7
Helicobacter pylori infection prevents allergic asthma in mouse models through the induction of regulatory T cells.
J Clin Invest. 2011 Aug 1; 121(8):3088-93
All selected articles haveThis article has been added to your saved articles
You can follow/unfollow articles via MyF1000 or via the article or browse pages.
02 Aug 2011
New Finding
DOI: 10.3410/f.12279956.13454054
The emergence of new epidemics such as bronchial asthma has been linked to the gradual disappearance of some childhood infections. An inverse association between Helicobacter pylori infection and asthma has been reported in humans. Its mechanism is unknown. This study confirms the association between...Continue reading
The emergence of new epidemics such as bronchial asthma has been linked to the gradual disappearance of some childhood infections. An inverse association between Helicobacter pylori infection and asthma has been reported in humans. Its mechanism is unknown. This study confirms the association between asthma and H. pylori infection.
The investigators utilized a mouse model of allergic airway disease induced by ovalbumin or house dust mite allergen to examine the inverse correlation between H. pylori infection and asthma. Infected animals were protected against airway hyperresponsiveness, tissue inflammation, and goblet cell metaplasia, hallmarks of asthma, and prevented allergen-induced pulmonary and bronchioalveolar infiltration with eosinophils, T helper 2 and 17 lymphocytes (Th2, Th17). Protection against asthma was more robust in mice infected neonatally and was abrogated by antibiotic eradication of H. pylori. Asthma protection was further associated with impaired maturation of dendritic cells and and accumulation of highly suppressive Treg lymphocytes. These findings confirm experimentally the clinical and epidemiologic reports of the inverse association between asthma and H. pylori infection and offer a compelling mechanistic explanation of the phenomenon based on immunologic dysregulation.
The investigators utilized a mouse model of allergic airway disease induced by ovalbumin or house dust mite allergen to examine the inverse correlation between H. pylori infection and asthma. Infected animals were protected against airway hyperresponsiveness, tissue inflammation, and goblet cell metaplasia, hallmarks of asthma, and prevented allergen-induced pulmonary and bronchioalveolar infiltration with eosinophils, T helper 2 and 17 lymphocytes (Th2, Th17). Protection against asthma was more robust in mice infected neonatally and was abrogated by antibiotic eradication of H. pylori. Asthma protection was further associated with impaired maturation of dendritic cells and and accumulation of highly suppressive Treg lymphocytes. These findings confirm experimentally the clinical and epidemiologic reports of the inverse association between asthma and H. pylori infection and offer a compelling mechanistic explanation of the phenomenon based on immunologic dysregulation.
References
1.
What are the consequences of the disappearing human microbiota?
Nat Rev Microbiol 2009 Dec; 12(7):887-94
PMID: 19898491
Disclosures
None declared
Add Comment
Correa P: F1000Prime Recommendation of [Arnold IC et al., J Clin Invest 2011, 121(8):3088-93]. In F1000Prime, 02 Aug 2011; DOI: 10.3410/f.12279956.13454054. F1000Prime.com/12279956#eval13454054
05 Aug 2011
New Finding
DOI: 10.3410/f.12279956.13589058
The decreased prevalence of Helicobacter pylori has been accompanied by an epidemic of allergic asthma among children in the US and other developed countries. However, evidence that the two phenomena are mechanistically related is lacking. Arnold and colleagues in the Müller lab have now elegantly shown...Continue reading
The decreased prevalence of Helicobacter pylori has been accompanied by an epidemic of allergic asthma among children in the US and other developed countries. However, evidence that the two phenomena are mechanistically related is lacking. Arnold and colleagues in the Müller lab have now elegantly shown that induction of regulatory T (Treg) cells by H. pylori infection can protect against ovalbumin (OVA)- and house dust mite-induced allergic airway disease in a mouse model of asthma.
The immune response to H. pylori entails both innate effectors and a complex mix of T helper (Th)1, Th17, and Treg adaptive immune responses. Treg cells are more prominent in children than in adults and the inflammatory response is correspondingly less severe. Previous work from the Müller lab showed that, compared to adult mice, neonatal mice infected with H. pylori have increased Treg cells, which leads to decreased gastritis but at the cost of an enhanced bacterial burden and impaired response to immunization. Now this same group has analyzed whether the immune tolerance phenotype induced in H. pylori-infected neonatal mice could also affect the inflammatory response to allergens in the lung. Airway constriction and inflammation were analyzed in C57Bl/6 mice that had been infected with H. pylori at 6 days (neonates) or 6 weeks (adults) of age, stimulated with adjuvanted OVA or house dust mite and challenged with methacholine.
