Materiały źródłowe

• #1 The immunopathogenesis of cow’s milk protein allergy (CMPA)

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3441837/

  The most frequent symptoms among the manifestations of cow milk protein allergy (CMPA) are gastrointestinal. CMPA pathogenesis involves immunological mechanisms with participation of immunocompetent cells and production of immunoglobulin E (IgE). […] Nevertheless, recent studies have been focused on the description of other forms of CMPA, not-mediated by IgE reactions, mostly involving the T lymphocite immune system. […] Thus, in this field it is important to note how different kind of cells are involved in the immunopathogenesis of CMPA, such as antigen-specific T cells, T regulatory cells, cytokines secreted by the different T lymphocite subsets, B lymphocytes, antingen-presenting cells, mast cells, that together orchestrate the complex mechanism leading to the phenotipic expression of CMPA.

• #2 The immunopathogenesis of cow’s milk protein allergy (CMPA) | Italian Journal of Pediatrics | Full Text

  https://ijponline.biomedcentral.com/articles/10.1186/1824-7288-38-35

  The most frequent symptoms among the manifestations of cow milk protein allergy (CMPA) are gastrointestinal. CMPA pathogenesis involves immunological mechanisms with participation of immunocompetent cells and production of immunoglobulin E (IgE). […] Thus, in this field it is important to note how different kind of cells are involved in the immunopathogenesis of CMPA, such as antigen-specific T cells, T regulatory cells, cytokines secreted by the different T lymphocite subsets, B lymphocytes, antingen-presenting cells, mast cells, that together orchestrate the complex mechanism leading to the phenotipic expression of CMPA. […] The immunological mechanism that lead to the development of cows milk allergy (or Cows Milk Protein Allergy- CMPA) is not still clarified. There are different mechanisms that contribute to the pathogenesis and the main two described mechanisms at the basis of this disease refer to IgE- and not-IgE- reactions. […] Nevertheless, even if these two pathogenic pathways are the main described, there is a third mechanism causing CMPA, as a third group of symptoms attributed to cows milk allergy are unpredictably associated with IgE antibody (IgE-associated/cell-mediated disorders).

• #3 Cow’s milk protein allergy in infants and children | Canadian Paediatric Society

  https://cps.ca/en/documents/position/cows-milk-protein-allergy

  Cows milk protein allergy (CMPA) is an immune-mediated reaction to cows milk proteins, which can involve multiple organ systems including the gastrointestinal tract. […] CMPA refers to immune-mediated adverse reactions to one or more proteins in cows milk, and is primarily seen in childhood. CMPA can be immediate (IgE-mediated), delayed (non-IgE- or cell-mediated) or mixed (IgE- and non-IgE/cell-mediated). […] In CMPA, activated T and B cells of lymphoid follicles migrate through the lymphatic system and blood vessels to different organs, causing an inflammatory reaction in the target organ, increased intestinal permeability, and clinical manifestations. […] The exact mechanism involved in tolerance development remains unclear. […] The natural history of non-IgE-mediated gastrointestinal food allergies is generally favourable, with most affected infants achieving tolerance in the first years of life and most cases resolving before school age.

• #4 The immunopathogenesis of cow’s milk protein allergy (CMPA)

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3441837/

  The immunological mechanism that lead to the development of cows milk allergy (or Cows Milk Protein Allergy- CMPA) is not still clarified. There are different mechanisms that contribute to the pathogenesis and the main two described mechanisms at the basis of this disease refer to IgE- and not-IgE- reactions. […] Nevertheless, even if these two pathogenic pathways are the main described, there is a third mechanism causing CMPA, as a third group of symptoms attributed to cows milk allergy are unpredictably associated with IgE antibody (IgE-associated/cell-mediated disorders). […] IgE-mediated reactions are based on simply immunological mechanisms that are better identified than not-IgE-mediated ones. Since the onset of symptoms rapidly evolves (from several minutes to several hours after the contact with the allergen), this kind of mechanism is referred as immediate hypersensitivity. […] IgE-mediated CMAP is characterized by two stages: the first, of sensibilization, develops when the immune system is programmed in an aberrant way, so that IgE antibodies against cow milk proteins are secreted. […] It is believed that both a deficiency in regulation and a polarization of milk-specific T cells toward type-2T helper cells (TH2) lead to B-cell signaling to produce milk protein-specific IgE. […] Treg dysfunction plays a prominent role in lack of tolerance.

• #5 Mechanisms Behind Cow’s Milk Protein Allergy | Healthcare

  https://www.cowsmilkallergy.com/hcp/mechanisms-behind-cmpa-development

  CMPA is an immune-mediated reaction and it is broadly split into two types: immunoglobulin (Ig)E-mediated and non-IgE-mediated. An infant may have an IgE-mediated reaction or a non-IgE-mediated reaction, or a combination of the two. […] The main difference between the two types of CMPA is the presence of antibodies. In IgE-mediated CMPA antibodies are present, whereas with non-IgE-mediated CMPA the immune system does not produce antibodies. […] Usually occurs within a few minutes to ~2 hours after exposure to the dairy proteins (‘early reactions’). […] The presence of these IgE antibodies means that cytokines and histamine are released, which trigger an inflammatory response. Symptoms associated with IgE-mediated CMPA are generally related to inflammation – itching, swelling, gastrointestinal problems like abdominal pain and diarrhea as well as difficulties breathing.

