperfectly with H. pylori sero- Page 1 of 7 (page number not for citation purposes) Infectious Agents and Cancer 2006, 1:3 http://www.infectagentscancer.com/content/1/1/3 prevalence . For example, seroprevalence reaches 80% specific responses. To test this hypothesis, we evaluated H. by 5 years of age in sub-Saharan Africa [6,7], highlighting pylori seropositivity and H. pylori-specific IgG subclass the particularly young age of infection acquisition, and antibodies in a rural population in northern Tanzania, therefore duration of infection. However, age-standard- where H. pylori infection was expected to be endemic and ized gastric cancer incidence rates are relatively low at 2– gastric cancer incidence is thought to be low. 21 per 100,000 person-years for both males and females . Subject selection and serological methods The study subjects were residents of the North Mara Dis- In Japan, seroprevalence increases more gradually with trict, located on the eastern shores of Lake Victoria in Tan- age to a prevalence of 40% to 70% among adults [9,10], zania, who participated in human immunodeficiency but the age-standardized gastric cancer incidence rates are virus (HIV) serological surveys from May through June, substantially higher, ranging from 65–92 and 24–39 per 1985 . Participants provided individual verbal con- 100,000 person-years among males and females, respec- sent, and parents provided verbal consent for their chil- tively . By comparison, seroprevalence estimates in the dren, to participate in serological surveys. Institutional U.S. range from 10 to 20% among adults [10,11], with the Review Boards gave ethical approval for the study. Partic- age-standardized gastric cancer incidence rates being 6.6 ipants were recruited from households, defined as com- and 2.6 per 100,000 person-years among white males and pounds where individuals shared meals and had one females, respectively . person designated as head. As previously observed , polygamy was frequently practiced in this population and These statistics highlight a paradoxical deficit of gastric headmen often had several wives. The households were cancer cases in sub-Saharan Africa, compared to Western randomly selected from nine villages located either on countries after controlling for age, the so-called "African hills (n = 5) or in valleys (n = 4). Participants provided enigma" . Gastric cancer deficits may be artifactual, sociodemographic information and gave a blood sample due to incomplete case ascertainment and competing . The samples were stored at -80°C and were thawed mortality [13,14]; however, those reasons do not explain once before current testing. Samples from all but 10 par- why gastric cancer rates vary in African populations that ticipants enrolled in the original study were available for have comparable access to medical care. Specifically, pop- H. pylori serologic testing. ulations residing in mountainous areas tend to have a higher relative frequency of gastric cancer as compared to Anti-H. pylori antibodies were measured using an IgG populations residing in lowland areas . enzyme immunoassay (EIA) as previously reported [22- 24]. This assay has been validated in various populations, Variation in gastric cancer rates within Africa, and else- including those from Africa and was shown to have high where, suggests the presence of modifying factors on H. sensitivity (89–96%) and specificity (92–97%), using pylori-associated gastric cancer risk. In other words, out- biopsy-proven H. pylori gastric mucosa infection as the comes of H. pylori infection could be influenced by bacte- gold standard [22,23]. The tests were run in triplicate rial, host, diet, or other environmental factors. One using a standard 96-well microtiter plate and placing the hypothesis, based on animal studies, posits that bacterial plates on a Benchmark microplate reader (BioRad, Her- and/or parasitic infections modulate H. pylori-induced cules, CA). EIA cut-off values were derived using known gastric cancer risk , perhaps by altering the quality of H. pylori-positive and negative control sera in which OD H. pylori-induced mucosal immunity in the stomach values < 0.8 were considered to be negative, OD values [17,18]. H. pylori infection is thought to cause gastric can- >1.3 were considered positive, and OD values between cer by eliciting vigorous T-helper (Th1) pro-inflammatory 0.8 and 1.3 were considered to be indeterminate, as previ- cellular immune responses in gastric mucosa  and the ously described [22,24]. To determine the IgG antibody resulting mucosal injury is mediated by pro-inflammatory subclasses (IgG1 or IgG2) in seropositive individuals, as a cytokines and oxygen