December 31, 2018
Part II Newborn Tolerance:
If the immune system wants to learn which ingested proteins are good and which are troublemakers at birth, where would it go wrong?
The answer is very complicated, however, one of the driving factors seems to be the lack of exposure to friendly bacteria that act as an immune educator. This is the basis of the biome depletion theory. In the absence of this natural exposure and education, the immune system is believed to become intolerant to perturbations over time.
As we discussed, the military police/Treg cells are critical to the immune system's ability to dampen inflammation after a robust response to an invading pathogen has occurred.
In order for the T regs to develop correctly, we currently know of three major stimuli that are necessary. First, we need adequate levels of vitamin D to turn on a gene called FoxP3, which in turn increases the production of the immune dampening beneficial Treg cells. Second, we need friendly bacteria in our intestines as they also have the ability to turn on FoxP3. Third, vitamin A is necessary for dendritic cells to promote Treg cell differentiation. (Tan et. al. 2016)
Achieving these three goals comes from natural living where an infant receives the nutrients from breastmilk and later the child is exposed to adequate sunlight daily, eats lots of colorful vegetables and fruits while being licked by a cat, dog or other animal that helps share good friendly bacteria. In truth, the historical route of exposure was through human exposure to dust, dirt and food that had animal endotoxin in it from local farm animals.
Now this is only the beginning of the process for the immune system. As a child ages, these events must continue to keep the immune system primed and happy.
Assuming that your child has been delivered vaginally, was breastfed and had adequate microbial exposure in infancy while being exposed to the sun, does that mean that we are out of the woods?
The answer is no!
Let us look at the gut lining in a child. At the level of the intestine, children have a long row of cells that protect 70+% of the immune system from being overtly exposed to the contents of the child's diet and ingested pathogens. In proper tolerant function, the dendritic cells are situated between some of the gut cells sending up a hand in between these cells to taste the intestinal world as bacteria and food slide by. This is really important! The system was set up to have a barrier wall between the outside world and us. This allows the immune system to keep bad guys in the intestine while memorizing them just in case they find their way to a sensitive location or grow in number becoming pathogenic. Ingested food should be used by us as nourishment and not memorized as a bad guy but conversely as a helper.
What is keeping this area healthy? Why would it breakdown? Is this the point at which food allergies arise?
To answer these questions, we need to look closer at the gut cells.
These cells are simple long columnar cells that form a row like soldiers in a line that are held tightly together by tight junctions. They gather to make a really long tube that we call the intestine.
As a child ingests food, it slides down into the stomach where it is digested into basic components. The beneficial nutrients travel onward and get absorbed in the small intestine leaving the remaining material to pass all the way until we have stool.
Soon after birth, the lining of the intestine is covered in bacteria hopefully from breastfeeding and a vaginal delivery. These friendly bacteria produce all sorts of chemicals that support this healthy column of cells. They also help produce a mucous layer that lines the tube adding another layer of protection. If everything goes well, then food proteins are utilized, bacteria and viral material are controlled and life is good.
(The following section is a posited belief about the mechanism of allergy/autoimmune development and is still in debate.)
Let us say that the child was born via c - section, bottle fed with cow's milk formula and had limited exposure to good bacteria. Uh oh. Now we have a problem where the bacteria in the intestine are likely not friendly nor beneficial. It is well known now that these abnormal bacteria are causing negative alterations in the immune system and thus the gut lining is poorly maintained. If this poorly maintained gut lining starts to allow large food proteins and other pathogens to leak into the immune sub layer, the risk for disease rises and we believe that we have a failure of tolerance. (Thum et. al. 2012)
Hypothetically in the case of allergy, if a child eats a peanut and that protein fragment happens to fall through the gut lining to the immune layer or is abnormally recognized by a hyper alert poorly tolerant immune system as foreign, we now have a tolerance break point. The child's immune system may abnormally recognize this peanut protein fragment as a foreign invader and develop an immune response that we see as an IGE antibody mediated food allergy. (Chinthrajah et. al. 2016) (Citi S 2018)
From then on every time the child consumes a peanut, the immune system thinks that he or she is being attacked by a pathogen and destroys it and unfortunately hurts the host as collateral damage.
This pattern of immune and gut lining dysfunction is believed to be the route to many diseases and it all starts at birth and progresses afterward based on our environmental experiences. Thought leaders like Drs. Alessio Fasano, Gerry Mullin and Jeffrey Bland are chasing this hypothesis mechanistically to its origin.
From the available evidence we now know that improper microbial exposure and a poorly developed microbiome in the early years of life is a major risk factor for the development of autoimmunity and allergic disease and likely most inflammation .
I have significantly oversimplified this process knowing that it is incomplete with the goal of making it understandable as we see it today. This hypothesis will evolve over time and become more clear. The main thrust of all this hypothetical theory is to give actionable advice in current terms to mitigate disease risk. So stay tuned for emerging data that adds more pieces to the puzzle of allergic and autoimmune disease and proves the pathway of disease.
Here is an excellent quote by Dr. William Parker, "A synthesis of evolutionary biology, epidemiology, modern medicine, and immunology strongly suggests that biome reconstitution and maintenance should be a major thrust of the medicine of the future. Old paradigms of pharmaceuticals as a cure for immune-associated disorders are potentially as inferior to biome reconstitution as anti-cholesterol drugs are inferior to a healthy diet and adequate exercise. We cannot escape the biology imposed by our evolution, and the medical science of the future will take that fact fully into account. At present, we need to direct intensive research toward biome reconstitution." (Parker EvMed article 2010)
Chinthrajah JACI Article
Corthay T Regulator Cells Article
Banchereau Nature Article
Raker Frontiers in Immunology Article
Proal Current Opinions in Rheumatology Article
Parker EvMed Review Article
Parker Evolution Medicine and Public Health Article
Stein NEJM Article
Tan Cell Reports Article
Thum Journal of Nutrition Article
NEJM Gut Lining Picture
Citi Science Article