• #6 Milk allergy – Wikipedia

  https://en.wikipedia.org/wiki/Milk_allergy

  Milk allergy is an adverse immune reaction to one or more proteins in cow’s milk. Symptoms may take hours to days to manifest, with symptoms including atopic dermatitis, inflammation of the esophagus, enteropathy involving the small intestine and proctocolitis involving the rectum and colon. However, rapid anaphylaxis is possible, a potentially life-threatening condition that requires treatment with epinephrine, among other measures. […] Conditions caused by food allergies are classified into three groups according to the mechanism of the allergic response: IgE-mediated (classic) the most common type, manifesting as acute changes that occur shortly after eating, and may progress to anaphylaxis; Non-IgE mediated characterized by an immune response not involving IgE; may occur hours to days after eating, complicating the diagnosis; IgE- and non-IgE-mediated a hybrid of the above two types.

• #7 Cow’s Milk Protein Allergy – Clinical Features – TeachMePaediatrics

  https://teachmepaediatrics.com/gastroenterology/upper-gi/cows-milk-protein-allergy/

  Cows milk protein allergy (CMPA) is an immune-mediated allergic response to naturally-occurring milk proteins casein and whey. It is classified according to the aetiology: IgE-mediated, non-IgE-mediated, and mixed. […] IgE-mediated: A type-I hypersensitivity reaction. CD4+ TH2 cells stimulate B cells to produce IgE antibodies against cows milk protein which trigger the release of of histamine and other cytokines from mast cells and basophils. […] Non-IgE-mediated: Involves T cell activation against cows milk protein.

• #8 Cow Milk Allergy – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK542243/

  Cow’s milk contains more than 20 protein fractions. The significant allergens belong to casein protein (alpha-s1-, alpha-s2-, beta-, and kappa-casein) and whey proteins (alpha-lactalbumin and beta-lactoglobulin). Most individuals with cow’s milk allergies have a sensitivity to both caseins and whey proteins. Immune-mediated adverse food reactions classify into two primary categories: IgE-mediated, non-IgE-mediated. A non-IgE mediated mechanism most frequently causes cow’s milk allergy. […] Food allergies stem from the host’s immune system. If an individual has an allergy to milk, the body’s immune system responds to a specific milk protein, triggers an immune response, and attempts to neutralize the triggering protein. The next time that the body comes into contact with the protein, the immune response recognizes the protein. It triggers the immune system to mount a response, including the release of histamine and other immune mediators. This release of chemicals causes the signs and symptoms of cow’s milk allergy.

• #9 Milk allergy – Wikipedia

  https://en.wikipedia.org/wiki/Milk_allergy

  Allergic reactions are hyperactive responses of the immune system to generally innocuous substances, such as proteins in food. Some proteins trigger allergic reactions while others do not. One theory is that resistance to digestion occurs when largely intact proteins reach the small intestine and the white blood cells involved in immune reactions are activated. […] Six major allergenic proteins from cow’s milk have been identified: s1-, s2-, -, and -casein from casein proteins and -lactalbumin and -lactoglobulin from whey proteins. There is some cross-reactivity with soy protein, particularly in non-IgE mediated allergy. Heat can reduce allergenic potential, so dairy ingredients in baked goods may be less likely to trigger a reaction than would milk or cheese. […] For milk allergy, non-IgE-mediated responses are more common than are IgE-mediated. The former can manifest as atopic dermatitis and gastrointestinal symptoms, especially in infants and young children. Some will display both, so that a child could react to an oral food challenge with respiratory symptoms and hives (skin rash), followed a day or two later with a flareup of atopic dermatitis and gastrointestinal symptoms, including chronic diarrhea, blood in the stools, gastroesophageal reflux disease (GERD), constipation, chronic vomiting and colic.

• #10 Association of cow’s milk and soy allergy | PPT

  https://www.slideshare.net/slideshow/association-of-cows-milk-and-soy-allergy/28943286

  PATHOGENESIS Acute (IgE-mediated) reactions to milk are due to various milk allergens. Caseins and whey proteins account for approximately 80% and 20% of total milk protein, respectively. The caseins include s1-, s2-, and -caseins (Bos d 8) and comprise 32%, 10%, 28% and 10% of the total protein, respectively. The most important whey allergens are -lactalbumin (ALA, Bos d 4) and -lactoglobulin (BLG, Bos d 5), comprising 5% and 10% of total milk protein. Other minor milk allergens include bovine serum albumin (BSA, Bos d 6), lactoferrin and immunoglobulins (Bos d 7). […] Sequential IgE-binding epitopes of the major milk allergens have been identified and several have been investigated for mutational analysis. The pathogenesis and causative allergens in non-IgE-mediated CMA, and milk allergy due to mixed IgE and non-IgE mediated processes, are less well understood.

• #11 Position document: IgE-mediated cow’s milk allergy | Allergologia et Immunopathologia

  https://www.elsevier.es/en-revista-allergologia-et-immunopathologia-105-articulo-position-document-ige-mediated-cow39s-milk-S0301054615000191

  Allergy to cow’s milk proteins develops early in life and is increasingly frequent in developed countries. […] The predominant milk allergens are caseins, beta-lactoglobulin (no homologous protein being found in human milk) and alpha-lactoalbumin. […] Allergen specific IgE plays a key role in the pathogenesis of IgE-mediated allergy to cow’s milk proteins. […] Two steps are therefore required in order for IgE-mediated CMPA to develop. In the first step, sensitisation to cow’s milk proteins is established, expressed by the production of specific IgE against cow’s milk proteins, which binds to the surface of the mast cells and basophils. In the second step, following exposure to cow’s milk proteins, the specific IgE on the cell surface binds on a two-by-two basis to the epitopes of the cow’s milk proteins, triggering the release of cell mediators and giving rise to the clinical manifestations of the allergic reaction.