radicals secreted by infiltrating marker of Th1/2-type cellular response , we used IgG chronic inflammatory cells [16,19]. Parasites and, to a subclass EIAs to mouse anti-human IgG1 and mouse anti- lesser extent, certain bacterial infections , elicit Th2 human IgG2 conjugated to HRP (Zymed Laboratory, San instead of Th1-dominant immune responses to thwart Francisco, CA). In brief, pooled serum was used as a refer- their elimination  and could plausibly modulate H. ence standard for the IgG subclasses. This standard was pylori-induced immune response towards one less damag- titrated using each of the IgG subclass antibodies (i.e. ing to the gastric mucosa. mouse anti human IgG1 and mouse anti human IgG2) to determine the highest dilution at which reactivity could We hypothesized that persons living in high H. pylori- still be detected and also remain linear on a standard prevalence areas with low gastric-cancer incidence in curve [22,23,26]. The maximal dilution for both IgG1 and Africa would therefore have Th2-type dominant H. pylori- IgG2 subclasses was 1:25,600. The serum was assigned an Page 2 of 7 (page number not for citation purposes) Infectious Agents and Cancer 2006, 1:3 http://www.infectagentscancer.com/content/1/1/3 arbitrary ELISA unit of 1 at this dilution. The ELISA was Results performed as previously stated using positive controls Of 788 participants, 351 (44%) were male. The majority diluted to 1:25,600 based on the previously mentioned 513 (65%) were 17 years old or younger (Table 1). Only standard curve and double the concentration at 1:12,800 2 subjects were HIV-positive, so this variable was not ana- dilution. The IgG subclass unit was calculated as ratio of lyzed further. Overall, 725 (92%) subjects were seroposi- the OD of the individual sample to the OD of the tive for H. pylori antibody; 27 (3%) were seronegative and 490 490 standard (i.e., IgG subclass unit = sample OD /reference 36 (5%) were indeterminate. H. pylori seropositivity rose OD ). These assays were modified to determine the steeply with age from 76% in children aged 0–4 years to optimal concentration of antigen in serum and IgG conju- 99% in adults (p < 0.001; Table 1). H. pylori seroposi- trend gate that discriminated between H. pylori-positive and H. tivity was similar among males and females. Among chil- pylori-negative samples. Each plate incorporated H. pylori- dren, those aged 10–17 years were more likely to be H. specific IgG subclass positive and negative control sam- pylori seropositive compared to those aged 0–4 years (OR ples. OD values for IgG1 and IgG2 subclasses were nor- 11.5, 95% CI 4.2–31.4; Table 1). Similarly, children of malized using standards previously reported . We higher birth-order (≥3) were more likely to be seroposi- calculated the ratio of IgG1/IgG2 subclasses to determine tive compared to first-born children (OR 11.1, 95% CI phenotype of Th1/2-type cellular immune response. 3.6–34.1; Table 1). In a multivariable model, both age Using a previously established criteria to determine Th1 group and birth-order were independently associated vs. Th2-type response in African and western populations with H. pylori seropositivity (OR 6.3, 95% CI 1.3–31, for rd [27,28], an IgG1/IgG2 ratio >1.0 suggests a Th2-(IgG1)- 10–17 vs. 0–4 years and OR 4.0, 95% CI 1.1–15, for ≥3 st dominant cellular immune response and a ratio ≤ 1.0 sug- vs. 1 born). H. pylori seropositivity was marginally higher gests a Th1-(IgG2)-dominant response. in children with a seropositive next-older sibling com- pared to those whose next-older sibling was seronegative Statistical analysis (OR 2.7, 95% CI 0.9–8.3). All 62 married men and their Associations between sociodemographic variables (sex, 113 wives were H. pylori seropositive. Their concordant age, village location) and H. pylori seropositivity were results precluded us from evaluating the association of determined using Chi-square or Fisher's exact tests. seropositivity between spouses and within parent-child Because of the high H. pylori seroprevalence, we grouped units. H. pylori seropositivity was not associated with loca- persons with indeterminate status with seronegative indi- tion of the village in valleys (OR 0.66; 95% CI 0.33–1.33). viduals for the analysis. Odds ratios (OR) and 95% confi- dence intervals (CI) of association of H. pylori Among seropositive individuals, the median values for seropositivity with age, sex, birth-order were estimated the IgG subclass antibodies were IgG1: 7.2 (inter-quartile using logistic regression models (PROC GENMOD in SAS range [IQR]: 3.6–12.4) and IgG2: 2.0 (IQR: 1.4–3.2). The 9.1 software package; SAS Institute). Because children are median