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Toward an understanding of Allergy and In-Vitro Testing

Food represents the largest antigenic challenge facing the immune system. Assuming complete digestion, an intact intestine, a sturdy constitution, and minimal antigenic exposure such that the immune system is not over whelmed, all goes well. Weaknesses in one or more of these areas, however, can result in immune attacks upon foods as if they were foreign invaders. A long list of conditions have been associated with food reactions including fatigue, migraine, irritable bowel disease, gallbladder disease, arthritis, asthma, rhinitis, ADHD, enuresis, epilepsy ,eczema, psoriasis, apthous ulcers and recurrent sinusitis, otitis media and other infections.

Reported food Intolerance and respiratory symptoms

The aim of the study was to assess the ability of the European Community Respiratory Health Survey (ECRHS) questionnaire to provide data on the prevalence, type and reported symptoms associated with food intolerance from a group of young adults in Melbourne. Six hundred and sixty nine randomly selected subjects completed the questionnaire with 553 attending the laboratory for skin-prick tests, anthropometry, and ventilatory function tests. A further 207 symptomatic participants completed the questionnaire, with 204 of them attending the laboratory. Seventeen per cent of all respondents reported food intolerance or food allergy. A wide variety of food items was cited as being responsible for food-related illnesses. Those with current asthma did not report food-related illness more frequently than those without asthma. Respondents who reported respiratory symptoms following food ingestion were more likely to be atopic, to have used inhaled respiratory medications in the previous 12 months, reported less exposure to regular passive smoking over the past 12 months and weighed more. These associations between respiratory symptoms and food intolerance require further prospective investigation and verification. The importance of using appropriate dietary methodology in future studies for determining diet-disease relationships was highlighted by this study.

A critical review of IgG Immunoglobulins and Food Allergy- Implications in systemic health

Food allergy is defined as an adverse clinical reaction due to an immune-mediated hypersensitivity response resulting from the ingestion of a food. A wide variety of foods have been shown to produce allergic reactions including cow’s milk; chicken eggs; legumes; fish and shellfish; and cereals. (1) Depending on the speed of onset of symptoms, less than 45 minutes to 2 hours to days, immediate and delayed food allergies have been described throughout the literature encompassing a variety of gastrointestinal, respiratory, and cutaneous pathologies. (2) The inflammatory response is the common theme to all allergic pictures and is characterized by the release of chemical mediators, vasodilation, increased vascular permeability, edema, and tissue damage.

The clinical relevance of IgG food allergy testing through ELISA (Enzyme-Linked Immunosorbent Assay

Allergic reactions to foods may be classified as either IgE-mediated or nonIgE-mediated–the role of the former in food allergy being well-established. However, interestingly enough, the majority of food allergies are associated with specific nonIgE-mediated immune sensitivities. As such, appropriate tests must be utilized to identify possible causes, including food-antigen specific IgG antibodies. There are many testing methods available for the detection of food allergies including the skin prick test and RAST, or radioallergosorbent test. Unfortunately, both of these methods only look for allergen-specific IgE antibodies from the patient’s serum. This poses considerable limitations in the clinical assessment of the chronically unwell patient.

IgG mediated food allergy as trigger of fibromyalgia complaints and the influence of an elimination diet

Functional and psychovegetative complaints of fibromyalgia patients (e.g. polytopic pain, stress intolerance, lassitude, migraines, depressions, sleep disorders, rapid fatigability, etc.) and especially irritable colon are similar to the complaints of patients with food allergies or food intolerances. Specific histological changes are absent up to now; cellular inflammatory signs cannot be detected. A deterioration of symptoms is frequently found with intermittent inflammatory illnesses. Spontaneous remissions are described, but this frequently concerns a chronic clinical picture. Physiotherapy procedures, heat applications, antidepressants, NSAID or corticoids will normally be employed for therapy.