• #12 Milk Allergy: Causes, Symptoms, Diagnosis & Treatment

  https://my.clevelandclinic.org/health/diseases/11315-milk-allergy

  A milk allergy causes your immune system to overreact to milk proteins. […] A milk allergy is one of the most common types of food allergy. Your immune system overreacts to one or more of the proteins in milk you’ve ingested (eaten or drunk). […] A milk allergy causes an allergic reaction in your body. An allergic reaction is your body’s response to an allergen. […] If you have a milk allergy, your body responds by creating immunoglobulin E (IgE) after your first exposure to milk. IgE are antibodies your immune system makes. Your body makes many different types of IgE, which target specific kinds of allergens. IgE antibodies bind to mast cells (allergy cells) in your skin, respiratory tract (airways) and cardiovascular system. When they encounter milk proteins, they release histamine. Histamine is what causes your allergy symptoms. […] IgE reactions happen quickly after ingesting milk. Reactions may include anaphylaxis, which is a severe allergic reaction that may cause death. […] If you have a milk allergy, proteins in milk cause your immune system to overreact. […] You may be allergic to one or both of the proteins.

• #13 What is a milk allergy? | Live Science

  https://www.livescience.com/what-is-a-milk-allergy

  Cows milk allergy is one of the most common food allergies in infants and adults, but not many people know what causes it or how it shows. […] If someone has a milk allergy, their immune system considers certain proteins in cows milk as invaders. In order to neutralize this perceived danger, it initiates a potentially life-threatening allergic reaction. […] According to the National Institute for Health and Care Excellence, milk allergy is an immune-mediated allergic response to one or more proteins in cow’s milk, such as casein and whey. There are three different types of milk allergy, depending on the underlying immune mechanism and timing of symptoms: (Ig)E-mediated, mixed IgE and non-IgE mediated. […] An immunoglobulin (Ig)E-mediated allergy happens when a person starts producing serum-specific IgE antibodies immediately after being exposed to trigger proteins. This type of milk allergy produces instant and consistently reproducible symptoms.

• #14 Milk allergy – Symptoms & causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/milk-allergy/symptoms-causes/syc-20375101

  Milk allergy is an atypical immune system response to milk and products containing milk. […] All true food allergies are caused by an immune system malfunction. If you have milk allergy, your immune system identifies certain milk proteins as harmful, triggering the production of immunoglobulin E (IgE) antibodies to neutralize the protein (allergen). The next time you come in contact with these proteins, immunoglobulin E (IgE) antibodies recognize them and signal your immune system to release histamine and other chemicals, causing a range of allergic signs and symptoms. […] Milk allergy can cause anaphylaxis, a life-threatening reaction that narrows the airways and can block breathing. Milk is the third most common food after peanuts and tree nuts to cause anaphylaxis.

• #15 Current Practice in Pediatric Cow’s Milk Protein Allergy–Immunological Features and Beyond

  https://www.mdpi.com/1422-0067/24/5/5025

  Cow’s milk protein allergy is one of the most common pediatric food allergies. It poses a significant socioeconomic burden in industrialized countries and has a profound effect on the quality of life of affected individuals and their families. Diverse immunologic pathways can lead to the clinical symptoms of cow’s milk protein allergy; some of the pathomechanisms are known in detail, but others need further elucidation. […] The key feature in food allergy pathogenesis is the lack of oral tolerance—a normal state of unresponsiveness—to food allergens. Sensitization is the preceding step in the development of symptomatic food allergy, and the “dual allergen exposure hypothesis” sheds light on multiple important mechanisms leading up to the development of food allergy. […] In patients with IgE-mediated food CMPA, the physiologic tolerance is disrupted, for example, after exposure to pathogen-associated molecular patterns (PAMPs) or epithelial damage, which leads to IL-25, IL-33, and thymic stromal lymphopoietin (TSLP) production. These changes cause an alteration in the induction of Treg cells, which are subsequently switched to antigen-specific Th2 cells. Th2 cells stimulate B cells through IL-4 production, which then results in immunoglobulin E (IgE) production and mast cell expansion. […] The molecular background of non-IgE-mediated CMPA is understood in far less detail than the IgE-mediated variant. Cellular immunity is presumed to be the key factor in the allergic response in the absence of circulating sIgE, although localized intestinal IgE response has been previously described.

• #16 The immunopathogenesis of cow’s milk protein allergy (CMPA)

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3441837/

  A high percentage of children and adults does not show circulating IgE specific for cows milk proteins and their skin prick test and serum specific IgE antibodies result negative. This occurs for the development of a not-IgE-mediated allergic disease. […] These reactions are characterized by a delayed set up, associated with the onset of symptoms after one hour or many days after the ingestion of cows milk proteins. […] However it is important to explain that the two reactions above described are not mutually exclusive and both can act in the same disease through different pathways. […] The pathogenesis of non-IgE mediated reactions is supported by different theories: reactions mediated by Th1 cells, interactions between T lymphocytes, mast cells and neurons that alters the function of the smooth muscle and the intestinal motility. […] A dysfunction on Treg cellular activity seems to be a necessary background for the spread of both reactions (IgE- and not-IgE mediated CMPA), as the induction of mucosal tolerance in children is linked with an increase of Treg lymphocytes.

