Antibodies In Health & Disease

Introduction

It has been estimated that food intolerances and related diseases affect at least 100 million people worldwide and have increased by more than 50% in adults and children in recent years. Etiological studies suggest that these diseases may be related to adverse food reactions (food hypersensitivity). According to recent data, IgG-dependent hypersensitivity, characterised by a delayed immune response, plays a significant role in the pathogenesis of food reactions, referred to in this review as ‘food intolerance’. Whilst this is not strictly the correct term by some definitions, this is however a term in common usage. Determination of serum IgG food antibodies potentially opens new diagnostic pathways for patients who are hypersensitive to food components, which can be alleviated by food elimination diets based on the results of such testing [1].
The specific characteristics of IgG-dependent responses result in a delayed nature for such reactions which is a considerable diagnostic obstacle, making it almost impossible for the patient to identify the factor causing the reaction [2]. While IgE antibodies are responsible for acute, immediately developing allergic reactions, IgG-dependent reactions take much longer to develop.
Elevated levels of IgG antibodies to food antigens have been observed substantially in diseases associated with increased intestinal barrier dysfunction, in particular, IgA deficiency, celiac disease, and inflammatory bowel disease (IBD) [3-5]. The controversy surrounding food IgG testing relates to the significance of food IgG antibodies in the pathogenesis and diagnosis of food intolerance and a number of chronic illnesses, including IBD, IBS, migraine, and arthritis. Clinical studies to date have largely been supportive of a role for food IgG testing in certain illnesses.

Background and Definitions

Food intolerance can be defined as a general term, describing an abnormal physiologic response to an ingested food or food additive. Such reactions are not considered to demonstrably involve the immune system, an example being lactose intolerance, where there is a deficiency in the enzyme responsible for breaking down ingested lactose. However, these classifications fail to include reactions mediated by immunoglobulin G (IgG), which since such reactions involve the immune system, would be classified as a form of allergy regarded as an example of a Type III hypersensitivity reaction. This has led to a great deal of confusion amongst lay people and professionals alike, where IgG mediated reactions are often referred to as food intolerance, or where IgG mediated reactions are referred inappropriately as ‘allergy’ tests. Food sensitivity is a term alternatively used to distinguish such reactions from classical allergy (IgE) and food intolerance (non-immune).
IgG mediated reactions are a distinct entity, with a very different clinical picture they are usually defined as ‘delayed reactions’ with a less severe symptom outcome compared to some IgE mediated reactions. Symptoms can typically affect many different body systems and are regarded as an example of a type III hypersensitivity reaction, characterized by the production of immune complexes with food specific IgG antibodies activating the complement pathway and thus initiating low grade inflammatory reactions [7].

Immunological Mechanisms

The breakdown in oral tolerance, and hence sensitization to dietary antigens, has been and continues to be the subject of intense scientific research worldwide, and considerable progress has been made in elucidating the role played by dietary proteins and the antibodies directed against them.

Studies have demonstrated:

1. A role for antigen-specific IgG in type I, immediate hypersensitivity through the aggregation of high affinity receptors (FcγRI) for IgG on human mast cells and basophils resulting in degranulation and the release of histamine and arachidonic acid metabolites. The mediator profile through activation of IgG receptors on human mast cells has been shown to be qualitatively indistinguishable from responses stimulated through the high affinity receptor for IgE [15,16].
2. The involvement of food specific IgG antibodies in type II, antibody-dependent hypersensitivity as in the case of milk-induced thrombocytopenia [17].
3. A role for food IgG antibodies in type III, immune complex-mediated hypersensitivity. IgG antibodies combine with food antigen to form circulating immune complexes to which complement is fixed. Such complexes deposit in various tissues promoting Arthus-like reaction resulting in vasculitis and tissue damage [18]. Based on histologic and immunofluorescent findings in intestinal biopsies, there is evidence that the Arthus-type reaction is involved in the pathogenesis of cow’s milk sensitive colitis [19]. Also, the findings of immune complex deposits in lung biopsy specimens taken from patients with Heiner syndrome implicate this type of reaction in the pathogenesis of this syndrome [20].
4. Increased intestinal permeability after oral challenge and a role for mast cells in the regulation of intestinal barrier dysfunction in patients with food allergy [21-25]. Whilst such studies focus on IgE-mediated allergy, the activation of mast cells through food IgG activation of IgG receptors as described above cannot be discounted, indeed the recent elucidation of novel mast cell activation pathways, have clearly implicated IgG as a potential trigger for such activation [26].
5. IgG receptor polymorphisms play an important role in the pathogenesis of inflammatory disease [27-30]. Aberrant regulation or function of these receptors in the presence of elevated food IgG antibodies would lead to magnified effector responses that initiate inflammatory disease and increased susceptibility to autoimmunity.