Gastrointestinal Candida colonisation promotes sensitisation against food antigens by affecting the mucosal barrier in mice

Backgrounds and aims: Controversy still exists as to whether gastrointestinal colonisation by Candida albicans contributes to aggravation of atopic dermatitis. We hypothesised that Candida colonisation promotes food allergy, which is known to contribute to a pathogenic response in atopic dermatitis. We tested this using a recently established murine Candida colonisation model. Methods: Candida colonisation in the gastrointestinal tract was established by intragastric inoculation with C albicans in mice fed a synthetic diet. To investigate sensitisation against food antigen, mice were intragastrically administered with ovalbumin every other day for nine weeks, and antiovalbumin antibody titres were measured weekly. To examine gastrointestinal permeation of food antigen, plasma concentrations of ovalbumin were measured following intragastric administration of ovalbumin. Results: Ovalbumin specific IgG and IgE titres were higher in BALB/c mice with Candida colonisation than in normal mice. Gastrointestinal permeation of ovalbumin was enhanced by colonisation in BALB/c mice.  Histological examination showed that colonisation promoted infiltration and degranulation of mast cells. Candida colonisation did not enhance ovalbumin permeation in mast cell deficient W/Wv mice but did in congenic littermate control +/+ mice. Reconstitution of mast cells in W/Wv mice by transplantation of bone marrow derived mast cells restored the ability to increase ovalbumin permeation in response to Candida colonisation. Conclusions: These results suggest that gastrointestinal Candida colonisation promotes sensitisation against food antigens, at least partly due to mast cell mediated hyperpermeability in the gastrointestinal mucosa of mice.

Ovalbumin-specific immunoglobulin G and subclass responses through the first 5 years of life in relation to duration of egg sensitization and the development of asthma

Background Egg sensitization, particularly persistent sensitization, is a risk factor for later asthma. However, little is known about accompanying IgG and subclass responses and how they might relate to asthmatic outcome.Objective To characterize hen’s egg ovalbumin (OVA) IgG and subclass responses through the first 5 years of life in relation to duration of egg sensitization and later asthma.Subjects and methods The subjects (n=46) formed part of a larger cohort, born to atopic parents, who had been evaluated prospectively for the development of asthma. Egg sensitization was classified as transient (positive egg skin prick test at 1 year only) or persistent (positive skin test for at least 2 years). Plasma OVA IgG, IgG1 and IgG4 concentrations at birth (cord), 6 months, 1 and 5 years of age were measured by ELISA.Results The kinetics of OVA IgG and IgG1 responses, but not IgG4, differed between egg sensitized and non-egg sensitized (NES) children. Only persistently sensitized children had a rise in OVA IgG1 concentration through the first year of life, and at 1 year of age they had significantly higher OVA IgG and IgG1 than either transiently sensitized or NES children. High OVA IgG1 was associated with later asthma: at 1 year of age, OVA IgG1 greater than 14 500 U predicted asthma with a sensitivity 64% and specificity 74%.Conclusion OVA IgG and subclass responses relate to the duration of egg sensitization. Measurement of OVA IgG1 concentration in infancy might offer a useful adjunct to identify those at an increased risk of asthma.

Inflammatory mediators in the elderly

Ageing is accompanied by 2-4-fold increases in plasma/serum levels of inflammatory mediators such as cytokines and acute phase proteins. A wide range of factors seems to contribute to this low-grade inflammation, including an increased amount of fat tissue, decreased production of sex steroids, smoking, subclinical infections (e.g. asymptomatic bacteriuria), and chronic disorders such as cardiovascular diseases and Alzheimer’s disease. Furthermore, there is some evidence that ageing is associated with a dysregulated cytokine response following stimulation. Several inflammatory mediators such as tumour necrosis factor-alpha and interleukin-6 have the potential to induce/aggravate risk factors in age-associated pathology, providing a positive feedback mechanism. Thus, it is possible that inflammatory mediators constitute a link between life style factors, infections and physiological changes in the process of ageing on the one hand and risk factors for age-associated diseases on the other. Consistent with this, inflammatory mediators are strong predictors of mortality independently of other known risk factors and co-morbidity in elderly cohorts. A direct pathogenetic role of inflammatory mediators would be highly likely if longevity was shown to be associated with cytokine polymorphisms regulating cytokine production. Several studies support indeed this hypothesis but, unfortunately, findings in this area are conflicting, which probably reflects the complexity of the effect of cytokine polymorphisms and their interaction with the lifestyle and sex.

