I always enjoy finding further updates, as well as medical and personal insights, written on FPIES. The perspectives of this little known clinical diagnosis are always interesting to read when you have a child with FPIES. View two well written articles here on Helium: Food Protein Induced EnterocolitisSyndrome: Diagnosis and Prognosis for FPIES.
The first, written by Dr.Nichole Evans is an informative synopsis of the the Up To Date article reviewed and updated in May 2011 on Food protein-induced proctitis/colitis, enteropathy, and enterocolitis of infancy and written by Dr. Alan M Lake, Associate Professor of Pediatrics Johns Hopkins University School of Medicine.
Dr.Evans outlines the Up To Date article nicely. "Food protein induced enterocolitis syndrome, also known as FPIES, is the most severe of all food protein-induced gastrointestinal diseases in infants". She goes on to outline the diagnosis of FPIES, based on recognition of symptoms and by monitoring response to elimination of offending proteins as well as endoscopy to rule out other conditions that may cause similar symptoms in infants. She concludes that "FPIES is an uncommon allergic disorder diagnosed by clinical features, endoscopic investigation and response to dietary management".
The next, by Dr. Pandula Siribaddana, provides a summary of the diagnosis and prognosis of FPIES utilizing two comprehensive references:
1). In 2008: "Enterocolitis Syndrome: Consensus Recommendations for Diagnosis and Treatment" written by the Japanese Research Group for Neonatal, Infantile, Allergic Disorders. Which I also, personally, have found to be a useful resource of information.
2). In 2009: Food Protein-Induced Enterocolitis Syndrome (FPIES) - a review from the UK Current Allergy & Clinical Immunology. Which happens to be one of my personal top resource articles on FPIES.
Dr. Siribaddana's article starts strong with "If ever there were a disease, which has been extensively under diagnosed and poorly managed, food protein induced enterocolitis syndrome (FPIES) would be right up in the list". He goes on to highlight the "possibility of serious complications, if not managed properly" and that "it's pathological basis is a svere cell-mediated-hypersensitivity reaction (non-IgE mediated) within the gut mucosa". His review provides the five-step process for diagnostic criteria set forth by the Japanese Research Group for Neonatal, Infantile, Allergic Disorders; which covers the symptoms, differential diagnosis, appropriate milk, body weight gain, and food challenges.
He concludes with a pivotal message to physicians, "although the paper was a consensus statement, it does not necessarily mean all affected infants and children should be managed in a similar manner. However, following the guidelines would reduce the chances of missing FPIES, which would bring long-term benefits and improved prognosis for sufferers".
Showing posts with label research. Show all posts
Showing posts with label research. Show all posts
Tuesday, July 19, 2011
Sunday, April 3, 2011
Research Studies on Non-IgE Allergy
We recently took my son to be involved in a research study at the PCRCD.
Dr.Jyonouchi runs this clinic and her current research is: Th cell polarization and candida reactivity in autistic children with food allergy. It is described: "Our previous study has shown that a high percentage of ASD children with GI symptoms reveal evidence of non IgE mediated, delayed type food allergy (NFA) against common dietary proteins (DPs) and their clinical features are similar to those in non-ASD children with NFA. In infants, the gut immune system is immature and oral tolerance develops slowly during the first 2-3 years of life. Thus, most non-ASD/NFA children outgrow this condition by 3-4 years of age. However, ASD/NFA children appear to require a longer time to outgrow NFA, indicating a possibility that ASD/NFA children have immune abnormalities rendering them more reactive to ‘harmless’ luminal antigens (food and commensal flora.) In this study, we thus hypothesize that dysregulated gut mucosal immune homeostasis is associated with altered innate immune responses that affects development of T-helper (Th) subsets. There are two specific aims for the current study: (1) Assessment of Th cell polarization in ASD children with NFA by intracellular staining of lineage-specific cytokines in Th cells. (2) Assessment of anti-inflammatory Th cell responses in ASD children with NFA by measuring production of counter-regulatory cytokines in response to specific luminal Ag
Dr.Jyonouchi has studied the effects of Non-IgE food allergy (by immune mechanisms to food proteins as described above) with populations of Autistic Spectrum disorders, as well as Inflammatory Bowel Diseases. She describes Non-IgE food allergy in her paper: Non-IgE Food Allergy.
