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Abstract

Atopic asthma is a chronic disease of the airways that has taken on epidemic proportions in the industrialized world. The increase in asthma rates has been linked epidemiologically to the rapid disappearance of Helicobacter pylori, a bacterial pathogen that persistently colonizes the human stomach, from Western societies. In this study, we have utilized mouse models of allergic airway disease induced by ovalbumin or house dust mite allergen to experimentally examine a possible inverse correlation between H. pylori and asthma. H. pylori infection efficiently protected mice from airway hyperresponsiveness, tissue inflammation, and goblet cell metaplasia, which are hallmarks of asthma, and prevented allergen-induced pulmonary and bronchoalveolar infiltration with eosinophils, Th2 cells, and Th17 cells. Protection against asthma was most robust in mice infected neonatally and was abrogated by antibiotic eradication of H. pylori. Asthma protection was further associated with impaired maturation of lung-infiltrating dendritic cells and the accumulation of highly suppressive Tregs in the lungs. Systemic Treg depletion abolished asthma protection; conversely, the adoptive transfer of purified Treg populations was sufficient to transfer protection from infected donor mice to uninfected recipients. Our results thus provide experimental evidence for a beneficial effect of H. pylori colonization on the development of allergen-induced asthma.

Authors

Isabelle C. Arnold ... Christian Taube, Anne Müller

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The role of interleukin 10 in the prevention of allergic asthma in mouse models with Helicobacter pylori infection

Submitter:Se Jin Park | shinji@yuhs.ac

Authors: Jae Il Shin

Se Jin Park's address: Department of Pediatrics, Ajou University School of Medicine, Ajou University Hospital, Suwon, Korea. Jae Il Shin's address: The Institute of Kidney Disease, Department of Pediatrics, Yonsei University College of Medicine, Severance Children’s Hospital, Seoul, Korea

Published October 11, 2011

Dear Editor,

We read with great interest the recent contribution by Arnold et al. (1) They reported that Helicobacter pylori (HP) infection prevents allergen-induced asthma in mouse models through the induction of regulatory T (Treg) cells, provding experimental evidence that the adoptive transfer of purified Treg populations was sufficient to transfer protection from infected donor mice to uninfected recipients. However, not only in mouse models but also in humankind, inverse correlation between allergy and HP infection exists (2). We would like to specify a possible mechanism of HP protecting from allergy.

According to a previous study by Codolo et al. (3), systemic HP neutrophil-activating protein (HP-NAP) significantly resulted in both reduction of total serum IgE and increase of interleukin 12 (IL-12) plasma levels. Mucosal administration of HP-NAP was equally successful as the systemic delivery in reducing eosinophilia, IgE, and T helper type 2 (Th2) cells cytokine levels in bronchoalveolar lavage. In contrast, Windle et al. (4) found that IL-10 production by lamina propria lymphocytes was significantly higher in the HP positive group after stimulation with HP-NAP (P < 0.05) than in the HP negative group. Bontems et al. (5) also showed that IL-10 concentration was increased in HP-infected children compared with adults (P < 0.05). Furthermore, Harris et al. (6) demonstrated that HP infection in the children was associated with markedly increased levels of gastric IL-10 messenger RNA, suggesting that gastric Treg cell responses down-regulate the inflammation and ulceration induced by HP in children. IL-10, originally named “cytokine synthesis inhibitory factor”, is an major agent in the resolution of asthmatic inflammation, inhibiting eosinophilia by suppression of IL-5 and granulocyte macrophage-colony stimulating factor, by direct effects on eosinophil apoptosis, and by effects on cell proliferation through down-regulation of IL-1 (7). It is thought to occur through the upregulation of suppressor of cytokine signaling-3. After stimulation by allegen, IL-10-secreting Treg cells inhibit cytokine seceretion by allergen-specific Th2 cells in an IL-10-dependent manner (8). The treatment of allergen-injection immunotherapy may induce IL-10-secreting Treg cells, leading to suppression of Th2 responses (9).

Therefore, there is a possibility when a patient is infected by CagA+ HP, IL-10 stimulated by HP-NAP may play a crucial role in preventing asthma through the induction of Treg cells. However, further studies are necessary to elucidate the exact molecular role of IL-10 and specific correlation between “hygiene hypothesis” or “disappearing microbiota hypothesis” including HP and asthma incidence in the future.

Correspondence to: Jae Il Shin, M.D. Address: 50 Yonsei-ro, Seodaemun-gu, C.P.O. Box 8044, Department of Pediatrics, Yonsei University College of Medicine, Seoul 120-752, Korea Tel.: +82-2-2228-2050, Fax: +82-2-393-9118, E-mail: shinji@yuhs.ac

References

  1. Arnold IC, et al. Helicobacter pylori infection prevents allergic asthma in mouse models through the induction of regulatory T cells. J Clin Invest. 2011;121(8):3088-3093.
  2. Serrano CA, et al. Inverse correlation between allergy markers and Helicobacter pylori infection in children is associated with elevated levels of TGF-β. Eur J Gastroenterol Hepatol. 2011;23(8):656-663.
  3. Codolo G, et al. The neutrophil-activating protein of Helicobacter pylori down- modulates Th2 inflammation in ovalbumin-induced allergic asthma. Cell Microbiol. 2008;10(11):2355-2363.
  4. Windle HJ, Ang YS, Athie-Morales V, McManus R, Kelleher D. Human peripheral and gastric lymphocyte responses to Helicobacter pylori NapA and AphC differ in infected and uninfected individuals. Gut. 2005;54(1):25-32.
  5. Bontems P, Robert F, Van Gossum A, Cadranel S, Mascart F. Helicobacter pylori modulation of gastric and duodenal mucosal T cell cytokine secretions in children compared with adults. Helicobacter. 2003;8(3):216-226.
  6. Harris PR, et al. Helicobacter pylori gastritis in children is associated with a regulatory T-cell response. Gastroenterology. 2008;134(2):491-499.
  7. Ogawa Y, Duru EA, Ameredes BT. Role of IL-10 in the resolution of airway inflammation. Curr Mol Med. 2008;8(5):437-445.
  8. Xystrakis E, et al. Reversing the defective induction of IL-10-secreting regulatory T cells in glucocorticoid-resistant asthma patients. J Clin Invest. 2006;116(1):146-155.
  9. Robinson DS, Larché M, Durham SR. Tregs and allergic disease. J Clin Invest. 2004;114(10):1389-1397.

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