The Role of Hidden Food Allergy/Intolerance in Chronic Disease

A large body of medical literature has indicated that hidden food allergy is a frequent cause of a wide range of physical and mental conditions. Hidden allergies can be “unmasked” by means of an elimination diet, followed by individual food challenges.Although the concept of hidden food allergy remains controversial, the evidence strongly suggests that identification and avoidance of allergenic foods can relieve a number of common and difficult-to-treat medical problems.

Patterns of immunoglobulin G responses to egg and peanut allergens are distinct: ovalbumin-specific immunoglobulin responses are ubiquitous, but peanut-specific immunoglobulinresponses are up-regulated in peanut allergy.

Background The clinical significance of food-specific IgG subclasses in food allergy and tolerance remains unclear. Specific IgG titres are often reported in non-standardized units, which do not allow comparisons between studies or allergens. Objective To quantify, in absolute units, ovalbumin (OVA)- and peanut-specific IgG levels in children with peanut or egg allergy (active or resolved) and in non-allergic controls. Methods Children aged 1–15 years were recruited. Peanut allergy was diagnosed by convincing history and a 95% predictive level of specific IgE; egg allergy or resolution was confirmed by oral challenge. Serum IgG, IgG1 and IgG4 levels (mg/mL) to OVA and peanut extract were quantified by ELISA. Results OVA- and peanut-specific IgG was detected in all subjects. In non-allergic controls (n = 18), OVA-specific IgG levels were significantly higher than peanut-specific IgG (median mg/mL IgG = 15.9 vs. 2.2, IgG1 =1.3 vs. 0.6, IgG4 = 7.9 vs. 0.7; Po0.01). There were no differences in OVA-specific IgG, IgG1 and IgG4 between egg-allergic (n = 40), egg-resolved (n = 22) and control (n = 18) subjects. In contrast, peanut-specific IgG (median mg/mL IgG = 17.0, IgG1 = 3.3, IgG4 = 5.2) were significantly higher in peanut-allergic subjects (n = 59) compared with controls and with non-peanut-sensitized but egg-allergic subjects(n = 26). Overall, the range of IgG4 was greater than IgG1, and IgG4 was the dominant subclass in 460% of all subjects. Conclusion OVA-specific IgG levels of egg-allergic, egg-resolved or control groups are not distinguishable. Higher peanut-specific IgG levels are associated with clinical allergy, but the range of IgG titres of the allergic and control groups overlapped. Hence, OVA and peanutspecific IgG measurements do not appear to be of diagnostic value. Strong IgG responses to OVA may be a normal physiological response to a protein frequently ingested from infancy, whereas up-regulated IgG responses in peanut allergy may be indicative of a dysregulated immune response to peanut allergens.

Serum IgG responses to food antigens in the italian population evaluated by highly sensitive and specific ELISA test

Using an optimized and validated ELISA method, we performed a serum test for assaying the binding capacity of serum IgG to proteins extracted from approx. 160 different foods to investigate the reactivity of specific IgG antibodies in the Italian population composed of 6,879 subjects (4,551 females and 2,328 males). 44 antigens showed an IgG response greater than 10% and only 14 aliments had an elevated reactivity greater than 20%, in particular, milk, from cow and goat, and several milk derivatives, along with egg albumen and yeasts. The IgG response to the high reactive food antigens depending on the age of the 6880 subjects was also analyzed. We demonstrated a high IgG response in a very large subject group to milk and milk derivatives, and egg albumin antigens, and we conclude that the validated ELISA test may be applied for the serum/plasma IgG antibody level determination as a useful indicator of adverse reactions to food and food hypersensitivity.