• #17 Mechanisms Behind Cow’s Milk Protein Allergy | Healthcare

  https://www.cowsmilkallergy.com/hcp/mechanisms-behind-cmpa-development

  These reactions are delayed and might not present for hours, or even several days after exposure to the implicated food (‘late reactions’). […] It is a common condition in children – 50% of all cases of CMPA are reported to be non-IgE but this does vary between countries. Research indicates that the reaction is mediated by the T cells of the immune system, but this mechanism is still not very well understood. […] Some infants can have mixed allergic reactions or combinations of early and delayed reactions with symptoms of both IgE-mediated and non-IgE-mediated allergy.

• #18 What is a milk allergy? | Live Science

  https://www.livescience.com/what-is-a-milk-allergy

  A non-IgE-mediated food allergy does not involve the production of specific antibodies and reactions to this type of milk allergy are typically delayed. […] According to the National Institute of Health and Care Excellence, the underlying mechanism behind milk allergy is not known, but it is thought that various genetic and environmental factors may play a part. Immunoglobulin (Ig)E-mediated cow’s milk allergy is expressed by the production of specific IgE antibodies in response to cow’s milk proteins. These antibodies bind to the surface of cells in the body, causing a release of cell mediators (such as histamine) that directly trigger the onset of the clinical symptoms. Whereas non-IgE-mediated cow’s milk allergy is thought to be mediated by malfunctioning T-cells a type of white blood cells essential to the functioning of a healthy immune system.

• #19 The immunopathogenesis of cow’s milk protein allergy (CMPA) | Italian Journal of Pediatrics | Full Text

  https://ijponline.biomedcentral.com/articles/10.1186/1824-7288-38-35

  IgE-mediated reactions are based on simply immunological mechanisms that are better identified than not-IgE-mediated ones. […] This mechanism developed in ancestors human beings to identify multicellular target parasites and to build up an immune response towards these organisms. […] IgE-mediated CMAP is characterized by two stages: the first, of sensibilization, develops when the immune system is programmed in an aberrant way, so that IgE antibodies against cow milk proteins are secreted. […] The interaction between APC and T lymphocytes promotes the modulation and the activation of B lymphocytes. […] The pathogenesis of non-IgE mediated reactions is supported by different theories: reactions mediated by Th1 cells, interactions between T lymphocytes, mast cells and neurons that alters the function of the smooth muscle and the intestinal motility. […] A dysfunction on Treg cellular activity seems to be a necessary background for the spread of both reactions (IgE- and not-IgE mediated CMPA), as the induction of mucosal tolerance in children is linked with an increase of Treg lymphocytes.

• #20 Cow’s Milk Allergy: A Cohort of Patients from a University Hospital – Irish Medical Journal

  https://imj.ie/2009-2/

  Cows milk protein allergy (CMPA) is an adverse immunological response to cows milk protein. CMPA may be caused by IgE-mediated or non-IgE mediated mechanisms and occasionally by a combination of both. IgE antibodies to cows milk proteins produce a type 1 hypersensitivity reaction. Symptoms consistent with a type 1 reaction include acute urticaria, angioedema, wheeze, cough, vomiting and anaphylaxis. Their onset is usually within 1 hour of exposure. Diagnosis is based on clinical history supported by skin prick testing (SPT) or specific IgE (SpIgE) testing. A double-blind food challenge remains the gold standard for diagnosis. […] The pathogenesis of non-IgE CMPA remains poorly understood, but may involve Th2 cell mediated mechanisms. There is currently no accepted laboratory test for non-IgE CMPA. Diagnosis is based on clinical history and elimination followed by, when feasible, oral food challenge. The history is of a delayed reaction producing gastrointestinal or, occasionally, cutaneous symptoms. Non-IgE CMPA may play a role in a wide array of conditions including eczema, gastroesophageal reflux disease (GORD), colic, constipation and food protein-induced enterocolitis syndrome (FPIES).

• #21 Frontiers | Research progress on the mechanism of probiotics regulating cow milk allergy in early childhood and its application in hypoallergenic infant formula

  https://www.frontiersin.org/journals/nutrition/articles/10.3389/fnut.2024.1254979/full