Increased intestinal permeability and food specific IgG antibodies

In a healthy normal intestinal tract where homeostasis is preserved, the intestinal barrier is tight and highly selective, so that only the desired nutrients enter the bloodstream from the intestinal lumen, while access of potentially damaging substances and pathogens is impeded. This barrier also plays a role in immune sampling and processing of potential allergens and in the prevention of infection (e.g. the binding of pathogens by secretory IgA (sIgA)). The main structural elements of the intestinal barrier responsible for its correct functioning include commensal microorganisms, secretory IgA, and enterocytes, along with their healthy tight junctions, Peyer’s patches, M cells, antigen presenting cells (APCs), and lymphocytes.
Studies have shown that damage to the tight junctions between the enterocytes is the precipitating cause for the development of food specific IgG antibodies. Correctly functioning tight junctions between the intestinal cells ensure that the barrier shows the required selectivity. Loosening of the tight junctions makes it possible for larger particles – not only nutrients, but also toxins, allergens, and microorganisms – to penetrate the barrier. The increased permeability of the intestinal barrier is often referred to as ‘leaky gut syndrome’. When elements that originate from the intestinal lumen enter the bloodstream, an immune response is triggered. While this response is necessary to eliminate potentially harmful substances and microorganisms, it is at the same time potentially undesirable with respect to harmless neutral food particles [35].
There is increasing evidence that damage to the tight junctions and the subsequent influx of toxins and allergens lead to abnormal immune reactions, in turn leading to the development of autoimmune diseases. Several studies have also shown that this damage to the tight junctions is the precipitating cause for the development of food specific IgG antibodies. Furthermore, there is evidence that this permeability is selective to food allergens. In a published review of all publications relating to increased permeability, IgG antibodies, and IBS by Pasquale et al., 2018, the authors concluded that the production of such antibodies is a specific reaction, rather than a nonspecific reaction as is widely believed [36].

Food Specific IgG antibodies and Inflammation
When elements that originate from the intestinal lumen enter the bloodstream, an immune response is triggered.
While this response is necessary to eliminate potentially harmful substances and microorganisms, it is at the same
time potentially undesirable with respect to harmless neutral food particles. Ingestion of food may therefore lead to chronic activation of the immune system in which IgG antibodies are involved, leading to the development of immune complexes which in turn cause chronic inflammation and mechanical damage to the surrounding tissues.
Low grade inflammation may play a causal role in the development of obesity, insulin resistance, diabetes mellitus, and atherosclerosis. In obese subjects, adults as well as children, inflammatory markers, such as C-reactive protein (CRP), correlate with the degree of obesity and insulin resistance and normalize after weight reduction [8].The authors of this study concluded that, obese children have significantly higher IgG antibody values directed against food antigens than normal weight children. Furthermore, anti- food IgG antibodies are tightly associated with low grade systemic inflammation, and with the intima media thickness (IMT) of the common carotid arteries. These findings raise the possibility that anti-food IgG is pathogenetically involved in the development of obesity and atherosclerosis.
Recently, immunoglobulin G (IgG) antibodies against food antigens have been suggested to cause low grade inflammation in irritable bowel syndrome by subtle mucosal inflammation [38]. Food elimination therapy based on IgG
testing was able to improve the symptoms of irritable bowel syndrome [6]. IgG-mediated food intolerance may be explained by low level absorption of food macromolecules from the gut [39]. Thus, IgG antibodies to some food components are detectable in healthy individuals, although at lower levels the role of this class of antibodies remains highly controversial [40 – 42].
The generation of other interleukins (IL-12, IFN) will result in increased IgG antibodies of the IgG1, IgG2, and IgG3 classes. These are pro-inflammatory and are responsible for chronic dietary disorders. Every time a food is consumed, increased levels of IgG1, IgG2, or IgG3 will generate the formation of an immune complex; these complexes will become bound where individual specific imperfections exist in the body. These “activated sites” may be small injuries that had previously become inflamed (e.g. joints), organs damaged by infections (e.g. intestines), or injuries (e.g. to the thyroid) caused by environmental toxins (e.g. mercury). It is not easy to predict which symptom will appear, because this primarily depends on the patient’s physical condition. If IgG1-IgG3 antibodies are present for regularly consumed foods, the formation of immune complexes leads to chronic inflammation. Non-specific systemic reactions in which low-grade inflammation plays a main role (cardiovascular disease, metabolic syndrome, and obesity) have also been linked to the generation of complement activating food specific IgG antibodies.