Detection of IgE, IgG, IgA and IgM antibodies against raw and processed food antigens

Background: Despite the first documented case of food allergy to cooked food in 1921 by Prausnitz and Kustner, all commercial food antigens are prepared from raw food. Furthermore, all IgE and IgG antibodies against dietary proteins offered by many clinical laboratories are measured against raw food antigens.  Methods: We developed an enzyme-linked immunosorbent assay for the measurement of IgE, IgG, IgA and IgM antibodies against raw and processed food antigens. Sera with low or high reactivity to modified food antigens were subjected to myelin basic protein, oxidized low density lipoprotein, and advanced glycation end products (AGE) such as AGE-human serum albumin and AGE-hemoglobin.  Results: Compared to raw food antigens, IgE antibodies showed a 3–8-fold increase against processed food antigens in 31% of the patients. Similarly, IgG, IgA and IgM antibodies against modified food antigens overall were found at much higher levels than antibody reactions against raw food antigens. Almost every tested serum with high levels of antibodies against modified food antigens showed very high levels of antibodies against myelin basic protein, oxidized low density lipoprotein, AGE-human serum albumin and AGE-hemoglobin.  Conclusion: We conclude that the determination of food allergy, intolerance and sensitivity would be improved by testing IgE, IgG, IgA and IgM antibodies against both raw and processed food antigens. Antibodies against modified food antigens, by reacting with AGEs and tissue proteins, may cause perturbation in degenerative and autoimmune diseases such as diabetes, atherosclerosis, inflammation, autoimmunity, neurodegeneration and neuroautoimmunity.

Testing for food reactions: the good, the bad, and the ugly

An increasing number of commercial tests for food allergies are marketed to consumers and healthcare practitioners with tenuous claims. The aim of this article is to provide an evidence-based review of the tests and procedures that currently are used for patients with suspected food allergy. A systematic review of the literature evaluating the validity of tests and procedures used in food reactions was performed using conventional search engines (eg, PubMed, Ovid) as well as consumer sites (eg, Google, Bing). The National Library of Medicine Medical Subject Headings (MeSH) term food hypersensitivity was used along with food allergy testing, food sensitivity testing, food intolerance testing, and adverse food reactions. Of the results obtained, testing for immunoglobulin E (IgE)-mediated food allergy was best represented in PubMed. IgE-based testing continues to be the gold standard for suspected food allergies. Among modalities used by many conventional and alternative practitioners, immunoglobulin G (IgG)-based testing showed promise, with clinically meaningful results. It has been proven useful as a guide for elimination diets, with clinical impact for a variety of diseases. Mediator release testing and antigen leukocyte cellular antibody testing were only represented on consumer sites. Further investigation into the validity and the clinical application of these tests and procedures is required. Disclosing the basis for food reactions continues to present a diagnostic challenge, and testing for food allergies in the context of an appropriate clinical history is paramount to making the correct diagnosis.

Serum antibodies to dietary antigens in patients with HIV-1 infection

Diarrhoea is a common complication of HIV-1 infection [1], but in a considerable proportion of patients, especially in earlier stages of the disease, the cause of diarrhoea remains unclear despite extensive investigation [2]. Increased levels of serum antibodies against food proteins have been described in HIV-infected children [3], similar to patients with non-IgE-mediated gastrointestinal food hypersensitivity [4], coeliac disease [5], or chronic inflammatory bowel disease [6]. These abnormalities are thought to result from increased gut permeability leading to increased uptake of dietary antigens and an aberrant mucosal IgG response in these patients [7]. Increased intestinal permeability [8] and an increase of IgG in mucosal secretions [9] have also been found in patients infected with HIV-1. Since abnormal immunity to dietary antigens may contribute to the pathogenesis of diarrhoea, we investigated serum antibodies to food proteins in HIV-1-infected patients with and without diarrhoea.

Increase in intranuclear nuclear factor KB and decrease in inhibitor KB in mononuclear cells after a mixed meal: evidence for a proinflammatory effect1–3

Background: In view of the stimulatory effect of glucose on reactive oxygen species (ROS) generation, we investigated the possibility that a mixed meal stimulates ROS generation and possibly induces concomitant proinflammatory changes. Objective: The objective was to determine whether the intake of a 900-kcal mixed meal induces an increase in ROS generation by leukocytes and an inflammatory response at the cellular level. Design: Nine normal-weight subjects were given a 900-kcal mixed meal, and 8 normal-weight subjects were given 300 mL water after an overnight fast. Blood samples were collected at 0, 1, 2, and 3 h. ROS generation by mononuclear cells and polymorphonuclear leukocytes and the expression of p47phox subunit were measured. Intranuclear nuclear factor B (NF-B) binding and the expression of inhibitor B[1] (IB[1]), IB kinase [1] (IKK[1]), and IB kinase  (IKK) were measured. Plasma concentrations of C-reactive protein (CRP) and soluble intercellular adhesion molecule were also measured. Results: ROS generation by mononuclear cells and polymorphonuclear leukocytes and p47phox expression increased significantly. The expression of IKK[1] and IKKand DNA-binding activity of NF-Bincreased significantly, whereas IB[1] expression decreased. Plasma CRP concentrations increased. The intake of 300 mL water did not induce a change in any of the above indexes. Conclusions: These data show that the intake of a mixed meal results in significant inflammatory changes characterized by a decrease in IB[1] and an increase in NF-B binding, plasma CRP, and the expression of IKK[1] , IKK , and p47phox subunit. These proinflammatory changes are probably relevant to the state of chronic hypertension and obesity and to its association with atherosclerosis.