Dr.Jyonouchi concludes much of her findings for treatment around gut homeostasis, and notes in this Pediatric Allergy and Immunology article that "it is crucial for gut mucousal immmune system to establish immune homeostasis that permits us to 1). cohabit with commensal flora under a mutual benefiical relationship, 2). digest huge amounts of macronutrients without provoking immune reactions (oral tolerance), and 3). maintain effective immune defense against pathogens. This somewhat conflicting task may make the gut mucousal immune system error prone, requiring active counter-regulatory measures such as developement of regulatory T (Treg) cells. These measures appear to develop gradually during the first few years of life and this is why infants are prone to be reactive to common dietary proteins in IgE or Non-IgE dependent manner."
I follow her here as much of my own research leads me here as well. While there is much of her research that we can transfer to learn more of FPIES immune responses, mechanisms, gut flora and homeostasis in our own children....but more FPIES-specific research is needed.
Dr.Jyonouchi runs this clinic and her current research is: Th cell polarization and candida reactivity in autistic children with food allergy. It is described: "Our previous study has shown that a high percentage of ASD children with GI symptoms reveal evidence of non IgE mediated, delayed type food allergy (NFA) against common dietary proteins (DPs) and their clinical features are similar to those in non-ASD children with NFA. In infants, the gut immune system is immature and oral tolerance develops slowly during the first 2-3 years of life. Thus, most non-ASD/NFA children outgrow this condition by 3-4 years of age. However, ASD/NFA children appear to require a longer time to outgrow NFA, indicating a possibility that ASD/NFA children have immune abnormalities rendering them more reactive to ‘harmless’ luminal antigens (food and commensal flora.) In this study, we thus hypothesize that dysregulated gut mucosal immune homeostasis is associated with altered innate immune responses that affects development of T-helper (Th) subsets. There are two specific aims for the current study: (1) Assessment of Th cell polarization in ASD children with NFA by intracellular staining of lineage-specific cytokines in Th cells. (2) Assessment of anti-inflammatory Th cell responses in ASD children with NFA by measuring production of counter-regulatory cytokines in response to specific luminal Ag
in comparison with responses to stimuli of innate immunity. Our long-term objective is to assess immune abnormalities associated with oral tolerance in ASD/NFA children. Obtained data are expected to be helpful for identifying risk factors for development of NFA and dysbiosis in autistic children."
(PI: Harumi Jyonouchi, M.D. University of Medicine and Dentistry of New Jersey-New Jersey Medical School.)
Our son, and the other FPIES children that are going there are among her "control" group. The Non-IgE Food Allergy children without ASD (autism spectrum disorder).
Dr.Jyonouchi has done a few studies of this nature. In the study, she tests for the production of proinflammatory (TNF-a, IFN-g, IL-5, IL-12) and counter-regulatory (Il-10, IL-17, TGF-b, ) cytokines production to milk (whey and casein), soy, wheat (gliadin), as well as Candida. The results can help determine classic, chronic, aytpical FPIES responses to these proteins; but mostly it can help determine where in these mechanisms the "break down" is. Does your child have too strong proinflammatory cytokine responses? Treating every protein as foreign and launching attacks of inflammatory mediators? Does the body respond with proinflammatory mediators only to lack sufficient counter regulatory cytokines? Does the body produce minimal proinflammatory mediators but then over-react with counter-regulatory cytokines? It can define more of what is happening at this cellular level. Past research has led to the T-cell mechanism of a Non-IgE food allergy; these tests help define that- with dairy, soy, wheat proteins. Our son, and the other FPIES children that are going there are among her "control" group. The Non-IgE Food Allergy children without ASD (autism spectrum disorder).
Dr.Jyonouchi has studied the effects of Non-IgE food allergy (by immune mechanisms to food proteins as described above) with populations of Autistic Spectrum disorders, as well as Inflammatory Bowel Diseases. She describes Non-IgE food allergy in her paper: Non-IgE Food Allergy.