IgG and Complement Activation
Any food antigen entering the bloodstream can produce symptoms associated with food intolerance. Most food antigens enter the bloodstream through the intestinal epithelium and stimulate the production of IgG antibodies. IgG antibodies bind to food antigens that are free in the blood or that have deposited in tissues and form immune complexes (IC). The IC activates complement C3 which becomes covalently linked to the IgG forming IC-C3b. Ultimately, the C3b on the IC is cleaved forming IC-C3d. Under normal circumstances, circulating IC-C3b bind to the CR1 receptors on red blood cells and are cleared from the circulation in the liver and spleen. However, continued production of IgG antibody and formation of IC may result in deposition of IC in tissues, leading to the activation of the terminal complement pathway C5-9 on the surface of the tissue, causing cell lysis and increased inflammation.

Effects of Elimination Diet
According to Isolauri et al., an elimination diet based on the results of the measurement of IgG levels may be equally beneficial in terms of symptom relief as is the case with IgE-dependent allergy [31]. A study conducted by the University of York on behalf of the British Allergy Foundation in 2001 investigated the usefulness of an elimination diet used after determination of serum levels of IgG antibodies. A total of 4200 patients with symptoms were enrolled in the study, but only 1761 were included in the final statistical analysis. As many as 50% of the subjects observed a considerable improvement of health after introduction of the elimination diet and 70% reported health benefits [32]. This study is suggestive enough to justify the need for investigating the potential contribution of IgG-dependent allergy to many disease entities. In this review, we characterize the mechanism underlying the effects of type III allergy on functional disorders and disease entities associated with the gastrointestinal tract.
The potential role of type III hypersensitivity in the pathogenesis of irritable bowel syndrome (IBS) has been extensively investigated. IBS is a chronic functional disorder of the intestines manifested by frequent abdominal pain, bloating and constipation, and/or diarrhoea, which may occur alternately. The prevalence of IBS in the population is high, and is estimated at 12–22% [33]. Given the heterogeneity of the abnormalities and the multifactorial aetiology of IBS, the involvement of IgG-dependent hypersensitivity in the initiation of the pathological changes seems likely. Interestingly, most patients suffering from functional disorders of the gastrointestinal tract report that certain foods exacerbate their symptoms [34]. The management of IBS focuses mainly on administration of antispasmodic drugs, drugs that modify
intestinal function, antibiotics, antidepressants, and analgesics. Atkinson et al. [6] showed that an elimination diet can be effective in relieving the symptoms of IBS. After 12 weeks of the diet, a 10% improvement in well-being and resolution of the symptoms were observed (p = 0.024). The quality of life also improved. Notably, in patients who decreased the restrictiveness of the diet, a 24% worsening of the symptoms was observed, compared to patients strictly adhering to the dietary guidelines. Drisco et al. [33] conducted a study in 20 patients meeting the Rome II criteria for IBS. The patients followed a diet for 6 months that was based on the results of the tests for IgG-dependent intolerance. The study showed abnormal titres of IgG antibodies specific for selected food components in all the patients. Using a diet based on the results of IgG-dependent intolerance testing led to a statistically significant improvement in symptoms (improved stool frequency, pain relief) (p =0.05) and the quality of life (p = 0.0001). The patients adhering to the diet reported considerable improvement that was greater than the improvement observed with the intake of a probiotic alone. Also, other researchers see the value in introducing a diet based on measurements of the levels of IgG antibodies to food antigens in patients with IBS [34, 35]. However, a necessity is emphasized to carefully select research tools, i.e. tests that are based on reliable methods and that assess the correct parameter [34].
The therapeutic application of a diet based on the results of the tests assessing type III hypersensitivity has also been shown in patients with Crohn’s disease [12]. The authors of the analysis, given the multifactorial aetiology of the disease, suggested a potential contribution of the immune response to food antigens to the maintenance of inflammation. For this reason, a pilot study was conducted in 79 adult patients with Crohn’s disease. The control group consisted of 20 healthy volunteers. The study showed markedly higher serum levels of IgG in patients with organic bowel disease, compared to the control group. IgG antibodies to cheese and to baker’s yeast were demonstrated in 84% and 83% of the patients, respectively. Following a diet based on the results of the measurement of specific IgG for food antigens considerably improved stool frequency, pain, and patients’ well-being. Decreased secretion of interferonγ (IFN-γ) by T cells was also observed. The levels of the eosinophil-derived neurotoxin (EDN protein) in the stool did not, however, change. The findings of the study demonstrate that implementation of a diet based on testing for IgG-dependent hypersensitivity in patients with Crohn’s disease is justified. However, this is the first analysis of this type, and therefore drawing any binding conclusions requires further dietary studies in a group of patients with inflammatory bowel disease.