IgG1/IgG2 ratio was 3.1 (IQR: 1.7–5.6). Children more likely to acquire infection from an infected older were more likely to have an IgG1/IgG2 ratio, consistent sibling, we also estimated the association between serop- with Th2-dominant immune response, compared with ositivity of a younger child with status of the next-older adults (OR 2.4, 95% CI 1.3–4.4). In analyses excluding sibling on whom samples were available. We accounted seronegative individuals, the proportion of persons show- for intra-familial or intra-household correlations among ing Th2-dominant responses increased from 33% among observations by using generalized estimating equations children aged 1 year to 100% among children 3–6 years (25). We used independence working correlation matrices and then declined somewhat to 80% among subjects aged in the computations and checked results by also using 45 years and older (Figure 1, panel A). Similarly, values of equi-correlated working correlations that assumed that the log-transformed IgG1/IgG2 ratio rapidly increased members in the same family would have equal correla- with age to peak between 3–4 years and then reached a tions. Both methods yielded similar results, so only the plateau in the adult years (Figure 1, panel B). Models of results using independent working correlations are pre- the log-transformed IgG1/IgG2 ratio that included age as sented. Values of IgG1/IgG2 ratio among seropositive a quadratic did not fit the data better than models with individuals were log-transformed to obtain a normal dis- linear age (Pearson χ -test = 0.72). The IgG1/IgG2 ratio tribution. We assessed the relationship between the log- was unrelated to gender, birth order, or village location transformed IgG1/IgG2 ratio and age in linear regression (data not shown). models. Age was used in the categories 0–4, 5–9, 10–17, and 18+ years. A two-sided p-value < 0.05 was considered Discussion statistically significant. We observed extremely high H. pylori seroprevalence in a rural population in northern Tanzania. Seropositive indi- viduals showed a high IgG1/IgG2 ratio, suggestive of Th2- dominant H. pylori-specific immune responses. Our cross- Page 3 of 7 (page number not for citation purposes) Infectious Agents and Cancer 2006, 1:3 http://www.infectagentscancer.com/content/1/1/3 Table 1: Frequency and risk of H. pylori seropositivity among persons residing in rural Tanzania (May to June, 1985) Characteristic No. H. pylori positive/Total No. (%) OR 95% CI P value Sex * 0.87 Female 402/436 (92%) Ref. Male 322/351 (92%) 1.04 0.67–1.62 Age group, years* <0.001 0–4 138/181 (76%) Ref. 5–9 168/180 (93%) 4.4 2.42–7.81 10–17 148/152 (97%) 11.5 4.22–31.4 ≥18 264/268 (99%) 20.6 7.57–56.2 Birth order† <0.001 1 79/105 (75%) Ref. 2 82/101 (91%) 3.3 1.7–6.8 ≥3 136/139 (97%) 11.1 3.7–34 Next-older sibling ± 0.08 Seronegative 23/29 (79%) Ref. Seropositive 189/208 (91) 2.70 0.90–8.34 Location of village 0.25 Hill 272/290 (94%) Ref. Valley 453/498 (91%) 0.66 0.33–1.33 Abbreviations: OR odds ratio; CI Confidence Interval * Sex is missing for one person and age is missing for 7 persons † Only children with information on birth-order included in this analysis ± "Next-older sibling" refers to the next-older sibling of the case child sectional study confirms high H. pylori seropositivity in Our study highlights one aspect of the gastric cancer para- rural Tanzania, and shows that seropositivity increases dox in Africa, i.e., early acquisition of H. pylori infection in steeply with age in childhood and is associated, among childhood and persistence of seropositivity into adult- children, with higher birth-order and with having a sero- hood in an area where gastric cancer is relatively rare. positive next-older sibling. These findings are consistent Competing mortality (causing deficits in the elderly pop- with prior studies of H. pylori infection in highly endemic ulation ≥ 60 years) has been advanced as one explanation areas [2,5]. A novel finding from our study is the Th2- for the lower age-sex specific gastric cancer incidence in dominant H. pylori-specific immune responses, which sub-Saharan Africa compared to developed countries. were strongest in children but were present also in adults. However, this explanation is not supported by data from As assessed by IgG subclass antibodies, the Th2-dominant South Africa where life expectancy prior to the AIDS epi- immune responses to H. pylori infection observed in this demic was 63 years . Investigators at Shirati Hospital, rural Tanzanian population contrasts to Th1-dominant North Mara District, who serve our study population and responses reported in Western populations [27,29]. We are actively engaged