Mouse and human neutrophils induce anaphylaxis

Anaphylaxis is a life-threatening hyperacute immediate hypersensitivity reaction. Classically, it depends on IgE, Fc!RI, mast cells, and histamine. However, anaphylaxis can also be induced by IgG antibodies, and an IgG1-induced passive type of systemic anaphylaxis has been reported to depend on basophils. In addition, it was found that neither mast cells nor basophils were required in mouse models of active systemic anaphylaxis.  Therefore, we investigated what antibodies, receptors, and cells are involved in active systemic anaphylaxis in mice. We found that IgG antibodies, Fc”RIIIA and Fc”RIV, platelet-activating factor, neutrophils, and, to a lesser extent, basophils were involved. Neutrophil activation could be monitored in vivo during anaphylaxis.  Neutrophil depletion inhibited active, and also passive, systemic anaphylaxis. Importantly, mouse and human neutrophils each restored anaphylaxis in anaphylaxis-resistant mice, demonstrating that neutrophils are sufficient to induce anaphylaxis in mice and suggesting that neutrophils can contribute to anaphylaxis in humans.  Our results therefore reveal an unexpected role for IgG, IgG receptors, and neutrophils in anaphylaxis in mice.  These molecules and cells could be potential new targets for the development of anaphylaxis therapeutics if the same mechanism is responsible for anaphylaxis in humans.

IgG-blocking antibodies inhibit IgE-mediated anaphylaxis in vivo

Although it has long been hypothsized that allergen immunotherapy inhibits allergy, in part, by inducing production of IgG Abs that intercept allergen before they can cross-link mast cell FceRI associatedIgE, this blocking Ab hypothesis has never been tested in vivo. We have studied active and passive immunization models in mice to approach these issues and to determine whether any inhibition of anaphylaxis observed was direct effect of allergen neutralization by IgG Ab or indirect effect cross-linking of FceRI to the inhibitory IgG receptor FcgRIIb.

Immunological mechanisms of allergen-specific immunotherapy

Allergen-specific immunotherapy has been carried out for almost a century and remains one of the few antigen-specific treatments for inflammatory diseases. The mechanism by which allergen-specific immunotherapy exerts its effects include the modulation of both T-cell and B-cell responses to allergen. There is a strong rationale for improving the efficacy of allergen-specific immunotherapy by reducing the incidence and severity of adverse reactions mediated by IgE. Approaches to address this problem include the use of modified allergen, novel adjuvants and alternative routes of administration. This article reviews the development of allergen-specific immunotherapy, our current understanding of its mechanisms of action and its future prospects.

Intestinal microflora: probiotics and autoimmunity

Lactobacillus casei strain Shirota (LcS) has been demonstraited to have beneficial effects in numerous murine disease model via host immune modulation. It has also been reported that LcS inducedrecovery of host immune responses that were decreases by treatment with carcinogenes and augmentes the natural killer activity and T-cell functions of host immune cells. After LcS is ingested by thehost, it is incorporated into M cells in Peyer patches (PP) and digested to form active components. In PP, macrophages and dendritic cells that phagocytosed LcS gained the ability to produce severalcytokines, especially tumor necrosis factor-a (TNFa). The components of LcS digested in PP were then recognized through toll-like receptor 2 (TLR2) in antigen-presenting cells, resulting in the production of several cytokines elicited varied responses in host immune cells. Also, it was observed by 2D-PAGE analyses that the expression level and/or the phsphorilation of some proteins in PPand mesenteric lymph nodees definitely altered by the ingestion of LcS, providing more evidence of cellular responses. These results suggest that some probiotic bacteria have the potential to augmentor modify the host immune function through the regulation of host immune cells