  Research progress on the mechanism of probiotics regulating cow milk allergy in early childhood and its application in hypoallergenic infant formula. Some infants and young children suffer from cow’s milk allergy (CMA), and have always mainly used hypoallergenic infant formula as a substitute for breast milk, but some of these formulas can still cause allergic reactions. This paper discusses the mechanism and clinical symptoms of CMA in children. This review critically examines the issue of how probiotics use intestinal flora as the main vector to combine with the immune system to exert physiological functions to intervene CMA in children, with a particular focus on four mechanisms: promoting the early establishment of intestinal microecological balance, regulating the body’s immunity and alleviating allergic response, enhancing the intestinal mucosal barrier function, and destroying allergen epitopes. CMA is an allergic immune response to cow milk protein (CMP) that usually develops in the first few months after birth. Cow’s milk is an important source of nutrients when breastfeeding is insufficient. Infants are prone to CMA, which is mainly caused by the immature development of intestinal barrier and the incomplete development of immune system. The intestinal mucosal cells of infants are sparsely arranged, the intestinal osmotic pressure is increased, and allergens are easy to enter the blood through mucosal cells to cause allergy. Based on immunological mechanisms, CMA can be divided into three types, including immunoglobulin E (IgE) -mediated, non IgE -mediated, and combined. An IgE-mediated CMA is a type I hypersensitivity reaction or immediate CMA, and the clinical manifestations occur within minutes to 2 h after milk ingestions, which involves mast cell degranulation. Non IgE-mediated CMA often present symptoms 2 h to even several days induced by exposure to cow milk, involving respiratory tract, gastrointestinal tract and other parts, including type II or type III hypersensitivity reactions mediated by IgG or IgM and tissue damage caused by complement, basophils and neutrophils, and type IV hypersensitivity reactions mediated by T lymphocytes. The allergic mechanism of non-IgE-mediated immune response is currently under debate and still needs further research. In recent years, more and more studies have shown that the imbalance of Treg and pro-inflammatory Th17 cells (Treg/Th17) is also one of the key factors causing allergic diseases. When milk protein allergic reaction occurs, Th17 is dominant, and the number of Treg decreases. Probiotics can also promote the establishment of children’s intestinal microecological balance by resisting pathogen colonization, because they may temporarily occupy the vacant functional niche in the resident microbiota and secrete reactive oxygen species to inhibit pathogen growth, thereby preventing opportunistic infections and reducing the occurrence of allergies. Probiotics can also regulate the inflammatory signaling of intestinal epithelial cells to alleviate allergy. Probiotics have been shown to suppress intestinal inflammation by down-regulating TLR expression. Probiotics can play a beneficial role by regulating the abundance of intestinal flora and its metabolites. Probiotics can also enhance the host intestinal immune barrier and improve the immune regulation ability of Treg cells in the immune system. Lactic acid bacteria can produce peptidase and protease to hydrolyze milk protein, destroy allergen epitopes, and thus reduce milk allergy.

• #22 Diagnostic and therapeutic approach to cow’s milk protein allergy

  http://www.scielo.org.co/scielo.php?pid=S0120-99572020000100092&script=sci_arttext&tlng=en

  The antigen, in this case the proteins from cows milk, passes through the intestinal lumen and is recognized by the M cells of the intestinal mucosa which carry the information to antigen presenting cells (usually dendritic cells of the submucosa). […] Thus, presenting cells show the antigen to helper T lymphocytes (T helper 0 or Th 0) which causes an overexpression of the response of the helper T lymphocytes type 2 (Th2) through cytokines such as interleukins (IL) 4 and 13 which it secretes. […] In clinical expressions not mediated by IgE, IL-5 and tumor necrosis factor alpha (TNF), cytokines secreted by the Th0 cell, promote recruitment of neutrophils and eosinophil activation and can determine the appearance of edema, pain and abnormal functioning of organs. Thus, when a child is exposed to the antigen again, an antigen-antibody reaction occurs that triggers the response of previously prepared B lymphocytes, or the degranulation of mast cells/eosinophils, which generates manifestations in different organs.

• #23 The immunopathogenesis of cow’s milk protein allergy (CMPA)

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3441837/

  In conclusion, it seems that T lymphocytes subsets play a key role in allergic reactions to cows milk proteins, above all in those not-IgE mediated, and Treg cells are at the basis of oral tolerance to food allergy, so that an altered pattern of the immune system leads to all those atopic reactions, that are not explained by an IgE background.

• #24 The establishment of cow’s milk protein allergy in infants is related with a deficit of regulatory T cells (Treg) and vitamin D | Pediatric Research

  https://www.nature.com/articles/pr201712

  Cows milk protein allergy (CMPA) is the most common food allergy in infants. However, little is known about which specific immune mechanisms are related with the CMPA onset. […] Establishment of CMPA in infants was related with lower Treg and vitamin D levels. These immune alterations would be crucial factors behind the CMPA establishment and they could constitute a therapeutic target for treatment of CMPA. […] The deficit of Tregs was correlated with decreased serum levels of vitamin D. […] The percentage of Treg cells into the CD4+ T-cell population, which is a relative measure that can be influenced by the expansion or depletion of other CD4+ T subsets, was comparable between both groups. However, when absolute counts of Treg cells (cells per l of total blood) were measured, we found significantly lower Treg numbers in the CMPA group than in controls.

• #25 The establishment of cow’s milk protein allergy in infants is related with a deficit of regulatory T cells (Treg) and vitamin D | Pediatric Research

  https://www.nature.com/articles/pr201712

  Other mechanism that could be implicated in a deficit of Treg cells in the context of allergy is the serum levels of 25-hydroxyvitamin D. This vitamin has demonstrated pronounced immunoregulatory properties and notable capacity to induce Treg cells in humans. […] The lower vitamin D values found in CMPA children, and the direct correlation observed between vitamin D and the quantity of circulating Tregs supports the hypothesis that the impaired survival of Treg cells could be influenced by the deficit of vitamin D. […] The demonstration that vitamin D sufficiency is an important protective factor for food allergy in the first year of life supports the hypothesis that restoring the Treg survival could be a potential strategy to prevent the establishment of CMPA in infants.

