Regulatory T cells help tolerate commensal bacteria on the skin during first few weeks of life

The human skin is the body’s first line of defense against pathogens that your body comes in contact with. Just like the gut and mouth, the skin lives in communion with bacteria. One important unanswered question that many scientists have is why commensal bacteria do not trigger an inflammatory immune response when they come in contact with the skin. An article published by Cell Press explores exactly this question, looking specifically at regulatory T cells (treg, a type of white blood cell that plays a major role in establishing homeostasis of the immune system).

Researchers engineered the genes of Staphylococcus epidermidis to produce a specific protein antigen that can be fluorescently viewed. To test whether the immune system plays a role in tolerance of skin commensal bacteria the researchers colonized the skin of 6-week-old mice with this fluorescent protein. Three weeks later the mice were compared to a group of control mice and it was found that pre-colonization with the protein was not enough to establish immune tolerance of the bacterial antigens. 

The researchers were curious as to what affect this bacterial antigen on the skin of infant mice had, so the same experiment was done with 7-day-old mice. After 3-4 weeks, when the mice were adult, a significantly diminished immune response to the commensal bacteria could be seen. This shows that exposure during the neonatal period promotes tolerance to commensal bacteria.

After examining adult vs. neonatal skin, this study concludes that there is a difference between the two in terms of immune response and windows of tolerance build-up. Specifically, the period of neonatal skin development seems to be essential in mice for the immune tolerance of commensal bacteria. The implications of this study are important for understanding of the human immune system and bacteria tolerance. Because the skin is our body’s first defense system, it is important to have an understanding as to what mediates its immune response.           

Helminths may influence fecundity rates in women

We’ve often discussed helminths and their impact on human health, and researchers have recently provided more insight as to how these infective parasites can influence female reproductive health.  The immune system plays an important role in fecundity in women.  Shifts in immune responses in regulation are dynamic and these changes can have influence on pregnancy.  Helminths are known to induce marked immunological changes and they infect 500 to 800 million people worldwide.  In addition to modulating systemic immune responses, helminths are also known to directly infect reproductive organs or even the fetus.  While studied extensively in animal models, there is little known as to how helminths influence reproductive processes in humans.  A conglomerate group of scientists sought investigate how helminth infection could affect fecundity rates in women, hypothesizing that helminth infection during pregnancy may increase fecundity because the helminth-mediated immunologic responses may in fact modulate those that impair fertility. 

The researchers collected 9 years-worth of health data from 986 Bolivian women who were forager-horticulturists residing in the Amazonian lowlands of the country.  Western medicine and contraceptives are not used in this region, and it is estimated that different types of helminths infect up to 70% of the population.  Cox proportional hazards model first determined that there was an association between helminth infection and birth spacing.  Next, it was shown that women infected with hookworm were associated with a delayed age of first pregnancy.  Interestingly, and in contrast to hookworm, roundworm infection was associated with early first births (in comparison to hookworm) and shortened interbirth intervals.  The researchers postulated that these differences in associations could be explained by each respective helminth species unique effect on the immune system modulation.  Specifically, roundworm infection is associated with regulatory T cell (Treg) Type 2 immune activation, while hookworm infections are associated with mixed Treg immune activation (e.g. both Type 1 and Type 2 activation).  The association with the specific immune response could also explain why roundworm association was shown to be more favorable to conception, as Treg Type 2 activation more closely resembles pregnancy immune system activity while a Type1/Type2 mix more closely resembles an inflammatory response. 

From a broad viewpoint, these findings are interesting as they point to a species-host interaction that may have an underlying - and underappreciated - influence on demographic/population distribution.  The study of helminths is deserving of more attention, as we continue to acquire a wealth of information from their interactions with humans and implications on human health.  

Helminths suppress the immune system by modulating the gut microbiota

The nematode Heligmosomoides polygyrus, which was used in this study, seen into an optical microscope. Taken from the digestive tractus of a rodent.

Helminths, or gut worms, are known to be powerful suppressants of the immune system.  In fact, this is the basis for using helminth therapy for various autoimmune conditions, such as IBD.  Still though, the mechanisms for helminth immunosuppression is unknown.  There have been some studies that suggest the worms are secreting molecules that have this anti-inflammatory effect, but this may not tell the whole story.  Researchers from Switzerland hypothesized that because helminths and our gut bacteria evolved together, it was likely that the helminths were modulating the bacterial gut microbiome, and that this modulation was anti-inflammatory.  They tested and published results that support this idea in the latest issue of Cell Immunity.