Mice that were infected with H. pylori as neonates showed significantly less airway restriction and inflammation than uninfected mice, while those infected as adults showed an intermediate phenotype. Decreased inflammation in the lungs was associated with fewer eosinophils and higher percentages of Treg cells and semi-mature macrophages, which express low or intermediate levels of major histocompatibility complex (MHC)II. Adoptive transfer of Treg cells isolated from protected mice reproduced the phenotype H. pylori infection on allergic asthma. These data provide strong evidence that Treg cells induced during H. pylori infection are sufficient to confer asthma protection, and they suggest that the decreased prevalence of H. pylori and the increase in asthma may be causally linked. If the immune effects of H. pylori infection could be phenocopied by immunomodulation, a vaccine strategy might be a reasonable approach to the prevention of asthma in developed countries. Preliminary evidence for this concept has already been provided showing that immunization with the H. pylori neutrophil-activating protein can downmodulate Th2 inflammation in OVA-induced asthma in mice {1}.
The immune response to H. pylori entails both innate effectors and a complex mix of T helper (Th)1, Th17, and Treg adaptive immune responses. Treg cells are more prominent in children than in adults and the inflammatory response is correspondingly less severe. Previous work from the Müller lab showed that, compared to adult mice, neonatal mice infected with H. pylori have increased Treg cells, which leads to decreased gastritis but at the cost of an enhanced bacterial burden and impaired response to immunization. Now this same group has analyzed whether the immune tolerance phenotype induced in H. pylori-infected neonatal mice could also affect the inflammatory response to allergens in the lung. Airway constriction and inflammation were analyzed in C57Bl/6 mice that had been infected with H. pylori at 6 days (neonates) or 6 weeks (adults) of age, stimulated with adjuvanted OVA or house dust mite and challenged with methacholine.
Mice that were infected with H. pylori as neonates showed significantly less airway restriction and inflammation than uninfected mice, while those infected as adults showed an intermediate phenotype. Decreased inflammation in the lungs was associated with fewer eosinophils and higher percentages of Treg cells and semi-mature macrophages, which express low or intermediate levels of major histocompatibility complex (MHC)II. Adoptive transfer of Treg cells isolated from protected mice reproduced the phenotype H. pylori infection on allergic asthma. These data provide strong evidence that Treg cells induced during H. pylori infection are sufficient to confer asthma protection, and they suggest that the decreased prevalence of H. pylori and the increase in asthma may be causally linked. If the immune effects of H. pylori infection could be phenocopied by immunomodulation, a vaccine strategy might be a reasonable approach to the prevention of asthma in developed countries. Preliminary evidence for this concept has already been provided showing that immunization with the H. pylori neutrophil-activating protein can downmodulate Th2 inflammation in OVA-induced asthma in mice {1}.
References
1.
The neutrophil-activating protein of Helicobacter pylori down-modulates Th2 inflammation in ovalbumin-induced allergic asthma.
Cell Microbiol 2008 Nov; 11(10):2355-63
PMID: 18671823
Disclosures
None declared
Solnick J and Moore M: F1000Prime Recommendation of [Arnold IC et al., J Clin Invest 2011, 121(8):3088-93]. In F1000Prime, 05 Aug 2011; DOI: 10.3410/f.12279956.13589058. F1000Prime.com/12279956#eval13589058
05 Oct 2011
New Finding
DOI: 10.3410/f.12279956.14688132
This is a very original and well-conducted study investigating the impact of an in-vivo infection of the human gastric pathogen, Helicobacter pylori, on asthma manifestation in mice. The rationale that legitimated this report comes from epidemiologic observations showing that individuals with an H....Continue reading
This is a very original and well-conducted study investigating the impact of an in-vivo infection of the human gastric pathogen, Helicobacter pylori, on asthma manifestation in mice. The rationale that legitimated this report comes from epidemiologic observations showing that individuals with an H. pylori colonization in their gastric niche have lower risks of childhood asthma, rhinitis and skin allergies than those without H. pylori. In addition, longitudinal studies have established that the progressive decline in H. pylori prevalence observed in developed countries in the last century was associated with the increased onset of asthma-related disorders.
The causal relationship between these events has not been clearly identified, but it was suspected that H. pylori deficiency impairs the immune tolerance of the gastric mucosa by modifying T- and B-cell trafficking and the production of immunosuppressive cytokines.
To investigate the mechanisms behind the inverse association between H. pylori colonization and asthma, orally infected and non-infected naïve mice were immunized and challenged with ovalbumin or with house dust mite (HDM) and hallmarks of asthma were assessed. The authors demonstrated that H. pylori infection protected immunized mice from asthma-like symptoms and airway inflammation by specifically modulating T-regulatory (Treg) and dendritic cells.
