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 allergy, 3, 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 immunology, 138(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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