Dr.Jyonouchi concludes much of her findings for treatment around gut homeostasis, and notes in this Pediatric Allergy and Immunology article that "it is crucial for gut mucousal immmune system to establish immune homeostasis that permits us to 1). cohabit with commensal flora under a mutual benefiical relationship, 2). digest huge amounts of macronutrients without provoking immune reactions (oral tolerance), and 3). maintain effective immune defense against pathogens. This somewhat conflicting task may make the gut mucousal immune system error prone, requiring active counter-regulatory measures such as developement of regulatory T (Treg) cells. These measures appear to develop gradually during the first few years of life and this is why infants are prone to be reactive to common dietary proteins in IgE or Non-IgE dependent manner."
I follow her here as much of my own research leads me here as well. While there is much of her research that we can transfer to learn more of FPIES immune responses, mechanisms, gut flora and homeostasis in our own children....but more FPIES-specific research is needed.
Saturday, March 19, 2011
Fruit Protein: Another cause of FPIES
I found this article: Fruit Protein; Another cause of FPIES while reading through the previous article I posted about (New FPIES study from Isreal). It, of course, grabbed my attention because of the commonality of so many kids in the support groups having problems with fruit proteins as much as the common triggers.
The article describes the documented case of an infant who had a positive, classic reaction to a fruit mixture. The confirmation was made when the fruits were stopped and symptoms subsided, and then reintroduction elicited an FPIES trigger response.
The concluding paragraph in the article is intriguing for more research, as it spells out some possible connections with fruits due to their plant tissue structures...."The present study clearly shows that also proteins contained in fruits can be responsible of FPIES, which may have a prolonged course. Plant tissues contain thousands of different proteins (5) and it is difficult to identify the culprit antigens. Common related proteins such as nonspecific lipid transfer proteins, which are resistant to proteolysis and thermal treatment, and/or pathogenesis-related proteins might be the antigens responsible for the reaction."
The article describes the documented case of an infant who had a positive, classic reaction to a fruit mixture. The confirmation was made when the fruits were stopped and symptoms subsided, and then reintroduction elicited an FPIES trigger response.
The concluding paragraph in the article is intriguing for more research, as it spells out some possible connections with fruits due to their plant tissue structures...."The present study clearly shows that also proteins contained in fruits can be responsible of FPIES, which may have a prolonged course. Plant tissues contain thousands of different proteins (5) and it is difficult to identify the culprit antigens. Common related proteins such as nonspecific lipid transfer proteins, which are resistant to proteolysis and thermal treatment, and/or pathogenesis-related proteins might be the antigens responsible for the reaction."
Wednesday, March 16, 2011
New study on FPIES!
Here is another great example of mom's helping mom's....another FPIES mom brought this article to my attention (thanks Ashley!) She found this article in her own researching for her son, and shared it with me. Here is the link: The prevalence and natural course of FPIES. It is a study done in Isreal.
In summary, they wanted to do a research study because the prevalence and natural history for FPIES have not been determined. The objective was to determine the prevalence, clinical manifestations, and rate of recovery for FPIES in this first large scale population based PROspective study. They studied the feeding history of 13,019 infants!! They studied them from birth (prospective vs. retrospective as other studies have been). The study was limited to cows milk protein induced enterocolitis (as apparently in Isreal that is predominant). Of the 13,019 infants- 44 had confirmed FPIES. The most common symptoms were: recurrent vomiting (100% of the patients experienced this marker for FPIES), lethargy, diarrhea, pallor, and bloody diarhea. They also note that all patients experienced symptoms within the first 6mo.(but they were being followed for this study so this had to have helped with diagnostics); also that by 3yrs of age, 90% of the 44 had recovered from the FPIES, they did not report any reactions to soy among these 44 (or other foods) but do note that 8 (of the 44) also had IgE allergy to cows milk proteins.
