This blog post on an allergy blog I follow: Grading the Severity of your Allergy: Sensitivity vs. Reaction Level, gives good advice on how to decipher your reaction levels, your severity. What do you (or your child) react to? Everything in the air? Cross contamination? Trace proteins? Food families? Through breastmilk? Through feed from the animal contaminating the meat? Through formula? On the skin?
With Non-IgE allergy, just as with an IgE Allergy, even the blood and skin tests will not tell the severity of an allergy; it will only tell the positive antibody production and the probability of reaction. The only tried and true way to tell a person's reaction level is by testing it with elimination and challenge. Eliminate the food from the diet, if symptoms subside, there are good chances you are allergic and need to eliminate that food, and all derivatives of it from the diet. Some reaction symptoms are obvious enough you don't have to, nor would you want to, challenge the food. A challenge would consist of a re-introduction of the food once suspected symptoms have resolved. This challenge can also help determine severity of the allergy; as addressed in the above blog article. Some people react to any and all minute derivatives or cross contamination of the allergen, some can handle derivatives or oils, etc. The only true way to know is to challenge, and in the meantime- question everything.
Showing posts with label Allergy. Show all posts
Showing posts with label Allergy. Show all posts
Saturday, July 9, 2011
Sunday, April 3, 2011
Gut Flora and Immune System
One of the roles of gut micro flora is to help regulate the immune system. Probiotics aren't residential gut flora- they are visitors to help that flora flourish, and even heal a damaged or immature gastrointestinal system.
We are most familiar with probiotics being responsible for changing the composition (numbers and density) of the resident microflora and thereby restore gut damage but another critical role is in regulation of the immune system.
"As such, your gastrointestinal tract is lined with its own set of immune cells to help prevent these harmful substances from gaining entry to your body. These immune cells are called the gut-associated lymphoid tissue (GALT). The GALT is the largest mass of immune tissue (lymphoid tissue) in the human body and as such is an important element of the body's immune system. You may be familiar with other lymphoid tissues such as the tonsils and spleen. The tonsils are also located in an area where you are commonly exposed to harmful substances (the throat)."- Allison Tannis, Probiotic Rescue: How You can use Probiotics to Fight Cholesterol, Cancer, Superbugs, Digestive Complaints and More.
Multiple studies have shown Lactobacillus strains promote Th3 (oral tolerance) immune responses.
This article shows that "overall pieces of evidence are beginning to accumulate that support a model whereby disruption of the micobiota also disrupts oral tolerance, potentially by interfering with the dendritic cells (DC) that promote allergen specific regulatory Tcell responses".
The mucosal barrier function of the gut depends on the establishment of of the microflora (at birth). "The immature gut barrier may lead to aberrant antigen transfer and immune responses, thus explaining increased vulnerability to breakdown of oral tolerance....In particular, intestinal colonization acts as an important antigenic stimulus for the maturation of the gut-associated lymphoid tissue. The demonstration that the gut microflora are an important constituent of the intestine's nonimmunologic and immunologic barrier has brought about the concept of probiotic therapy: therapeutic application of consumption of cultures of potentially beneficial bacteria.....Moreover, the intestinal microflora contribute to the processing of food antigens in the gut, and probiotics have been shown to modify the structure of potentially harmful antigens and reduce their immunogenicity in vitro and in vivo, together with a potential to dampen hypersensitivity reactions . These effects are seen as a significant improvement in the clinical course of atopic dermatitis (eczema) in infants given probiotic-supplemented elimination diet, and in parallel, markers of intestinal and systemic allergic inflammation decreased significantly."Functional Foods and Probiotics.
As I read through several articles in my research on the role of probiotics and established micro flora, I come across language that suggests that with impaired immunity regulations, the body isn't just attacking food proteins but the established micro flora as well. This article on Early Nutrition is an insightful read for this concept.
