Cell-mediated Food Allergy Research Articles

Food protein-induced enterocolitis syndrome (FPIES): Beyond the guidelines.

Food protein-induced enterocolitis syndrome (FPIES) is a non-immunoglobulin E (IgE) cell mediated food allergy that can cause severe symptoms and is considered an allergic emergency. To describe FPIES epidemiology and appraise the approach to diagnosis and management. A review of the relevant articles published in the peer-reviewed journals since the publication of the First International FPIES Consensus Guidelines in 2017. FPIES is estimated to affect 0.51-0.9% of children and 0.22% of adults in the United States. It typically presents with protracted, projectile vomiting, which occurs within 1-4 hours of ingesting culprit foods, sometimes followed by diarrhea within 24 hours of ingestion. In ∼15-20% of severe cases, patients go into hypovolemic or distributive shock. In chronic FPIES, infants may have failure to thrive and weight loss. The most common triggers include cow's milk, oat, rice, and avocado, with egg and peanut being more frequently reported. Examples of other common fruit and vegetable triggers include banana, apple, and sweet potato. FPIES can be classified into acute, chronic, adult-onset, or atypical subtypes. FPIES is associated with comorbid atopic conditions of IgE-mediated food allergy, atopic dermatitis, asthma, allergic rhinitis, and eosinophilic esophagitis. The natural history of infantile FPIES is generally favorable, with the exception of fish FPIES. Seafood FPIES in adults has low rates of resolution over 3-5 years. Correctly identifying FPIES can be challenging because there are no specific biomarkers for diagnosis and the constellation of symptoms may mimic those of infectious enteritis or sepsis. Management relies on dietary food avoidance, periodic re-evaluations for tolerance with oral food challenges, and management of acute reactions with rehydration and antiemetic ondansetron. Although the pathophysiology of FPIES remains poorly understood, underlying mechanisms such as cytokine release, leukocyte activation, and impaired gastrointestinal mucosal barrier function may act as cornerstones for further research. Prevention, laboratory diagnostic testing, and strategies to accelerate tolerance development are urgent unmet needs in FPIES.

Evaluation of the Clinical Characteristics of Patients with Food Protein-Induced Enterocolitis Syndrome: A Multicenter Study

Introduction: Food protein-induced enterocolitis syndrome (FPIES) is a rare non-IgE, cell-mediated food allergy disorder. We aimed to report the demographic characteristics, clinical features, and management of pediatric patients with FPIES. Methods: This retrospective study included all children diagnosed with FPIES at the pediatric allergy departments of the participating twelve study centers from January 2015 to November 2020. Results: A total of 73 patients (39 males, 53.4%) with a male/female ratio of 1.1 were included in the study. The median (interquartile ranges) age at symptom onset was 6 months (0.5–168, 4–9.5). The most frequent offending foods were cow’s milk, egg’s yolk, fish, and egg’s white, identified in 38.4% (n = 28), 32.9% (n = 24), 21.9% (n = 16) and 20.5% (n = 15) of the patients, respectively. The total number of reported FPIES episodes was 290 (3.9 episodes per child). Oral food challenge (OFC) was performed in 54.8% (n = 40) of the patients, and tolerance was detected in 17 OFCs (42.5%) at a median age of 15 months (range 8–132 months). Conclusion: FPIES is a non-IgE-mediated food hypersensitivity that commonly affects infants and is often misdiagnosed. The pathophysiology of the disease remains unclear and the low awareness of FPIES among physicians and parents highlights the need for more education.

Adult Food Protein-Induced Enterocolitis Syndrome.

Food protein-induced enterocolitis syndrome (FPIES) is a non-IgE, cell-mediated food allergy, commonly diagnosed in infants and young children. In recent years, new-onset adult FPIES has been recognized. The underlying pathogenic mechanism of FPIES has yet to be elucidated, thus disease-specific diagnostic biomarkers have yet to be determined and an oral food challenge (OFC) remains the gold-standard for the diagnosis. Pediatric patients with FPIES classically present with symptoms of delayed, repetitive vomiting approximately 1 to 4 hours following ingestion of a food allergen. However, adults with FPIES have been reported to have a different symptom profile and different food triggers compared to the pediatric FPIES population. The current FPIES diagnostic criteria may not be appropriate for the diagnosis of adult FPIES patients, thus an oral food challenge remains a diagnostic tool. This review provides an overview of the current literature on the clinical presentation, epidemiology, diagnosis, triggers and management of adult FPIES.

