Lack of Genetic Influence on the Innate Inflammatory Response to Helicobacter Infection of the Gastric Mucosa

John G Nedrud,Thomas G Blanchard,William Twaddell,Raymond W Redline,Brandon M Zagorski,Steven J Czinn,Hua Ding

doi:10.3389/fimmu.2012.00181

Abstract

Helicobacter pylori (H. pylori) is a bacterial pathogen that resides at the gastric mucosa and has a world-wide prevalence of over 50%. Infection usually lasts for the life of the host, and although all infected individuals will develop histologic gastritis only a subset will develop symptomatic gastritis, peptic ulcer disease, gastric MALT lymphoma, or gastric adenocarcinoma. The bacterial and host factors that determine clinical outcome and influence the development of widely varying diseases have not been elucidated. We compared disease in Helicobacter-infected severe combined immunodeficient (SCID) mice on different genetic backgrounds with their corresponding immunocompetent partners to determine if the genetics of the host significantly impacts the innate inflammatory outcome, independent of variations in bacterial virulence factors. BALB/c SCID and C57BL/6 SCID mice developed equivalent histologic gastritis by 8 weeks of infection. Immunocompetent BALB/c mice and C57BL/6 mice developed significantly lower or higher degrees of inflammation respectively. Innate inflammation in immunodeficient mice on the C57BL/6 background remained low even in the absence of the regulatory cytokine IL-10. These results demonstrate that adaptive immunity is not required for the generation of low level inflammation in response to Helicobacter infection and that the degree of inflammation is consistent among different genetic backgrounds. Additionally, this inflammation is limited even in the absence of regulatory T cells.

Highlights

Infection of the gastric mucosa by Helicobacter pylori (H. pylori) can result in a variety of distinct pathologic outcomes including symptomatic gastritis, peptic ulcer disease, gastric MALT lymphoma, and gastric adenocarcinoma
HELICOBACTER INDUCES MORE GASTRIC INFLAMMATION IN severe combined immunodeficient (SCID) MICE THAN WILD TYPE BALB/C MICE In two separate experiments, 8–12 BALB/c and C57BL/6 mice along with their SCID counterparts were orally inoculated with H. felis and sacrificed 8 weeks post infection
IL10−/− mice had significantly fewer bacteria than both rag 1−/− mice (P < 0.001) and C57BL/6 mice (P < 0.01). These results indicate that host genetics are of limited influence on the innate inflammatory response to gastric Helicobacter infections in the absence of adaptive immunity

Summary

Introduction

Infection of the gastric mucosa by Helicobacter pylori (H. pylori) can result in a variety of distinct pathologic outcomes including symptomatic gastritis, peptic ulcer disease, gastric MALT lymphoma, and gastric adenocarcinoma. The diversity of H. pylori-associated diseases and severity can not be explained solely on the basis of specific virulence factors, certain allelic variants of such genes as cagA, vacA, oipA, and dupA are attributed to more severe disease (Atherton et al, 1995; Blaser et al, 1995; van Doorn et al, 1998; Yamaoka et al, 2002; Amieva and El-Omar, 2008; Yamaoka, 2010). Factors such as diet or geography seem to be correlative of disease frequency in certain populations but these associations are not universal. Polymorphisms in other host genes such as TNFα, IL-10, IL-8, and some TLRs have been reported to influence H. pylori pathogenesis (Amieva and El-Omar, 2008)

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