Within much of the research is reminders that there is so much more to be researched in the field of microbiota and probiotic therapy (effects and limitations of). Initial research has shown addition of beneficial strains of lactobacillus and bifida bacteria to be a helpful component in the treatment of inflammatory disorders.
We are most familiar with probiotics being responsible for changing the composition (numbers and density) of the resident microflora and thereby restore gut damage but another critical role is in regulation of the immune system.
"As such, your gastrointestinal tract is lined with its own set of immune cells to help prevent these harmful substances from gaining entry to your body. These immune cells are called the gut-associated lymphoid tissue (GALT). The GALT is the largest mass of immune tissue (lymphoid tissue) in the human body and as such is an important element of the body's immune system. You may be familiar with other lymphoid tissues such as the tonsils and spleen. The tonsils are also located in an area where you are commonly exposed to harmful substances (the throat)."- Allison Tannis, Probiotic Rescue: How You can use Probiotics to Fight Cholesterol, Cancer, Superbugs, Digestive Complaints and More.
Multiple studies have shown Lactobacillus strains promote Th3 (oral tolerance) immune responses.
This article shows that "overall pieces of evidence are beginning to accumulate that support a model whereby disruption of the micobiota also disrupts oral tolerance, potentially by interfering with the dendritic cells (DC) that promote allergen specific regulatory Tcell responses".
The mucosal barrier function of the gut depends on the establishment of of the microflora (at birth). "The immature gut barrier may lead to aberrant antigen transfer and immune responses, thus explaining increased vulnerability to breakdown of oral tolerance....In particular, intestinal colonization acts as an important antigenic stimulus for the maturation of the gut-associated lymphoid tissue. The demonstration that the gut microflora are an important constituent of the intestine's nonimmunologic and immunologic barrier has brought about the concept of probiotic therapy: therapeutic application of consumption of cultures of potentially beneficial bacteria.....Moreover, the intestinal microflora contribute to the processing of food antigens in the gut, and probiotics have been shown to modify the structure of potentially harmful antigens and reduce their immunogenicity in vitro and in vivo, together with a potential to dampen hypersensitivity reactions . These effects are seen as a significant improvement in the clinical course of atopic dermatitis (eczema) in infants given probiotic-supplemented elimination diet, and in parallel, markers of intestinal and systemic allergic inflammation decreased significantly."Functional Foods and Probiotics.
As I read through several articles in my research on the role of probiotics and established micro flora, I come across language that suggests that with impaired immunity regulations, the body isn't just attacking food proteins but the established micro flora as well. This article on Early Nutrition is an insightful read for this concept.
Within much of the research is reminders that there is so much more to be researched in the field of microbiota and probiotic therapy (effects and limitations of). Initial research has shown addition of beneficial strains of lactobacillus and bifida bacteria to be a helpful component in the treatment of inflammatory disorders.
The Immunological Basis for Gastroinestinal Food Allergy (Understanding FPIES mechanisms series, part 3)
My review of the article: The Immunological Basis for Gastrointestinal Food Allergy
Summary: Food Allergies are now being recognized as being a treatable component of the atopic march.
Food allergies are common in children. Significant impact on quality of life (more research is needed because of this increasing). Recently there has been a shift in the recommendations after realization that delayed food exposures may be harmful in immune sensitization. “Instead strategies aimed at early introduction of foods to induce oral tolerance are now being re-evaluated…very encouraging results are being obtained in desensitizing allergic children via oral tolerance.” (TH3 vs. Th1 responses). The goal is not to induce complete tolerance in all cases but to raise thresholds, thus minimizing reactions to trace proteins (increasing quality of life by better control of allergy).
Research has shown that all infants have T cell responses to food antigens . In a small subset of children, there is an inappropriate immune response which results to sensitization of food antigens. “The critical question is not necessarily exposure to food antigens but the nature and type of immune response which an individual generates to these antigens.”… not the type, timing or dose of exposure but these variables are imposed on the individual, and complex immune system- in a time when the immune system is still developing (infancy).