The article starts out with it's references- dating back to a 1967 paper from Gryboski who studied 21 children with FPIES, and where the original description can be found. Noting that their symptoms were vomiting, diarrhea, vomiting with diarrhea, and colic with resolution of symptoms upon removal of cows milk protein and recurrence of symptoms with reintroduction. They note that the next big study was 20yrs later when Dr.Sicherer studied 22 patients (11 to milk, 11 to soy and 7 of those reacted to both) with the same above criteria for delayed vomiting, diarrhea, resolution of symptoms with removal of proteins and recurrence with reintroduction. It goes on to report how studies have shown that there are some lab reports that may indicate positive correlation with FPIES but are not necessary; such as increased neutrophils in the blood counts 5-8hrs after ingestion and that the mechanisms are not clearly understood but have found involvement with Tumor Necrosis Factor-alpha (TNF-a) increase response and a decrease in Transforming Growth Factor-beta (TGF-b) may be an important role in understanding the mechanisms for diagnosis. In covers that other studies have shown that FPIES can be triggered by other food proteins and common ones include: rice,oats,barley,peas,sweet potato,chicken and turkey. They also go on to say that the largest report to date was on 35 children and that milk protein is actually the 3rd most common offender.
Something I find very interesting to find in print, in an FPIES study, is something so many moms have observed as "classic" ways of determining if symptoms are FPIES trigger while trialing a new food....stop the trial, rest, and restart, if symptoms return stronger- consider it a fail, is something so many moms have connected- on our own. This study puts it into print...."A distinguishing feature of FPIES is that reintroduction of the offending food, either inadvertently or by an oral food challenge, leads to characteristic symptoms delayed approx.2hrs after the ingestion of the offending food".
The article clarifies that this study is the first largest population based study on FPIES (to cows milk protein). The criteria used for their cows milk protein induced FPIES diagnosis was:
The study statisical analysis on their population including: infant sex, gestational week, birth weight, maternal age, type of delivery, number of siblings, dairy product consumption of mother, and religion (Jewish or non-Jewish), and finally age of when cows milk proteins were introduced. The study found the correlation with FPIES to be with type of delivery and religion of the parents.
It goes on to discuss that of the population base of 13,019 infants, 44 were given the diagnosis of FPIES based on classic criteria:
There was also discussion about the oral challenge and how not every infant reacted on the first dose, stating most infants tolerated up to 121ml or more without symptoms but all experienced symptoms by the 2hr time frame (not sure what this showed because with delayed reactions such as this you would have to stop at 5ml and wait 2hrs for symptoms to see if 5ml was indeed enough to elicit a reaction response. They did note this also, in their discussion points of the article: "Because all doses were given within 4 hours or less, it is not possible to know which dose was responsible for the reaction. An optimal study design would be to administer a single dose and increase it every 2 or more days." The other interesting finding to note was that all the infants who participated in the oral food challenge recovered on oral re hydrating drinks and close monitoring- none required an IV (although, again note that a few parents refused the oral challenge due to such severe reaction on first exposures).
The study also addressed "rate of recovery"...ie, when did they outgrown it? Reporting that 50% of the patients had outgrown it by 1yr, 75% by 18mo., and 88.9% by 2yrs.; with only 2 patients still remaining positive for symptoms by 42mo. Of very interesting note is that "among the patients undergoing an oral food challenge, there was a tendency for them to have a later recovery age compared with those for whom the parents refused a challenge". Which I interpret to mean, without strict avoidance; there is greater chance of sensitizing the cell mediators memory which leads to longer time for outgrowing. Strict avoidance is necessary.
In discussion points, a few points of interest for further study is the criteria for diagnosis (involvement of diarrhea, as found that diarrhea is not always present and appears to more of a result of chronically exposed children). And, as mentioned above, the study was inconclusive for the amount of milk that could induce the reaction. Interesting to note that, with this population base, C-section delivery and religion were noted as risk factors although unclear why.
Of note, they noted that Dr.Sicherer's study has been conducted on FPIES in solid foods, where none of the infants in this study developed FPIES to solid foods. They reviewed Dr.Sicherer's study to find that only 7 of the patients he studied had FPIES to solid foods and considered this a "more severe and unique subgroup of FPIES". Also noted that none of the infants in this study required IV placement for their oral food challenges and the study questions if this is necessary as per protocols in hospital now.