Computational and Mechanistic Study of the Therapeutic Potential of Compound Formononetin in Preventing Mast Cell Activation and IgE Production in Food Anaphylaxis

The prevalence of allergic diseases such as Asthma, Rhinitis, Anaphylaxis, Eczema, Urticaria, and Angioedema have been rising dramatically in low‐ and middle‐income countries around the world. According to American College of Allergy, Asthma & Immunology, allergies are the 6th leading cause of chronic illness in the U.S. and more than 50 million Americans suffer from allergies each year. Extensive data suggest that food allergies affect up to 10% of the world population and have been increasing in the last two to three decades. Globally 300 million people have asthma and about 200 to 250 million people suffer from food allergies. Previously we have shown that a small molecule compound, formononetin have shown decreases IgE production from B cells. We hypothesize that formononetin will be a potential candidate for preventing food anaphylaxis in food allergy by regulating molecular pathways that involved in IgE production in B cells, mast cell activation and degranulation. The objective of this study is to reveal potential therapeutic mechanisms of formononetin in prevention and treatment of food anaphylaxis from food allergy, by using computational modeling, including target mining, gene ontology enrichment, pathway analyses, protein‐protein interaction analyses and in silico molecular docking to identify gene and protein targets that are regulated in food allergy and mast cells diseases. The targets identified were further validated using qRT‐PCR in B cell multiple myeloma cell line. U266 cells were cultured to 1.0 × 106 cells/mL and then incubated with formononetin at different concentrations of 20 μg/mL for 72 hours. Supernatants were collected for measuring IgE levels by ELISA and cell viability was determined using Trypan blue dye. mRNA expression was determined for the top targets identified and compared with GAPDH. Mining formononetin targets into obtained disease targets uncovers 25 targets for food allergy, 51 targets for IgE diseases and 19 targets for mast cell diseases. This targets where further used for gene ontology, KEGG pathway analysis, CTPD network and protein‐protein interaction. Top regulated KEGG pathways include the primary immunodeficiency pathway, Epstein Barr virus infection pathway, Th17 cell differentiation, PI3K‐Akt pathway. Regulated gene ontology biological processes include B cell proliferation, B cell differentiation, B cell activation and apoptotic process. Formononetin decreased IgE at after 72 hours, P < 0.05 without cytotoxicity. Formononetin decreased mRNA expression of P53, TYK2, CASP8 significantly (P < 0.05) and IgEH very significantly (P < 0.01) and increased the mRNA expression of BCL2, NFKBIA and BTK significantly (P < 0.05) after 72 hours in the culture group compared to the untreated group. These findings suggest that formononetin may be a novel therapeutic candidate for treatment and prevention of IgE/mast cell mediated food allergy and other allergic diseases.

Epigenetic Regulation via Altered Histone Acetylation Results in Suppression of Mast Cell Function and Mast Cell-Mediated Food Allergic Responses.

Mast cells are highly versatile cells that perform a variety of functions depending on the immune trigger, context of activation, and cytokine stimulus. Antigen-mediated mast cell responses are regulated by transcriptional processes that result in the induction of numerous genes contributing to mast cell function. Recently, we also showed that exposure to dietary agents with known epigenetic actions such as curcumin can suppress mast cell-mediated food allergy, suggesting that mast cell responses in vivo may be epigenetically regulated. To further assess the effects of epigenetic modifications on mast cell function, we examined the behavior of bone marrow-derived mast cells (BMMCs) in response to trichostatin A (TSA) treatment, a well-studied histone deacetylase inhibitor. IgE-mediated BMMC activation resulted in enhanced expression and secretion of IL-4, IL-6, TNF-α, and IL-13. In contrast, pretreatment with TSA resulted in altered cytokine secretion. This was accompanied by decreased expression of FcεRI and mast cell degranulation. Interestingly, exposure to non-IgE stimuli such as IL-33, was also affected by TSA treatment. Furthermore, continuous TSA exposure contributed to mast cell apoptosis and a decrease in survival. Further examination revealed an increase in I-κBα and a decrease in phospho-relA levels in TSA-treated BMMCs, suggesting that TSA alters transcriptional processes, resulting in enhancement of I-κBα transcription and decreased NF-κB activation. Lastly, treatment of wild-type mice with TSA in a model of ovalbumin-induced food allergy resulted in a significant attenuation in the development of food allergy symptoms including decreases in allergic diarrhea and mast cell activation. These data therefore suggest that the epigenetic regulation of mast cell activation during immune responses may occur via altered histone acetylation, and that exposure to dietary substances may induce epigenetic modifications that modulate mast cell function.