Progress in GI food allergy remains slow, given all the complexities. Food allergy in children remains treatable when properly diagnosed and after a period of avoidance, oral tolerance is developed. The studies have increasing emphasis on immunology.
The paper goes on to discuss current research on the timing (early exposures or delayed introductions of food proteins into the infants diet) is affecting the rise in food allergy. It sites this article article for references as an excellent read on the growing/ongoing subject of research into infant food allergy (delayed introductions past 4-6mo. May have negative effects vs. previously thought of protective effects on oral tolerance.
The article goes on to discuss Regulatory T Cells and Food Allergy. “it is clear that there exists a population of CD4+, CD25+ T cells in blood whose primary function is to regulate immune responses”. Studies have shown that infants who develop food allergies have lower Treg cells function than non-allergic infants…”suggesting that a defect in Tregs may predispose to food allergy”. More research is needed in this area.
It covers a little in this article on desensitization in food allergy- by repeated systemic treatment with allergen. It is being recognized as treatment for allergies although specific mechanisms remain unclear it is thought to be “induction of Treg cells or blocking anti-bodies, or both. Desensitization is sublingual immunotherapy (SLIT)- small amount of allergen is placed under the tongue, and oral immunotherapy (OIT) which is feeding small amounts of the allergen". It does go onto to describe a more recent approach of introducing allergens via extensively heated proteins (with IgE antibody allergy) and studies have confirmed this with milk allergic children tolerating extensively heated milk. It goes onto to clarify that the goal of this immunotherapy isn’t only to allow the food to be completely tolerated (non-allergenic) but to simply raise the threshold of tolerance in anaphylaxis response allergy (thereby increasing quality of life).
The article also sites the Finnesh Allergy Programme 2008-2018 as a “highly ambitious project to reduce the burden of allergies” Stating that the background is based on immunological responses- focused on continuous exposure to antigens and strengthening and restoring immune tolerance mechanisms.
The article wraps up with a mention of delayed onset food allergies (and how slow research is in understanding it), but points out that IgE allergy are T-cell dependant as well so that there can be crossovers in strategies.
Summary: Food Allergies are now being recognized as being a treatable component of the atopic march.
Food allergies are common in children. Significant impact on quality of life (more research is needed because of this increasing). Recently there has been a shift in the recommendations after realization that delayed food exposures may be harmful in immune sensitization. “Instead strategies aimed at early introduction of foods to induce oral tolerance are now being re-evaluated…very encouraging results are being obtained in desensitizing allergic children via oral tolerance.” (TH3 vs. Th1 responses). The goal is not to induce complete tolerance in all cases but to raise thresholds, thus minimizing reactions to trace proteins (increasing quality of life by better control of allergy).
Research has shown that all infants have T cell responses to food antigens . In a small subset of children, there is an inappropriate immune response which results to sensitization of food antigens. “The critical question is not necessarily exposure to food antigens but the nature and type of immune response which an individual generates to these antigens.”… not the type, timing or dose of exposure but these variables are imposed on the individual, and complex immune system- in a time when the immune system is still developing (infancy).
Progress in GI food allergy remains slow, given all the complexities. Food allergy in children remains treatable when properly diagnosed and after a period of avoidance, oral tolerance is developed. The studies have increasing emphasis on immunology.
The paper goes on to discuss current research on the timing (early exposures or delayed introductions of food proteins into the infants diet) is affecting the rise in food allergy. It sites this article article for references as an excellent read on the growing/ongoing subject of research into infant food allergy (delayed introductions past 4-6mo. May have negative effects vs. previously thought of protective effects on oral tolerance.
The article goes on to discuss Regulatory T Cells and Food Allergy. “it is clear that there exists a population of CD4+, CD25+ T cells in blood whose primary function is to regulate immune responses”. Studies have shown that infants who develop food allergies have lower Treg cells function than non-allergic infants…”suggesting that a defect in Tregs may predispose to food allergy”. More research is needed in this area.