The scientists started by showing the efficacy of a mouse helminth, Heligmosomoides polygyrus bakeri (Hpb), in reducing inflammation in mouse models of asthma.  The scientists infected mice with the parasite and exposed those mice, along with non-infected control mice, to dust mites in order to elicit and immune response.  The scientists observed that the Hpb mice had much lower circulating levels of specific cytokines and immune cells after exposure to dust mites than the controls.  Next, the scientist gave the Hpb infected mice antibiotics, which eliminated the gut bacteria but left the helminths intact.  They then exposed these mice and control mice to dust mites to elicit the immune response.  Interestingly, while the helminths alone did decrease the levels of some inflammatory molecules and cells, inflammation still occurred, similar to what was observed in controls.  This meant that the gut bacteria play a role in modulating the helminthic immune suppression.  In order to validate these findings, the scientists then performed fecal microbiota transplants from control mice or helminth infected mice into germ free mice (with no worms).  After, the challenged these mice with house dust mites and discovered that the gut bacteria alone created an immune suppression in the mice, even in the absence of the worms.

The researchers attempted to identify which bacteria may be causing this immune suppression, and measured the microbiomes of the mice.  They noted that higher levels of Clostridiales occurred in the Hpb mice.  They then measured the levels of short chain fatty acids (SCFAs) in the mice’s guts, because Clostridiales are known to produce SCFAs.  They noticed that higher levels of SCFAs, which have previously been linked to immune suppression, did occur in higher levels in mice with Hpb compared to controls.  The scientists then studied this connection between worm infection and increase in SCFAs in pigs and humans.  Remarkably, the increase in SCFAs in helminth-infected subjects compared to controls was observed across species, suggesting the immune suppressing helminth phenomenon is extensible to many mammals.  The researchers even investigated possible mechanisms for why SCFAs were able to suppress the immune system.  They discovered the SCFAs were binding specific receptors that modulate T-cells, and more depth on this issue can be found by reading the paper. 

This study is quite important as it shows that helminths in combination with the bacterial microbiome are important to immune suppression.  This suggests that future therapeutics that may take advantage of helminth-derived molecules may not be as effective.  It does, however, support helminth therapy as an immune suppressant.  However, helminths are also very dangerous and can lead to various diseases.   So, while clinical trials that use helminths are underway, there are still no approved uses for worms.  

Immune cells are educated in the gut to not attack beneficial bacteria

The gastrointestinal tract is made up of trillions of bacteria that are largely ignored by the body’s immune system.  Why is it that the body’s immune system knows to ignore these beneficial bacteria that are so important for our ability to live a healthy life? The answer to this question could play an important role in understanding how to maintain a healthy gut and how to treat diseases. Scientists led by Gregory Sonnenberg at Weill Cornell Medical College may have answered this question in a study published last week in Science.

The researchers studied T cells, cells that are made in the thymus and are trained there to kill-off foreign microbes and other intruders that make their way into the human body. But why don’t these T cells attack helpful bacteria in the GI tract? They found that the T cells are again educated in the gut to not attack beneficial bacteria but when this education is disrupted, it can lead to disease.  For example, inflammatory bowel diseases like Crohn’s disease and ulcerative colitis occur when the immune system attacks the GI tract and bacteria in the GI tract.

In the thymus, T cells that could attack the body are destroyed before they are released into circulation. In the gut, a type of cell called innate lymphoid cells (ILCs) educate the T cells to not attack beneficial bacteria. These ILCs had previously been found to make a physical barrier between the bacteria in the gut and the immune system.

In mice, they found that ILCs attacked T cells that were destroying beneficial bacteria and when they prevented this attack by ILCs on the T cells, severe intestinal inflammation resulted. They also looked at intestinal biopsies of young patients with Crohn’s disease. In the biopsies they found that the ILCs lacked specific molecules that are important for educating the T cells not to attack the bacteria in the gut. They found that a decrease in this molecule correlated with an increase in pro-inflammatory cells in children with Crohn’s disease.

The authors state that it may be possible to get rid of these T cells that are causing the inflammation and by doing so you may be able to help treat the disease.  By restoring this molecule (Major Histocompatibility Complex class II) that is preventing the education of the T cells, pro-inflammatory T cells may be reduced resulting in reduced intestinal inflammation.