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Saturday, December 8, 2018

Like Mother like Child: Transferring Protection from Allergic Reactions Through Bacteria



Based on the article: Transmaternal Helicobacter pylori exposure reduces allergic airway inflammation in offspring through regulatory T cells, Kyburz et al (2018).

Allergic responses to certain particles in the environment and foods can cause unpleasant symptoms of sneezing, itchiness, shortness of breath, and can sometimes be life-threatening.  The immune system’s response to allergens such as grass, pet dander, etc. is exaggerated since the body should have mechanisms in place to avoid mounting attacks against these innocuous pathogens.  Allergies and asthma are a major lifestyle factor for many Americans, with about 60 million having some type of allergic disease or sensitivity (1).  The prevalence of allergic disorders has increased in recent decades, especially in more developed countries (2).  Some researchers have proposed the ‘hygiene hypothesis’ which suggests that exposure to infectious agents can help to educate the immune system and protect against development of severe allergy (2). Hygiene is not entirely bad, but has led to the investigation of ways that some pathogens might confer protection from allergic inflammatory conditions.
One studied relationship is that of allergy/asthma with Helicobacter pylori infection. H. pylori is a type of bacteria that colonizes in the gut and is associated with inflammatory conditions that increase risk of developing chronic gastritis and gastric cancers (3).  Prevalence rates are often higher in groups of lower socioeconomic status and in developing countries (3).  There is an inverse relationship between H. pylori infection and asthma and allergy, wherein infection with H. pylori confers some protective role in inhibiting the allergic response (3)
In allergic responses, a subset of helper T cells, called Th2, are important in directing the specific inflammatory response to allergens.  These cells secrete cytokines, or chemical messenger signals, that help to activate responses in other cells such as B cells and mast cells, activating the production of IgE antibodies (2).  The first exposure to an allergen sensitizes or arms the mast cells with lots of IgE antibodies coated on their surface.  Subsequent exposure to the allergen binds to those antibodies and triggers these armed cells to release inflammatory molecules and messengers causing many of the irritating symptoms associated with allergies (4). When H. pylori bacteria colonize in the gut, they activate immune cells to follow a different style of response, using Th1 cells instead.  These cells secrete different types of cytokines, and promote different inflammation, that also inhibits the Th2 response.  Since the Th2 cells are critical in allergic reactions, the suppression of this response limits the reactivity to allergens (2). 


Diagram showing how H. pylori secretes toxins and molecules that influence the shift towards an inflammatory Th1 response (2). 

Regulatory T cells (Tregs) are another type of cell implicated in allergy/asthma, as they promote and sustain tolerance of allergens to prevent allergic responses in the immune system (5).  These cells can secrete molecules and express proteins to suppress responses and activities of immune cells, like the helper T cells.  Thus, Kyburz et al (2018) sought to further investigate the relationship between these concepts with their study focused on the potential transferring of protective benefits of H. pylori from mothers to their offspring to decrease allergic airway inflammation. 
Diagram showing the relationship between H. pylori and the possibility that they induce Tregs to suppress both Th1 and Th2 responses (2). 
 
In this experiment, the researchers treated pregnant and lactating mice with an extract of H. pylori bacteria.  Their offspring received an initial dose of allergen to arm their immune cells, followed by a second dose of allergen to detect the degree of reaction.  Samples were collected from the fluid from the offspring’s bronchiolar/lung area (BALF), which would be analyzed to evaluate the inflammatory airway responses (6). Some of the effects that were observed were related to decreased airway inflammation and immune cell migration to the lung area.  There were decreased amounts of IgE and Th2 cytokines as well, suggesting that the bacterial exposure helped to decrease the allergic inflammatory response compared to the control group which did not receive H. pylori (6).  When they tested this with other bacteria, such as E. coli, the same results were not observed, suggesting that it was a specific bacterial response (6).  Additionally, they noted that the overall immune system was not suppressed, but isolated to the areas of the airway (6).  More specifically, exposure to one of the toxins that H. pylori can produce, VacA, reduced the inflammatory allergic response in the airway (Figure 1, 2).


Figure 1E, 2E.  This shows what researchers called the lung inflammation score, a measurement of reaction to allergens assessed by viewing stained lung sections.  1E shows the H. pylori decreases the inflammation score in offspring when exposed to H. pylori (pre or post natally) as compared to E. coli, another bacteria, or PBS (a phosphate buffer), the control.  2E shows that exposure to just the VacA toxin released by H. pylori also decreases inflammation (6).  