It covers a little in this article on desensitization in food allergy- by repeated systemic treatment with allergen. It is being recognized as treatment for allergies although specific mechanisms remain unclear it is thought to be “induction of Treg cells or blocking anti-bodies, or both. Desensitization is sublingual immunotherapy (SLIT)- small amount of allergen is placed under the tongue, and oral immunotherapy (OIT) which is feeding small amounts of the allergen". It does go onto to describe a more recent approach of introducing allergens via extensively heated proteins (with IgE antibody allergy) and studies have confirmed this with milk allergic children tolerating extensively heated milk. It goes onto to clarify that the goal of this immunotherapy isn’t only to allow the food to be completely tolerated (non-allergenic) but to simply raise the threshold of tolerance in anaphylaxis response allergy (thereby increasing quality of life).
The article also sites the Finnesh Allergy Programme 2008-2018 as a “highly ambitious project to reduce the burden of allergies” Stating that the background is based on immunological responses- focused on continuous exposure to antigens and strengthening and restoring immune tolerance mechanisms.
The article wraps up with a mention of delayed onset food allergies (and how slow research is in understanding it), but points out that IgE allergy are T-cell dependant as well so that there can be crossovers in strategies.
Tuesday, March 22, 2011
Managing Allergy
What a great find! An entire book to view, and a great resource on Allergy in general! Find it here: Managing Allergy.
Chapter 10 (pg. 157) is the overview on Food Allergy. Each chapter is divided to describe allergies in depth, all complete with their own reference section!
On pg. 165, the discussion of FPIES. It defines it in a table (of IgE, Non-IgE and mixed allergy) of disease manifestations, which include:"Irritability, excessive, vigorous vomiting and diarrhea a few hours after ingestion of the allergen, hypotension, lethargy, hyponatremia, acidosis, a "left-shift", and methemoglobinaemia may occur. Stool smears may reveal blood, leukocytes or eosinophils. A more indolent course, with failure to thrive, hypoalbuminaemia, chronic vomitting and diarrhea may occur for young infants chronically eating the allergen."
It continues and devotes a paragraph on pg.167 for an action plan, ER treatment, resolutions of FPIES, triggers, and recommendations for challenges (.3-.6g of protein per kg of body weight to be fed in 1-2 doses...with IV inserted prior).
I think it is a good synopsis of FPIES (especially for a book copyrighted in 1999). I like that it gives both classic and chronic symptoms in the disease manifestations table. Putting together more of what is known about FPIES, from research and from moms is what will help guide what should be researched next. But if this much was known in 1999....why don't more doctors already know about it?
Chapter 10 (pg. 157) is the overview on Food Allergy. Each chapter is divided to describe allergies in depth, all complete with their own reference section!
On pg. 165, the discussion of FPIES. It defines it in a table (of IgE, Non-IgE and mixed allergy) of disease manifestations, which include:"Irritability, excessive, vigorous vomiting and diarrhea a few hours after ingestion of the allergen, hypotension, lethargy, hyponatremia, acidosis, a "left-shift", and methemoglobinaemia may occur. Stool smears may reveal blood, leukocytes or eosinophils. A more indolent course, with failure to thrive, hypoalbuminaemia, chronic vomitting and diarrhea may occur for young infants chronically eating the allergen."
It continues and devotes a paragraph on pg.167 for an action plan, ER treatment, resolutions of FPIES, triggers, and recommendations for challenges (.3-.6g of protein per kg of body weight to be fed in 1-2 doses...with IV inserted prior).
I think it is a good synopsis of FPIES (especially for a book copyrighted in 1999). I like that it gives both classic and chronic symptoms in the disease manifestations table. Putting together more of what is known about FPIES, from research and from moms is what will help guide what should be researched next. But if this much was known in 1999....why don't more doctors already know about it?
Tuesday, March 15, 2011
Treatment Plans
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.
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.
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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