Epigenetic regulation of mast cell function via inhibition of histone acetylation results in suppression of mast cell responses

Abstract Mast cells are highly versatile cells that perform a variety of functions depending on the immune trigger, context of activation and cytokine stimulus. Antigen-mediated mast cell responses are regulated by transcriptional processes that result in the induction of numerous genes contributing to mast cell function. Recently, we also showed that exposure to dietary agents with known epigenetic actions such as curcumin can suppress mast cell-mediated food allergy, suggesting that mast cell responses in vivo may be epigenetically regulated. To further assess the effects of epigenetic modifications on mast cell function, we examined the behavior of bone marrow-derived mast cells (BMMCs) in response to trichostatin A (TSA) treatment, a well-studied histone deacetylase inhibitor. IgE-mediated BMMC activation resulted in enhanced expression and secretion of IL-4, IL-6, TNF-a and IL-13. In contrast, pretreatment with either curcumin or TSA resulted in altered cytokine secretion. This was accompanied by decreased expression of FceRI and mast cell degranulation. Interestingly, exposure to non-IgE stimuli such as IL-33, was also affected by TSA treatment. Furthermore, long-term TSA exposure contributed to mast cell apoptosis and a decrease in survival. Further examination revealed a decrease in phospho-relA levels in TSA-treated BMMCs, suggesting that TSA alters transcriptional processes, resulting in decreased NF-kB activation. These data therefore suggest that the epigenetic regulation of mast cell activation during immune responses may occur via regulation of histone acetylation, and that exposure to dietary substances such as curcumin may induce epigenetic modifications that modulate mast cell function.

Is food protein induced enterocolitis syndrome only a non IgE-mediated food allergy?

Food protein induced enterocolitis syndrome (FPIES) is classified as non-IgE-mediated or cell-mediated food allergy, although there is an atypical phenotype so defined for the presence of specific IgEs. All diagnostic criteria for FPIES include the absence of skin or respiratory symptoms of IgE-mediated type. We present four cases that suggest that specific IgEs may have a pathogenic role, resulting in the existence of different FPIES phenotypes. This could be important from a diagnostic and therapeutic point of view.

Food Protein-Induced Enterocolitis Syndrome.

Food protein-induced enterocolitis syndrome (FPIES) is a non-IgE-, cell-mediated food allergy of unknown prevalence and pathophysiology. Onset is typically during the first year of life; seafood-induced FPIES may start in adulthood. Acute FPIES manifests within 1-4 hours after ingestion with repetitive emesis, pallor, and lethargy progressing to dehydration and hypovolemic shock in 15% of cases. Chronic FPIES manifests with intermittent emesis, watery diarrhea, and poor growth progressing to dehydration and hypovolemic shock over a period of days to weeks. Chronic FPIES has been only reported in infants aged less than 3 months fed with cow milk (CM) or soy formula. The most common triggers are CM, soy, rice, and oat. Diagnosis of FPIES relies on recognition of a pattern of clinical symptoms and may be missed owing to the absence of typical allergic symptoms (eg, urticaria, wheezing) and delayed onset in relation to food ingestion. Physician-supervised food challenge is recommended if diagnosis or the trigger food is not clear and to evaluate for resolution. Testing for food-specific IgE is usually negative, although a subset of patients, usually with CM-induced FPIES may develop sensitization to foods. Such atypical FPIES tends to have a more prolonged course. Despite the potential severity of the reactions, no fatalities have been reported, and FPIES has a favorable prognosis. In most cases, FPIES resolves by age 3-5 years, although persistence of CM-induced FPIES and soy FPIES into adulthood has been reported. The first international consensus guidelines on diagnosis and management of FPIES were published in 2017. Given that the pathophysiology of FPIES is poorly understood, there are no diagnostic biomarkers and no therapies to accelerate resolution. These unmet needs warrant future investigations to improve the care of patients with FPIES.