• #26 Cow’s Milk and Autoimmunity | 2021, Volume 2 – Issue 3 | Journal of Experimental and Basic Medical Sciences

  https://jebms.org/full-text/70

  The imbalance between Th2 and Treg cells causes Th2 response to increase and inhibit Treg cells production. These in general stimulate the development of inflammation. Treg cells negatively affect allergy development while Th2 cells are contributing to the allergy. Thus, among the individuals with CMA, more Treg cells in the blood is a sign of less severe symptoms of this allergy. […] In conclusion, since T and B lymphocyte dysfunction has been linked to autoimmunity, allergy may contribute to autoimmune diseases by disrupting T and B cell functions. The link between cow’s milk and autoimmunity was found to be indirectly related to the immune system’s response to CMA in this review.

• #27 Cow’s Milk and Autoimmunity | 2021, Volume 2 – Issue 3 | Journal of Experimental and Basic Medical Sciences

  https://jebms.org/full-text/70

  When a mother stops breastfeeding, the baby is given cow’s milk-based baby foods. The prominent proteins found in cow’s milk are frequently known to be significant allergens. Cow’s milk allergy (CMA) develops in a protein-specific manner, resulting in a rapid or gradual immune response. The pathogenesis of cow’s milk allergy is influenced by both innate and adaptive immunity. This pathogenesis is linked to the progressive increase in immune response due to T-helper 2 (Th2) cells, as well as the decrease in the functionality and density of regulatory T (Tregs) cells. This situation may contribute to the autoimmunity that is occurring as a result of the activation malfunction of T and B cells which are the principal agents of the immune system. Additionally, the inflammation which becomes chronic because of the CMA may contribute to a group of autoimmune diseases.

• #28 Position document: IgE-mediated cow’s milk allergy | Allergologia et Immunopathologia

  https://www.elsevier.es/en-revista-allergologia-et-immunopathologia-105-articulo-position-document-ige-mediated-cow39s-milk-S0301054615000191

  The synthesised allergen-specific IgE binds to amino acid groups of the cow’s milk proteins called IgE-binding epitopes. […] A number of studies have compared the epitope recognition profiles of the different milk allergens (alpha(s1)-casein, beta-casein, kappa-casein, alpha-lactoglobulin, beta-lactoglobulin) between patients under 3 years of age with low allergen-specific IgE titres versus older patients with higher allergen-specific IgE titres. […] The milk antigens come into contact with the immune system fundamentally through the intestine. […] The intestinal immune system is the most frequent sensitisation pathway for food allergens. […] Different antigen- and host-related factors have been described as being capable of influencing the induction of either food antigen tolerance or sensitisation. […] The reasons why a small proportion of the population exhibits an abnormal immune response manifesting as hypersensitivity to food components (basically proteins) are not clear.

• #29 Allergenicity of Milk Proteins | IntechOpen

  https://www.intechopen.com/chapters/38834

  Cow’s milk allergy (CMA) is a complex disorder that implies an immunologically mediated hypersensitivity reaction with varying mechanisms and clinical presentations. […] The mechanisms underlying allergic sensitization to food include genetic susceptibility, aberrant barrier functions of the skin epithelium and gut mucosa and dysregulation of immune functions. […] The incidence of immune-mediated adverse reactions to foods has increased in recent decades. […] Immune reactions that cause tissue damage may be mediated by four reaction types that were defined by Coombs and Gell. […] The type I reactions appear to be the most common immune reaction to milk. […] Non-IgE-mediated hypersensitivity has been increasingly diagnosed, and it is likely that several mechanisms operate in an individual patient.

• #30 Probiotic formula reverses cow’s milk allergies by changing gut bacteria of infants – UChicago Medicine

  https://www.uchicagomedicine.org/forefront/biological-sciences-articles/2015/september/probiotic-formula-reverses-cows-milk-allergies-by-changing-gut-bacteria-of-infants

  Emerging evidence suggests that modern environmental influences, including widespread antibiotic use, high-fat and low-fiber diets, reduced exposure to infectious diseases, Caesarean birth and formula feeding have altered the mutually beneficial relationship between humans and the bacteria that live in our gastrointestinal tract. This dysbiosis, or skewing of the structure of the microbial community, can predispose genetically susceptible individuals to allergies. […] Overall, the gut microbiome of infants with a cow’s milk allergy was significantly different than healthy controls, suggesting that differences in the structure of the bacterial community indeed influence the development of allergies. Infants treated with the LGG probiotic formula who developed tolerance to cow’s milk also had higher levels of bacteria that produce butyrate than those who were fed the probiotic formula but did not develop tolerance. This further suggests that tolerance is linked to the acquisition of specific strains of bacteria, including Blautia and Coprococcus, which produce butyrate. […] „This suggests a novel mechanism by which commensal bacteria regulate allergic responses to food.”

• #31 Natural course of IgE-mediated food allergy in children

  https://www.e-cep.org/journal/view.php?doi=10.3345/cep.2022.01004

  The prevalence of food allergy and food-induced anaphylaxis in children is increasing worldwide. […] Although our understanding of the mechanism underlying the resolution of food allergy is incomplete, the roles of dendritic cells, regulatory T cells, and regulatory B cells are important. […] Tolerance to food allergens is driven mainly by antigen-presenting cells within the gut lamina propria by the promotion of T-cell differentiation. […] Regulatory T cells, especially Foxp3+ regulatory T cells characterized by CD25 expression, play an essential role in oral tolerance. […] Immunosuppressive regulatory B cells regulate the immune responses by suppressing effector T cells via the production of suppressor cytokines such as IL-10 and TGF-. […] Evidence of markers predicting the resolution or persistency of food allergy remains insufficient today.