Evidence-Based Clinical Relevance of Food Specific Serum IgG Antibodies
A growing body of medical literature supports the clinical value of measuring food-specific IgG antibodies to guide therapeutic dietary changes. A number of studies involve IBS patients. In all studies, significant clinical improvement was gained by using IgG (total) testing to screen for foods for dietary exclusion [1,6,43-45] Irritable Bowel Syndrome is estimated to occur in 12% to 22% of the UK population, and is a disorder of high direct and indirect medical costs [68]. Any improved treatment and management would be of significant benefit not only to patient outcome, but also to the reduction in healthcare costs. In a review of all published literature from 1966 to 2015 relating to IBS, a report in the World Journal of Gastroenterology in 2015 [36], concluded that hypersensitivity reactions may play a role in causing IBS symptoms in a subset of patients. Furthermore, the increase of food-specific IgG titres could be a specific reaction, rather than a non-specific response, to increased gut mucosal permeability. The authors concluded that “Pending further scientific evidence, the concept of food allergy (adverse food reactions) should be included as a possible cause of IBS, and a dietary approach may have a place in the routine clinical management of IBS”. A number of other studies looking at a variety of conditions showed IgG testing to be clinically useful in ameliorating symptoms [2,8,47].

Discussion
Despite the large volume of published works implicating IgG mediated immune responses as part of the aetiology of these complex diseases, the clinical utility of specific food IgG antibody measurements has been called into question. Frequently position statements from various allergy societies are used as evidence to support this view. A typical example that is often cited is that of the European Academy of Allergy & Clinical Immunology (EAACI) task force report of 2008 [43]. One of the points that the EAACI report states is, “there is a lack of any controlled studies on the diagnostic value of IgG testing in food allergy”. However, in a review of all published literature from 1966 to 2015 relating to IBS, a report in the World Journal of Gastroenterology in 2015 [36] concluded that hypersensitivity reactions may play a role in causing IBS symptoms in a subset of patients. Furthermore, the increase of food-specific IgG titres could be a specific reaction, rather than a non-specific response to increased gut mucosal permeability. The authors concluded that “Pending further scientific evidence, the concept of food allergy (adverse food reactions) should be included as a possible cause of IBS, and a dietary approach may have a place in the routine clinical management of IBS”.
The efficacy of a diet based on the measurement of IgG antibodies specific for food components has been demonstrated for a number of disease entities. Excellent results have been obtained in patients with migraine, respiratory disease, IBS, obesity and IBD [8,12,36,44,45].A diet based on testing for food specific IgG antibodies has shown to be an alternative and safe treatment for patients with chronic conditions [7]. It is important to remember that such testing has been performed by many reputable laboratories all over the world for many years, resulting in many hundreds of thousands of tests, that in a great many cases have resulted in relief for the patient from persistent symptoms. It is therefore nonsensical to suggest that such testing merely reflects a normal immune response and has no clinical value. With the large body of evidence that has now been accumulated, and with the recent evidence demonstrating the crucial role that IgG class antibodies play in initiating tolerance [48], it is time for a balanced medical discussion about what such testing can be used for, and its limitations. The determination of serum IgG food antibodies potentially opens up new diagnostic and therapeutic pathways for patients who are hypersensitive to food components, which can be alleviated by food elimination diets based on specific IgG antibody levels, for a variety of complex and challenging conditions.

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