Syndrome d’entérocolite induit par les protéines alimentaires : nouvelle observation et revue de la littérature

We report one case of food protein-induced entererocolitis syndrome (FPIES) with milk whose signs of intolerance to milk began as of the first life days, by minor and nonspecific symptoms. Three foods are in question, cow's milk, soya and corn. The diagnosis of FPIES is suspected at the age of 9 months after three hospitalizations for vomiting out of jet, sometimes associated with lethargy and hypotension, occurring two hours after the cow milk ingestion, This symptomatology is associated with negative results of specific IgE and cutaneous tests. Signs then occurred with soja and wheat. Because of late diagnosis, three anaphylactic shocks occurred. FPIES is an uncommon cell-mediated food allergy reaction. This syndrome is characterized by gastrointestinal symptoms, especially severe vomiting, sometimes associated with anaphylactic shock. Usually, signs occur two hours after ingestion. These reactions begin early in the first months of life and regress at the age of 3 years in 38% to 100% of cases depending on the food. They are usually induced by cow milk and soy proteins. Diagnosis is difficult and delayed because of non-specific symptoms. Oral food challenge is the only examination that confirms the diagnosis. The treatment involves the exclusion of the specific food. Severe reaction requires treatment of the shock and, what is particular in that pathology, the adjunction of corticosteroid.

Syndrome d’entérocolite induit par les protéines alimentaires, à propos d’une observation

We report a case of food protein-induced enterocolitis syndrome (FPIES) with milk whose signs of milk intolerance began in the 1st days of life, consisting in minor and nonspecific symptoms. The 3 foods in question were cow's milk, soja, and wheat. The diagnosis of FPIES was suspected at the age of 9 months, after 3 hospitalizations for vomiting, sometimes associated with lethargy and hypotension, which occurred around 2 h after cow's milk ingestion. Symptoms were not associated with positive specific IgE and cutaneous tests. Signs then occurred with soja and wheat. Because of the late diagnosis, 3 anaphylactic shock episodes occurred. FPIES is an uncommon cell-mediated food allergy reaction. This syndrome is characterized by gastrointestinal symptoms, especially severe vomiting, sometimes associated with anaphylactic shock. Usually signs occur 2 h after ingestion. These reactions begin early, in the 1st months of life, and regress by the age of 3 years in 38–100% of cases depending on the responsible food. They are usually induced by cow's milk and soy proteins. Diagnosis is difficult and delayed because of nonspecific symptoms. Oral food challenge is the only examination that confirms the diagnosis. Treatment involves the exclusion of the specific food involved. Severe reactions require treatment of shock and adjunction of corticosteroids.

Syndrome d’entérocolite induit par les protéines alimentaires, à propos d’une observation

We report a case of food protein-induced enterocolitis syndrome (FPIES) with milk whose signs of milk intolerance began in the 1st days of life, consisting in minor and nonspecific symptoms. The 3 foods in question were cow's milk, soja, and wheat. The diagnosis of FPIES was suspected at the age of 9 months, after 3 hospitalizations for vomiting, sometimes associated with lethargy and hypotension, which occurred around 2h after cow's milk ingestion. Symptoms were not associated with positive specific IgE and cutaneous tests. Signs then occurred with soja and wheat. Because of the late diagnosis, 3 anaphylactic shock episodes occurred. FPIES is an uncommon cell-mediated food allergy reaction. This syndrome is characterized by gastrointestinal symptoms, especially severe vomiting, sometimes associated with anaphylactic shock. Usually signs occur 2h after ingestion. These reactions begin early, in the 1st months of life, and regress by the age of 3 years in 38-100% of cases depending on the responsible food. They are usually induced by cow's milk and soy proteins. Diagnosis is difficult and delayed because of nonspecific symptoms. Oral food challenge is the only examination that confirms the diagnosis. Treatment involves the exclusion of the specific food involved. Severe reactions require treatment of shock and adjunction of corticosteroids.

Quels sont les examens complémentaires à réaliser en allergologie pédiatrique ?

The diagnostic of respiratory allergy is done by the concordance of clinical history and the positivity of the skin prick testing. Blood sample is not essential but must be done before specific immunotherapy. In IgE food allergy, positivity of skin prick testing and specific IgE allows to make the diagnostic of allergic sensitisation. The diagnostic of food allergy is done by the positivity of the oral food challenge. In mixed IgE and cell-mediated food allergy, it is necessary to do skin prick testing and atopy patch testing with the food usually ingested by the child. If these tests are positive, they are pertinent when the food eviction improves the clinical symptoms. The release of the symptoms during the oral food challenge will confirm the diagnostic of food allergy.