Basophils play a pivotal role in immunoglobulin-G-mediated but not immunoglobulin-E-mediates systematic anaphylaxis

Anaphylaxis is an acute, severe, and potentially fatal systematic allergic reaction. Immunoglobulin E (IgE), mast cells, and histamine have long been associated with anaphylaxis, but an alternative pahtwaymediated by IgG has been suggested to be more important in the elicitation of anaphylaxis. Here, we showed that basophils, the least common blooed cells, were dispensable for IgE-mediates anaphylaxis but played a critical role in IgG-mediated, passive and active systemic anaphylaxis in mice. In vivo depletion of basophils but not macrophages, neutrophils, or NK  cells ameliorated IgG-mediated passive anaphylaxis and rescued mice from death in active anaphylaxis. Upon capture of IgG-allergen complexes, basophils relased platelet-activating factor (PAF), leading to increasedvascular permeability. These results high-light a pivotal role for basophils in vivo and contrast two major, distinct pathways leading to allergen-induced systematic anaphylaxis: one mediated by basophils, IgG, and PAF and the other „classical” pathway mediated by mast cells, IgE, and histamine.

The immuno modifying effects of amino acids on gut-associated lymphoid tissue

The intestine and gut-associated lymphoid tissue (GALT) are essential components of whole body immune defense, protecting the body from foreign antigens and pathogens, while allowing tolerance tocommensal bacteria and dietary antigens. The requirement for protein tu support the immune system is well established. Less is known regarding the immune modifying properties of individual amino acidsparticularly on the GALT. Both oral availabbility of specific dietary amino acids (in particular glutamine, glutamate, and arginine, and perhaps methionine, cysteine and threonine) are essential to optimizing the immune functions of intestine and the proximal resident immune cells. Future studies should be designed using amino acid mixtures that target a number of specific functions of GALT in order to optimize immune function in domestic animals and humans during critical periods of development and various disease states.

Identification of markers that distinguish IgE- from IgG-mediated anaphylaxis

IgG-mediated anaphylaxis occurs in mice and may contribute to human reactions to infused drugs. To distinguish IgE- from putative IgG-mediated human anaphylaxis, we developed blood markers for murine anaphylaxis and evaluated their human relevance. Both IgG- and IgE-mediatesd anaphylaxis were characterized by decreased basophil and monocyte percentages and an increased neutrophilpercentage in mouse blood. IgE- but not IgG-mediated murine anaphylaxis was accompanied by large increase in IL-4 secretion, plasma soluble IL-4 receptor-a (IL-4Ra) concentration, and T-cellmembrane IL-4Ra expression. Murine IgG- but not IgE-mediated anaphylaxis was characterized by decreased neutrophil Fcg receptor III (FcgRIII) expression that was observed even when the antigendose was insufficient to induce shock. Human neutrophils culture with IgG immune complexes also lost FcgRIII. These observations sugegst that decreased blood neutrophil FcgIII expression without IL-4Ra expression can be used to determine whether and when IgG mediated anaphylaxis occurs in man.

Nutritional medicine as mainstream in psychiatry

Psychiatry is at an important juncture, with the current pharmacologically focused model having achieved modest benefits in addressing the burden of poor mental health worldwide. Also the determinants of mental health are complex, the emerging and compelling evidence for nutrition as a crutial factor in the high prevalence and incidence of mental disorders sugggests that dietis as important to psychiatryas it is to cardiology, endocrinology, and gastroenterology. Evidence is steadily growing for the relation between dietary quality (and potential nutritional deficiensies) and mental health, and for the selectuse of nutrient-based supplements to address deficiencies, or as monotherapies or augmentation therapies. We present viewpoint from an international collaboration of academics (members of the International Society for Nutritiona Research), in which we provide a context and overview of current evidence in this emerging field  of research, and discuss the future direction. We advocate recogntionof diet and nutrition as central determinants of both physical and mental health.

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