The data presented herein showed that the in-vivo infection of neonate (6 days of age) or adult (6 weeks of age) C57BL/6 mice with H. pylori prevented ovalbumin- and HDM-induced bronchial hyperreactivity to methacholine, eosinophil accumulation and Th2 type cytokine release (interleukin (IL)-5 and IL-13) in the bronchoalveolar lavage fluid, T-helper (Th)-2 and Th-17 cell infiltration into the airway and epithelium mucus hypersecretion. Notably, asthma protection by H. pylori was more prominent when the infection was induced in neonates, suggesting that the mechanisms involved in this effect are more efficient in early life. In addition, antibiotic therapy given at the time of antigen sensitization resulted in bacteria killing and suppression of asthma protection.
In further experiments the authors showed that, when compared to uninfected mice and to adult-infected counterparts, neonatally H. pylori-infected mice had elevated numbers of Tregs and of immature dendritic cells with low major histocompatibility complex (MHC)-II expression in the lung. Immunologic Treg depletion during antigen challenge abrogates asthma protection, whereas adoptive transfer of purified Tregs from infected mice to uninfected recipients was sufficient to restore this response.
In conclusion, these findings indicate that early infection with H. pylori induces the development of Tregs that, in turn, confer protection against asthma manifestations partly through impairment of dendritic-cell maturation.
The relationship between humans and their commensal microbial populations and the role of these interactions in the emergence of allergic diseases are matters of debate {1}. Numerous epidemiological, clinical and animal studies have suggested that exposure to commensal, non-pathogenic microorganisms early in life leads to protection against immunoglobulin-E (IgE)-mediated allergies, including asthma. Therefore, a better assessment of the risks or benefits of deliberately modifying the composition of gastrointestinal commensal microbia is an important challenge for potential future therapeutic or preventive interventions.
The causal relationship between these events has not been clearly identified, but it was suspected that H. pylori deficiency impairs the immune tolerance of the gastric mucosa by modifying T- and B-cell trafficking and the production of immunosuppressive cytokines.
To investigate the mechanisms behind the inverse association between H. pylori colonization and asthma, orally infected and non-infected naïve mice were immunized and challenged with ovalbumin or with house dust mite (HDM) and hallmarks of asthma were assessed. The authors demonstrated that H. pylori infection protected immunized mice from asthma-like symptoms and airway inflammation by specifically modulating T-regulatory (Treg) and dendritic cells.
The data presented herein showed that the in-vivo infection of neonate (6 days of age) or adult (6 weeks of age) C57BL/6 mice with H. pylori prevented ovalbumin- and HDM-induced bronchial hyperreactivity to methacholine, eosinophil accumulation and Th2 type cytokine release (interleukin (IL)-5 and IL-13) in the bronchoalveolar lavage fluid, T-helper (Th)-2 and Th-17 cell infiltration into the airway and epithelium mucus hypersecretion. Notably, asthma protection by H. pylori was more prominent when the infection was induced in neonates, suggesting that the mechanisms involved in this effect are more efficient in early life. In addition, antibiotic therapy given at the time of antigen sensitization resulted in bacteria killing and suppression of asthma protection.
In further experiments the authors showed that, when compared to uninfected mice and to adult-infected counterparts, neonatally H. pylori-infected mice had elevated numbers of Tregs and of immature dendritic cells with low major histocompatibility complex (MHC)-II expression in the lung. Immunologic Treg depletion during antigen challenge abrogates asthma protection, whereas adoptive transfer of purified Tregs from infected mice to uninfected recipients was sufficient to restore this response.
In conclusion, these findings indicate that early infection with H. pylori induces the development of Tregs that, in turn, confer protection against asthma manifestations partly through impairment of dendritic-cell maturation.
The relationship between humans and their commensal microbial populations and the role of these interactions in the emergence of allergic diseases are matters of debate {1}. Numerous epidemiological, clinical and animal studies have suggested that exposure to commensal, non-pathogenic microorganisms early in life leads to protection against immunoglobulin-E (IgE)-mediated allergies, including asthma. Therefore, a better assessment of the risks or benefits of deliberately modifying the composition of gastrointestinal commensal microbia is an important challenge for potential future therapeutic or preventive interventions.
References
1.
Influence of gastrointestinal commensal bacteria on the immune responses that mediate allergy and asthma.
J Allergy Clin Immunol 2011 May; 5(127):1097-107; quiz 1108-9
PMID: 21420159
Disclosures
None declared
Pretolani M: F1000Prime Recommendation of [Arnold IC et al., J Clin Invest 2011, 121(8):3088-93]. In F1000Prime, 05 Oct 2011; DOI: 10.3410/f.12279956.14688132. F1000Prime.com/12279956#eval14688132
11 Oct 2011
Steven Moss
F1000 Gastroenterology & Hepatology
Rhode Island Hospital and The Warren Alpert Medical School of Brown University,
Providence, RI, USA.