in cancer research , previously speculate that Th2-dominant H. pylori-specific immune reported gastric cancer to be rare. In an analysis of 279 responses in this population can be modulated by concur- malignancies seen at the Hospital from 1952–1965, only rent infection with parasitic or bacterial infections as has 12 (4.3%) were diagnosed as gastric cancer . Con- been observed in animal models [16,18]. Th2-dominance versely, gastric cancer is relatively more frequent on the rapidly increased with age and peaked between 3–7 years. slopes of Mount Kilimanjaro, where it contributes ~15% This trend with age may reflect a tendency for younger of malignancies . Moreover, there are similar reports children to have a Th2-dominant pattern or may be due to of higher gastric cancer rates in mountainous or dry areas a high frequency and burden of parasitic and bacterial elsewhere in Africa [15,35,36]. The variation in relative infections among children, or both. Parasite egg and/or frequency of gastric cancer in the context of similar H. worm burden for schistosomiasis and soil-transmitted pylori prevalence, similar access to medical care, and simi- helminths have been shown to peak at young ages in this lar life expectancy has led to the hypothesis that environ- population . mental co-factors, perhaps diet (nitrates or fresh fruits and Page 4 of 7 (page number not for citation purposes) Infectious Agents and Cancer 2006, 1:3 http://www.infectagentscancer.com/content/1/1/3 Th Figure 1 2 type response by age group, in years Th2 type response by age group, in years: Panel A: Percent of H. pylori seropositive individuals with Th2-dominant IgG H. pylori specific immune response by age group. Panel B: Log-transformed IgG1/IgG2 ratio by age group among H. pylori serop- ositive individuals in rural Tanzania. The X-axis shows age groups in years, the Y-axis shows log-transformed values. The y-line marks the cut-off value for T helper (Th)-dominant 1 vs. Th2-dominant response: values above the line indicate Th2-dominant responses, while values below the line indicate Th1-dominant responses. The line plot connects the median log-transformed IgG1/2 ratios for each age group and the scattered points indicate actual values for each age group. vegetables), are important. However, no dietary factors The role of Th1/2 immunity and H. pylori-induced gastric have been convincingly implicated in Africa. An alterna- cancer has been investigated in two prior studies. In one tive hypothesis posits that enteric or other parasites may conducted in Soweto, South Africa, where gastric cancer influence gastric cancer risk . This hypothesis is based incidence is low, found Th2-dominant H. pylori-specific on the observations in mice that Helicobacter-induced gas- immune responses in blacks with gastric symptoms  tric atrophy, a precursor lesion to gastric cancer, improved whereas study of symptomatic white subjects from Austria in mice concurrently infected with enteric parasites but and Germany, where gastric cancer incidence is high, not in mice that were not. Improvements were associated demonstrated Th1-dominant responses . The authors with concomitant down-regulation of the pro-inflamma- suggested that the Th2-dominant responses in blacks were tory responses due to a shift from Th1 toward Th2-domi- likely induced by co-infection with parasites, which they nant cellular immune response in mice with concurrent postulated may modulate gastric risk cancer among Afri- enteric parasite infection . Our finding of Th2-domi- cans. In the other study conducted in Columbia in per- nant immune response in H. pylori infected persons from sons from low and mountainous regions where gastric northern rural Tanzania, where gastric cancer is relatively cancer incidence is low and high, respectively, evaluated rare, is consistent with this hypothesis. Although we lack H. pylori seropositivity and parasitic infections. Persons data on parasite or colonic bacterial infections, it is rea- from Tumaco, a low lying area where gastric cancer inci- sonable to assume that people who live in remote rural dence is low, had Th2-dominant immune responses and African villages without access to running water or other a higher prevalence of helminth infections . Con- amenities, such as ours, are frequently infected with para- versely, those from Pasto, a high altitude area where gas- sitic and/or bacterial conditions in addition to H. pylori tric cancer incidence is high, had predominantly Th1- [30,37]. dominant immune responses and a lower prevalence of Page 5 of 7 (page number not for citation purposes) Infectious Agents and Cancer 2006, 1:3 http://www.infectagentscancer.com/content/1/1/3 