The researchers next examined the profile of T cells in the offspring’s lungs and found that offspring who were exposed to their mother’s H. pylori in utero or during lactation had lower amounts of T cells, especially ones that secrete cytokines in the Th1 response (6).  While there were not huge discrepancies in the amoung of Tregs, the mice exposed to bacteria had higher amounts of certain subsets of Tregs that are associated with higher suppressive activity (6). Tregs secrete an important cytokine called IL-10, which focuses on suppressing the mast cells and other Th2 responses that are involved in asthma and allergy (5).  The researchers manipulated the Treg populations in the mice by depleting them through targeting them with a toxin called Diphtheria Toxin.  Then, they gave them a dose of the allergen and measured the allergic reactions in the airway.  Losing the Treg function reduced the protective effects of the bacteria, as Tregs are able to help suppress the Th2 responses stimulated by allergens (6, Figure 5).

Figure 5E. This shows the measurement of lung inflammation in control (PBS, phosphate buffer) and H. pylori conditions where the Diphtheria Toxin treatment was added to eliminate Treg populations.  When DT was used in H. pylori exposed mice, the inflammation score was higher than the treatment where Treg populations were not manipulated (6). 

Finally, the researchers investigated how this protective advantage was transferred to offspring and future generations. Maternal exposure to things such as tobacco, microbes, and nutrients in the environment have been linked to influencing fetal immune systems (6).  They explored an epigenetic explanation for this phenomenon.  The field of epigenetics studies how gene expression can be activated or inactivated by modifications to the DNA rather than changes in the genetic code (7).  Methylation of DNA adds a carbon group to the DNA so that it is more difficult to express that gene.  This study found that the Foxp3 gene was demethylated in mice that were exposed to H. pylori (6).  Foxp3 is a gene that is expressed in Tregs, and thus, demethylation would allow it to be expressed more readily (5).  This confirmed a relationship between Tregs protecting from allergic responses in the mice that had exposure to H. pylori.  
Not only does this study further confirm the relationship between certain bacterial exposure and decreased allergy, but points to epigenetic modifications that allow this advantage to be transferred to subsequent generations of offspring through maternal pathways.  It is limited in its application, however, as it would not be advisable to infect everyone with H. pylori just to suppress allergic reactions.  Further research could investigate the role that the gut microbiome has in these processes to determine whether it is a cause or consequence of allergic immune responses.  The data is most applicable for future studies examining how to treat and mediate individuals with allergies, given that this bacterial exposure did not induce immunosuppression everywhere in the body. 
 


References:

1.     What is Allergic Disease? Asthma and Allergy Foundation of America. Retrieved December 8, 2018 from http://fightthecauseofallergy.org/page/what-allergic-disease-0.
2.     Amedei, A., Codolo, G., Del Prete, G., de Bernard, M., & D'Elios, M. M. (2010). The effect of Helicobacter pylori on asthma and allergy. Journal of asthma and allergy3, 139-47. doi:10.2147/JAA.S8971
3.     Parikh NS, Ahlawat R. Helicobacter Pylori. [Updated 2018 Nov 14]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2018 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK534233/. 
4.     Mak, T.W., Saunders, M.E., & Jett, B.D. (2014). Primer to the Immune Response. Burlington, MA: Elsevier Inc. 
5.     Noval Rivas, M., & Chatila, T. A. (2016). Regulatory T cells in allergic diseases. The Journal of allergy and clinical immunology138(3), 639-652.
6.     Kyburz, A., Fallegger, A. Zhang, X. … & Müller, A. (2018).  Transmaternal Helicobacter pylori exposure reduces allergic airway inflammation in offspring through regulatory T cells. Journal of Allergy and Clinical Immunology, https://doi.org/10.1016/j.jaci.2018.07.046.
7.     A Super Brief and Basic Explanation of Epigenetics for Total Beginners (2018, November 26). Retrieved from https://www.whatisepigenetics.com/what-is-epigenetics/. 
8.   Immune Cells: NIH: National Institute of Allergy and Infectious Diseases. (2018, November 30). Retrieved from https://www.niaid.nih.gov/research/immune-cells







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