F1000 Gastroenterology & Hepatology
Rhode Island Hospital and The Warren Alpert Medical School of Brown University,
Providence, RI, USA.
Songhua Zhang
F1000 Gastroenterology & Hepatology
Rhode Island Hospital and The Warren Alpert Medical School of Brown University,
Providence, RI, USA.
F1000 Gastroenterology & Hepatology
Rhode Island Hospital and The Warren Alpert Medical School of Brown University,
Providence, RI, USA.
New Finding
DOI: 10.3410/f.12279956.14707109
This useful study conducted on ovalbumin (OVA)- or house dust mite (HDM)-challenged, Helicobacter pylori-infected neonatal and adult mice experimentally addressed and demonstrated the hypothesis that H. pylori infection may protect against childhood asthma {1}.
The link among H. pylori infection, T helper...Continue reading
The link among H. pylori infection, T helper...Continue reading
This useful study conducted on ovalbumin (OVA)- or house dust mite (HDM)-challenged, Helicobacter pylori-infected neonatal and adult mice experimentally addressed and demonstrated the hypothesis that H. pylori infection may protect against childhood asthma {1}.
The link among H. pylori infection, T helper cells, regulatory T cells (Tregs), immature dendritic cells and allergen-induced asthma was addressed in a mouse model. Neonatal and adult C57BL/6 mice were infected with H. pylori (the PMSS1 strain or an isogenic CagE-deficient mutant), and then asthma was induced by sensitization and rechallenge with OVA or HDM. Neonatally infected mice in particular had a marked reduction in airway resistance, inflammation, goblet cell metaplasia, eosinophil infiltration and secretion of interleukin (IL)-5 and IL-13 in comparison with uninfected mice. This was associated with pulmonary Treg recruitment. Experiments with adoptive Treg transfer and CD25 depletion further implicated H. pylori-specific Tregs in the protection against airway hyperresponsiveness and inflammation afforded by H. pylori infection, unrelated to H. pylori's Cag A. These results demonstrate that early exposure to H. pylori protects mice from a model of allergic asthma. They provide experimental support for the inverse relationship between H. pylori infection and allergic diseases that has been described in several recent clinical case-control and cross-sectional studies {2,3}.
The link among H. pylori infection, T helper cells, regulatory T cells (Tregs), immature dendritic cells and allergen-induced asthma was addressed in a mouse model. Neonatal and adult C57BL/6 mice were infected with H. pylori (the PMSS1 strain or an isogenic CagE-deficient mutant), and then asthma was induced by sensitization and rechallenge with OVA or HDM. Neonatally infected mice in particular had a marked reduction in airway resistance, inflammation, goblet cell metaplasia, eosinophil infiltration and secretion of interleukin (IL)-5 and IL-13 in comparison with uninfected mice. This was associated with pulmonary Treg recruitment. Experiments with adoptive Treg transfer and CD25 depletion further implicated H. pylori-specific Tregs in the protection against airway hyperresponsiveness and inflammation afforded by H. pylori infection, unrelated to H. pylori's Cag A. These results demonstrate that early exposure to H. pylori protects mice from a model of allergic asthma. They provide experimental support for the inverse relationship between H. pylori infection and allergic diseases that has been described in several recent clinical case-control and cross-sectional studies {2,3}.
References
1.
Helicobacter pylori colonization is inversely associated with childhood asthma.
J Infect Dis 2008 Aug 15; 4(198):553-60
PMID: 18598192
2.
Does Helicobacter pylori protect against asthma and allergy?
Gut 2008 May; 5(57):561-7
PMID: 18194986
3.
What are the consequences of the disappearing human microbiota?
Nat Rev Microbiol 2009 Dec; 12(7):887-94
PMID: 19898491
Disclosures
None declared
Moss S and Zhang S: F1000Prime Recommendation of [Arnold IC et al., J Clin Invest 2011, 121(8):3088-93]. In F1000Prime, 11 Oct 2011; DOI: 10.3410/f.12279956.14707109. F1000Prime.com/12279956#eval14707109
F1000Prime Recommendations, Dissents and Comments for [Arnold IC et al., J Clin Invest 2011, 121(8):3088-93]. In F1000Prime, 22 May 2013; F1000Prime.com/12279956
Only registered/signed-in users can make comments.
Sign in or Subscribe to create your user account and join the discussion.
Sign in or Subscribe to create your user account and join the discussion.
No comments yet.
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.
DOI: 10.1172/JCI45041
PMID: 21737881