They summarized with a statement I agree completely on: "....the prevalence of FPIES is relatively high, and thus pediatricians should be aware of this condition to avoid unnecessary hospitalizations and over treatment". And I would add to that avoiding under-treatment as well.
In summary, they wanted to do a research study because the prevalence and natural history for FPIES have not been determined. The objective was to determine the prevalence, clinical manifestations, and rate of recovery for FPIES in this first large scale population based PROspective study. They studied the feeding history of 13,019 infants!! They studied them from birth (prospective vs. retrospective as other studies have been). The study was limited to cows milk protein induced enterocolitis (as apparently in Isreal that is predominant). Of the 13,019 infants- 44 had confirmed FPIES. The most common symptoms were: recurrent vomiting (100% of the patients experienced this marker for FPIES), lethargy, diarrhea, pallor, and bloody diarhea. They also note that all patients experienced symptoms within the first 6mo.(but they were being followed for this study so this had to have helped with diagnostics); also that by 3yrs of age, 90% of the 44 had recovered from the FPIES, they did not report any reactions to soy among these 44 (or other foods) but do note that 8 (of the 44) also had IgE allergy to cows milk proteins.
The article starts out with it's references- dating back to a 1967 paper from Gryboski who studied 21 children with FPIES, and where the original description can be found. Noting that their symptoms were vomiting, diarrhea, vomiting with diarrhea, and colic with resolution of symptoms upon removal of cows milk protein and recurrence of symptoms with reintroduction. They note that the next big study was 20yrs later when Dr.Sicherer studied 22 patients (11 to milk, 11 to soy and 7 of those reacted to both) with the same above criteria for delayed vomiting, diarrhea, resolution of symptoms with removal of proteins and recurrence with reintroduction. It goes on to report how studies have shown that there are some lab reports that may indicate positive correlation with FPIES but are not necessary; such as increased neutrophils in the blood counts 5-8hrs after ingestion and that the mechanisms are not clearly understood but have found involvement with Tumor Necrosis Factor-alpha (TNF-a) increase response and a decrease in Transforming Growth Factor-beta (TGF-b) may be an important role in understanding the mechanisms for diagnosis. In covers that other studies have shown that FPIES can be triggered by other food proteins and common ones include: rice,oats,barley,peas,sweet potato,chicken and turkey. They also go on to say that the largest report to date was on 35 children and that milk protein is actually the 3rd most common offender.
Something I find very interesting to find in print, in an FPIES study, is something so many moms have observed as "classic" ways of determining if symptoms are FPIES trigger while trialing a new food....stop the trial, rest, and restart, if symptoms return stronger- consider it a fail, is something so many moms have connected- on our own. This study puts it into print...."A distinguishing feature of FPIES is that reintroduction of the offending food, either inadvertently or by an oral food challenge, leads to characteristic symptoms delayed approx.2hrs after the ingestion of the offending food".
The article clarifies that this study is the first largest population based study on FPIES (to cows milk protein). The criteria used for their cows milk protein induced FPIES diagnosis was:
- less than 9mo. of age at onset of symptoms
- GI symptoms: repetitive vomiting, diarrhea, or both within 24hrs.
- absence of IgE sources
- resolution of symptoms with removal of cows milk proteins
- positive symptoms with re-challenge
The study statisical analysis on their population including: infant sex, gestational week, birth weight, maternal age, type of delivery, number of siblings, dairy product consumption of mother, and religion (Jewish or non-Jewish), and finally age of when cows milk proteins were introduced. The study found the correlation with FPIES to be with type of delivery and religion of the parents.
