The goal of treatments plans should be to develop oral tolerances and control inflammatory responses, while managing gut dysbiosis to achieve homeostasis.
To understand FPIES, it is helpful to understand where current thinking of the root mechanisms are, which are multi-factorial:
- Genetics- immune responses (via cytokines) driven my genetic markers
- Environmental influences- how the immune system is influenced by the digestive tract (birth environment, breast milk, formula, antibiotics,etc...)
- Gut Micro flora - digestion (GALT) and gut homeostasis can influence the degree and severity of the protein intolerance's (increased intestinal permeability- or also referred to as leaky gut).
- Other factors still to be determined (more research needed).
Understanding Oral Tolerance (immune responses):
Food consumed enters the body, begins the immunological process, involving white blood cells (WBC's) called Leukocytes and the chemicals they produce, called Cytokines. When the food causes an immune response, it is an antigen. That antigen activates the lymphocytes. Lymphocytes are the first to recognize and respond to foreign substances in the body. Lymphocytes are B cells or T cells. Tcells (commonly referred to as the gatekeepers of the immune system) assign T helper cells (Th) to release messaging cytokines (Cytokines are were the messaging may be part of the dysfunction in FPIES- where the immune system meets the genetics...more on this in an upcoming posts). Thelper cells are divided into 3 main category's for molecule recognition:
Th1- response when anything foreign enters the body, releases cytokines (messengers) to inflammatory markers, Tumor Necrosis Factor-alpha (TNF-a). Necrosis= death, inflammation can be a protective measure involving cell death of the invading molecule- but it needs regulating (or you have auto-immune disorder of the body attacking itself); which is where Transforming Growth Factor (TGF-B1) comes in as it is anti-inflammatory cytokine that is a regulator to balance of inflammation in immune responses. There are other cytokines involved, but this is the level at where research has been, more research is needed to study the role of further cytokines, and the impact genetics, environment and gut flora play in this mechanism. IgG antibodies will be present from this response, although IgG testing remains inconclusive to diagnosis FPIES trigger responses as these antibodies will be raised in any Th1 response (viral, immunization,etc) but may be part of a diagnostic tool in the future as it already is with gluten intolerance and Celiac disease. Th1 is designed to protect the body from virus, pathogens, tumor cells (to attack and rid them in the body); but an immature immune system is susceptible to producing Th1 responses to food proteins as well. Why some childrens' immune systems are immature at a time when they should be matured (breast milk, formula, first foods) is not yet fully understood and may involve genetics, environment factors, or both.
Th2- IgE antibodies are produced in response to antigens. Some FPIES kids can have co-existing IgE (Th2) and Non-IgE (Th1) responses.
Th3 - oral tolerance, the body recognizes food proteins as safe and nourishment to cells and does not initiate an immune response.
Understanding Inflammatory Responses:
Food is broken down into molecules, molecules are picked up by the cells in the gut (via the lymphoids- GALT) where antigenic proteins are presented to T cells (as described above). Food molecules couple with the Tcells and travel through the lymph system to the Thymus gland, where the regulatory (Treg)cells can stop any attack by the process carried out by the Cytokines (messengers). In FPIES, the cytokines involved are thought to be Transforming Growth Factor- beta (TGF-b) and possibly interleukin such as IL-10. TGF-b is an anti-inflammatory mediator (promotes oral tolerance- as stated above, the cytokine responsible for not allowing inflammation, or cell death). So, Treg cells regulate the initial response by sending out correct messengers (cytokines- TGF-b, IL-10, IL-17...). It is understood that this process is dysfunctional in FPIES, the degree of it's function/dysfunction may be what differientes the chronic vs. classic and and the severe cases of FPIES. Again, further research is needed to identify the mechanisms involved at this cytokine level and what is influencing the dysfunction. Understanding Digestion and Gut Microflora:
Intestinal flora forms a natural barrier to pathogens and also work together with the GALT (intestinal immune system within the GI tract made of lymphoid cells), Food allergic response in the gut activated by the immune system (via the GALT), is thought to lead to increased intestinal permeability, which can lead to further intolerance's and dysbiosis. One of the roles of gut micro flora is to help regulate the immune system. Disturption of microflora disrupts Treg responses (which regulates the cytokine responses- which regulates inflammation or anti-inflammatory mediators). When the antigenic presenting dendritic cell (where micro flora have their role) activates the lymphocytes, it leaves the mucousa via the lymph and enters the blood stream via the thoracic duct. The activated lymphocytes then travel back to the gut and can colonize in the same mucousa or other mucousal sites along the GI tract. This is where the Tmemory cells are then stored and activated upon re-exposure to trigger (antigen) proteins (and likely why the re-exposure can be a more intense response because of the recognition from previous activated lymphocytes. Probiotics can help manage the gut homeostasis and further reduce the mechanism of allergy responses and restore the natural barrier.
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