helminth infections . The authors attributed differ- Authors' contributions ences in Th1 or Th2-dominant responses across the low SMM conceived of the study, contributed to analysis and vs. mountainous regions to differences the prevalence of interpretation of data, and drafted the manuscript. BDG helminth infections and suggested that parasitic infection carried out the serological studies, contributed to interpre- may modify H. Pylori-induced gastric cancer risk in tation of data and writing the report. RMP carried out the Columbia. Thus, those studies and ours lend support to statistical analyses and interpreted data. GRB and JCS did the hypothesis that Th1/2 immunity modulated by para- the field work, contributed to interpretation of data. RJB site infections may influence the risk of H. pylori-associ- participated in the design of the study, field work, and ated gastric cancer in diverse environments [15,28,35,36]. contributed to analysis and edited the manuscript. MH participated in study design and coordination and helped Our study has some limitations. H. pylori infection was with analysis, interpretation of data, and editing the man- measured using serological assays, and some subjects may uscript. All authors read and approved the final manu- have been misclassified. The finding of almost universal script. seropositivity among adults is surprising because we would have expected a small proportion of individuals to Acknowledgements We thank participants in the survey and Tanzanian authorities for permit- be seronegative due to loss of bacterial colonization that ting this work to be done. We are grateful to Frances Yellin (Computer occurs with age in chronically infected persons or with Services, Ltd, Rockville) for preparing the data files, to Violet Devairakkam development of chronic gastric atrophy. We lacked endos- (Research Triangle Institute, Rockville) for handling the samples, to Dexter copy data on the state of gastric mucosa (presence of ulcer, Thompson (Division of Pediatric Gastroenterology and Nutrition, Depart- gastric atrophy or not) and therefore are unable to draw ment of Pediatrics, Emory University School of Medicine) for performing H. conclusions about the relationship between Th2 domi- pylori serology, and to James J. Goedert for comments on the manuscript. nance and severity of gastric mucosal inflammation. This project was funded by the Intramural Research Program of the Direct measurement of pepsinogen levels could have also National Cancer Institute, National Institutes of Health, Department of provided some information on the presence or not of gas- Health and Human Services, under Purchase Order number 263-NQ- tric atrophy, but the volume of residual samples from the study population were inadequate for additional testing. References Furthermore, our study was cross-sectional so we cannot 1. Schistosomes, liver flukes and Helicobacter pylori. IARC infer temporality of associations demonstrated. We note Working Group on the Evaluation of Carcinogenic Risks to that our "highland" area villages were in low hills, not Humans. Lyon, 7-14 June 1994. IARC Monogr Eval Carcinog Risks Hum 1994, 61:1-241. mountainous areas, thus our study does not provide data 2. 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Poggensee G, Krantz I, Nordin P, Mtweve S, Ahlberg B, Mosha G, Publish with Bio Med Central and every Freudenthal S: A six-year follow-up of schoolchildren for uri- scientist can read your work free of charge nary and intestinal schistosomiasis and soil-transmitted helminthiasis in Northern Tanzania. Acta Trop 2005, "BioMed Central will be the most significant development for 93:131-140. disseminating the results of biomedical researc h in our lifetime." 31. Kuipers EJ, Meijer GA: Helicobacter pylori gastritis in Africa. Sir Paul Nurse, Cancer Research UK Eur J Gastroenterol Hepatol 2000, 12:601-603. 32. Brubaker G, Levin AG, Steel CM, Creasey G, Cameron HM, Linsell Your research papers will be: CA, Smith PG: Multiple cases of Burkitt's lymphoma and other available free of charge to the entire biomedical community neoplasms in families in the North Mara District of Tanzania. Int J Cancer 1980, 26:165-170. peer reviewed and published immediately upon acceptance 33. Eshleman JL: A study of the relative incidence of malignant cited in PubMed and archived on PubMed Central tumours seen at Shirati Hospital in Tanzania. East Afr Med J 1966, 43:274-283. yours — you keep the copyright BioMedcentral Submit your manuscript here: http://www.biomedcentral.com/info/publishing_adv.asp Page 7 of 7 (page number not for citation purposes)
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