It goes on to discuss that of the population base of 13,019 infants, 44 were given the diagnosis of FPIES based on classic criteria:
- recurrent vomiting
- lethargy
- diarrhea
- pallor
- bloody diarrhea
There was also discussion about the oral challenge and how not every infant reacted on the first dose, stating most infants tolerated up to 121ml or more without symptoms but all experienced symptoms by the 2hr time frame (not sure what this showed because with delayed reactions such as this you would have to stop at 5ml and wait 2hrs for symptoms to see if 5ml was indeed enough to elicit a reaction response. They did note this also, in their discussion points of the article: "Because all doses were given within 4 hours or less, it is not possible to know which dose was responsible for the reaction. An optimal study design would be to administer a single dose and increase it every 2 or more days." The other interesting finding to note was that all the infants who participated in the oral food challenge recovered on oral re hydrating drinks and close monitoring- none required an IV (although, again note that a few parents refused the oral challenge due to such severe reaction on first exposures).
The study also addressed "rate of recovery"...ie, when did they outgrown it? Reporting that 50% of the patients had outgrown it by 1yr, 75% by 18mo., and 88.9% by 2yrs.; with only 2 patients still remaining positive for symptoms by 42mo. Of very interesting note is that "among the patients undergoing an oral food challenge, there was a tendency for them to have a later recovery age compared with those for whom the parents refused a challenge". Which I interpret to mean, without strict avoidance; there is greater chance of sensitizing the cell mediators memory which leads to longer time for outgrowing. Strict avoidance is necessary.
In discussion points, a few points of interest for further study is the criteria for diagnosis (involvement of diarrhea, as found that diarrhea is not always present and appears to more of a result of chronically exposed children). And, as mentioned above, the study was inconclusive for the amount of milk that could induce the reaction. Interesting to note that, with this population base, C-section delivery and religion were noted as risk factors although unclear why.
Of note, they noted that Dr.Sicherer's study has been conducted on FPIES in solid foods, where none of the infants in this study developed FPIES to solid foods. They reviewed Dr.Sicherer's study to find that only 7 of the patients he studied had FPIES to solid foods and considered this a "more severe and unique subgroup of FPIES". Also noted that none of the infants in this study required IV placement for their oral food challenges and the study questions if this is necessary as per protocols in hospital now.
They summarized with a statement I agree completely on: "....the prevalence of FPIES is relatively high, and thus pediatricians should be aware of this condition to avoid unnecessary hospitalizations and over treatment". And I would add to that avoiding under-treatment as well.
Tuesday, March 15, 2011
My doctors are unfamiliar with FPIES, now what?
If you suspect your child has FPIES, a consult to a Pediatric Allergist or Pediatric Gastroenterologist is warrented. A workup to rule out other medical conditions that may mimic FPIES symptoms in infants may be performed. If you have been referred to these subspecialists and they still are unsure of FPIES, or have never treated it. It may be helpful to take FPIES research articles with and keep these things in mind about treatment protocols.
Articles that may be helpful:
FPIES protocols do not yet exsit. Doctors are too unfamiliar with the multiple mechanisms for this illness. Allergists treat it under IgE protocols, which primarily work, especially when you think of this Non-IgE allergy as an anaphyalaxis of the gut. GI's treat it under EoE protocols, which are helpful and resourceful- especially in the beginning stages when the treatment is to remove all foods, give the gut rest and find a baseline, and then trial foods. Ideally, FPIES needs to be a multi-disciplinary approach driven protocols that are individualized to the specific needs of the child.
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:
Th2- IgE antibodies are produced in response to antigens. Some FPIES kids can have co-existing IgE (Th2) and Non-IgE (Th1) responses.
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.
Articles that may be helpful:
- 2010 Guidelines for Diagnosis and Management of Food Allergy in the US
- FPIES- a Review
- FPIES Pediatrics 2003 Journal Article
- FPIES 2009 Journal (abstract)
FPIES protocols do not yet exsit. Doctors are too unfamiliar with the multiple mechanisms for this illness. Allergists treat it under IgE protocols, which primarily work, especially when you think of this Non-IgE allergy as an anaphyalaxis of the gut. GI's treat it under EoE protocols, which are helpful and resourceful- especially in the beginning stages when the treatment is to remove all foods, give the gut rest and find a baseline, and then trial foods. Ideally, FPIES needs to be a multi-disciplinary approach driven protocols that are individualized to the specific needs of the child.
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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