• #32 Cow’s Milk Allergy: A Cohort of Patients from a University Hospital – Irish Medical Journal

  https://imj.ie/2009-2/

  Current research suggests that baked milk is well tolerated in the majority of cases and that graded introduction of cows milk, starting with baked milk, may encourage resolution of CMPA. CMPA is usually a temporary condition. Most cases resolve by three years, but a minority persists into childhood. In this study, 53% of children who had reached 2 years by the time of follow up had acquired tolerance. The rate of co-morbid allergies was high in this study. IgE-mediated CMPA is one of the earliest manifestations of the atopic march which can progress to asthma and allergic rhinitis. Children with CMPA are at increased risk of developing other food allergies, some of which are more persistent than CMPA and carry a greater risk of anaphylaxis.

• #33 Cow’s Milk Allergy in Adults | Allergy UK | National Charity

  https://www.allergyuk.org/resources/adult-cows-milk-allergy/

  Cow’s milk allergy is an abnormal response by the body’s immune (defence) system in which proteins in a food (in this case casein and whey proteins in cow’s milk) are recognised as potentially harmful. […] Immediate allergy (IgE mediated) is quick to appear and caused by the immunoglobulin E antibody. Typically, these allergic symptoms happen within minutes of consuming cow’s milk or up to two hours afterwards. This type of reaction is described as IgE mediated food allergy. This is the most common type in adults. In some adults with mild IgE-mediated milk allergy, a period of prolonged and strict avoidance may result in the allergy becoming more severe. […] Delayed allergy (non IgE mediated) is slow to appear and caused by a different part of the immune system reacting in a different way. This type of reaction is described as Non-IgE mediated food allergy but it is less common in adults. The symptoms typically develop from two hours after consumption but can take up to 72 hours. If cow’s milk continues to be consumed in the diet, the immune system will continue to produce such symptoms over days or even weeks.

• #34 Differentiating milk allergy (IgE and non-IgE mediated) from lactose intolerance: understanding the underlying mechanisms and presentations | British Journal of General Practice

  https://bjgp.org/content/66/649/e609

  Children with food allergy and, in particular, infants with suspected adverse reactions to cows milk, commonly present to primary care. […] Milk allergy can be either immunoglobulin E (IgE) or non-IgE mediated. IgE-mediated reactions typically occur immediately after ingestion whereas non-IgE mediated are delayed and take up to 48 hours to develop, but still involve the immune system. […] It is the symptoms of non-IgE mediated disease, which are commonly wrongly labelled as symptoms of intolerance, using either the terms lactose intolerance or milk intolerance. […] An infant with suspected IgE-mediated milk allergy will require testing for specific IgE to milk (skin prick test or blood tests). Infants with suspected non-IgE-mediated disease do not need these tests. […] Dietary management involves removing the allergenic protein from the diet. […] Acquisition of tolerance in cows milk allergy should be considered after at least 6 months on a diet free from milk protein.

• #35 Cow milk protein allergy | PPT

  https://www.slideshare.net/slideshow/cow-milk-protein-allergy-238467437/238467437

  Clinical Manifestations of Cows Milk Protein Allergy IgE mediated syndromes (Onset- immediate to 1 hour): Immediate food hypersensitivity Perioral urticaria/erythema Angioedema/anaphylaxis Generalised rash Vomiting Wheezing/ cough. […] Non-IgE mediated (Onset – late 24 h, usually after 5-7 d): Proctocolitis: Fresh bleeding per rectum, constipation Enteropathy: Watery diarrhea, failure to thrive, protein losing enteropathy, occult gastrointestinal bleeding Enterocolitis: Bloody diarrhea, anemia/hypoproteinemia. […] Esophagitis: Reflux like symptoms, vomiting/feed refusal, dysphagia. Gastritis/Gastro-duodenitis: hematemesis, occult gastrointestinal bleed. Atopic dermatitis. […] Mixed (Onset-intermediate, 24 hours): Food protein induced enterocolitis syndrome (FPIES): Vomiting, diarrhoea, colitis, shock like symptoms with severe vomiting diarrhoea, neutrophilic leukocytosis and metabolic acidosis.

• #36 Non-IgE-mediated cow’s milk allergy: Consensus document of the Spanish Society of Paediatric Gastroenterology, Hepatology, and Nutrition (SEGHNP), the Spanish Association of Paediatric Primary Care (AEPAP), the Span

  https://analesdepediatria.org/en-non-ige-mediated-cow39s-milk-allergy-consensus-articulo-S234128791930033X

  Reactions that are not mediated by IgE usually result from cellular immune responses, although in most cases the involvement of an immune mechanism cannot be proven. […] The diagnosis of non-IgE-mediated CMPA requires elimination of CMP from the diet for a period not exceeding 6 weeks (trial of elimination), verification of the resolution of symptoms, and controlled reintroduction of CMP (oral food challenge), except in cases of severe FPIES.

• #37 Non-IgE mediated food allergy

  https://www.rch.org.au/clinicalguide/guideline_index/Non-IgE_mediated_food_allergy/

  Non-IgE-mediated food allergies are delayed immune-mediated reactions to food […] Non-IgE-mediated allergies are diagnosed on the basis of clinical history and do not require allergy testing […] Non-IgE-mediated food allergies are characterised by a delayed onset of signs and symptoms, usually over hours to days following ingestion […] Non-IgE-mediated allergies do not cause anaphylaxis and therefore are not treated with adrenaline […] CMPI (Cows Milk Protein Intolerance) is an umbrella term still used by many clinicians, which encompasses the non-IgE-mediated allergic conditions Food Protein-Induced Allergic Proctocolitis and Food Protein-Induced Enteropathy […] Allergy testing with skin prick tests or allergen-specific IgE testing is not indicated for suspected non-IgE-mediated food allergies […] Allergy testing will not assist with a diagnosis of non-IgE food allergies, and may even cause harm by driving unnecessary food eliminations.

• #38 Natural course of IgE-mediated food allergy in children

  https://www.e-cep.org/journal/view.php?doi=10.3345/cep.2022.01004

  The current leading treatment for modifying the natural course of food allergy is oral immunotherapy, an allergen-specific approach based on progressive incremental ingestion of the food allergen doses until a daily maintenance dosage is reached to achieve desensitization. […] To provide the optimal treatment to patients with food allergy and help improve their quality of life, it is essential that clinicians understand the natural course of individual food allergies.

• #39 Does your child have a IgE mediated cow’s milk allergy? – Newcastle Hospitals NHS Foundation Trust

  https://www.newcastle-hospitals.nhs.uk/news/does-your-child-have-a-ige-mediated-cows-milk-allergy/

  A new clinical trial run by paediatric teams at Newcastle Hospitals hopes to help babies overcome immunoglobulin (lg)E-mediated cow’s milk allergy. […] Cow’s milk allergy is one of the most common food allergies in children and, while many eventually become tolerant, some remain allergic for many years. […] In the DREAM study, we’ll compare the traditional hypoallergenic formula with the partially hydrolysed version, given in very small doses as a supplement (termed Oral Immunotherapy) and under the strict supervision of a doctor during a visit to the Great North Children’s Hospital. […] We hope that, by slowly increasing the dose, the body will learn to ‘accept’ the cow’s milk protein rather than see it as a threat. […] The study aims to recruit approximately 150 babies between six – twelve months-old who have been diagnosed with IgE mediated CMA.

• #40 Does your child have a IgE mediated cow’s milk allergy? – Newcastle Hospitals NHS Foundation Trust

  https://www.newcastle-hospitals.nhs.uk/news/does-your-child-have-a-ige-mediated-cows-milk-allergy/

  These infants on the trial will be split into two different groups for the oral immunotherapy – one group will receive the traditional hydrolysed formula supplement, and the other will receive the partially hydrolysed version. This will help to compare whether one supplement is more effective than the other. […] DREAM is funded by an award from the Efficacy and Mechanism Evaluation (EME) programme, a Medical Research Council and NIHR partnership.

• #41 Cow milk protein allergy | PPT

  https://www.slideshare.net/slideshow/cow-milk-protein-allergy-238467437/238467437

  CMPA is a clinical diagnosis, and there is no single test or biomarker that is pathognomonic of the condition. […] The initial diagnosis of CMPA should be made on the basis of a diagnostic elimination test. Response to CMP withdrawal is noticed within 3-5 days for those with immediate manifestations, 1-2 weeks for those with delayed clinical manifestations, and 2-4 weeks for those with chronic diarrhea/failure to thrive. […] If the child does not show any improvement during this time period, a diagnosis of CMPA is ruled out on most occasions. […] The elimination diet should be continued for at least one year and re-evaluation done every 6 months subsequently. The prognosis of infants and children with CMPA is good as 50% will tolerate CMP by 1 year, 75% by 3 years and 90% by 6 years of age. Only 5% would continue into adulthood.

• #42 Milk – FoodAllergy.org

  https://www.foodallergy.org/living-food-allergy/food-allergy-essentials/common-allergens/milk

  When a person with a milk allergy is exposed to milk, proteins in the milk bind to specific IgE antibodies made by the persons immune system. This triggers the persons immune defenses, leading to reaction symptoms that can be mild or very severe. […] Most children, up to 75%, eventually outgrow a milk allergy. The allergy is most likely to continue in children who have high levels of cows milk antibodies in their blood. […] Ingestion of baked forms of cow milk may help lead to tolerance or resolution of the allergy with time. Be sure to speak to your practitioner about a formal baked milk challenge before trialing at home.

• #43 Association of cow’s milk and soy allergy | PPT

  https://www.slideshare.net/slideshow/association-of-cows-milk-and-soy-allergy/28943286

  Cooking diminishes the allergenicity of whey proteins, particularly that of BLG, presumably by denaturation of heat-labile proteins resulting in loss of conformational epitopes. This may explain why many CM allergic patients tolerate extensively heated milk. Similarly, yogurt cultures, which ferment and acidify milk, contain less intact whey protein, and therefore individuals with CMA exclusively sensitized to whey proteins may tolerate yogurt-based dairy products. […] The specificity of soy allergens is variable and complex. As many as 28 different soy proteins were recognized as able to bind IgE in soy-allergic patients. However, only a few of these proteins are considered major allergens, defined as those to which more than 50% of tested population reacted. In this context, only the birch-pollen-related allergens, Gly m 3, a profilin, and Gly m 4, a PR-10 protein, in addition to soybean hull proteins Gly m 1 and Gly m 2 have been officially accepted as soybean allergens by the International Union of Immunological Societies Allergen Sub-Committee.

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