The Role Of Igg And Its Diagnostic Value In Food Sensitivitiy

The Role of IgG and Food Sensitivity in Chronic Disease

This independent literature review was carried out between the dates of 01/09/99 and 09/10/99 by Alison Mathery B.Sc. (Hons) Biochemistry, Ph.D. Immunology (submission in process).

CONTENTS

SECTION PAGE

1. SUMMARY . . . . . . . . . 1

2. INTRODUCTION . . . . . . . . . 2

3. THE CASE AGAINST IgG AND FOOD SENSITIVITY IN CHRONIC DISEASE 3

4. THE CASE FOR IgG AND FOOD SENSITIVITY IN CHRONIC DISEASE . 4

4.1 INDEPENDENT BEHAVIOUR OF FOOD SPECIFIC IgG . . . 4

4.2 COW’S MILK SENSITIVITY . . . . . . 5

4.3 ECZEMA . . . . . . . . . 6

4.4 FOOD SENSITIVITY IN ATOPY . . . . . . 7

4.5 INFLAMMATORY BOWEL DISEASE . . . . . 8

4.6 IRRITABLE BOWEL SYNDROME . . . . . . 9

4.7 MIGRAINE . . . . . . . . . 10

4.8 RHEUMATOID ARTHRITIS . . . . . . . 11

5 CONCLUSIONS . . . . . . . . . 11

6 APPENDIX I (search strategy) . . . . . . . 13

7 REFERENCES . . . . . . . . . 14

1. SUMMARY

Ø YNL have developed an ELISA to detect food specific IgG in the serum of individuals with suspected food sensitivity. They have good testimonial evidence that shows that the dietary modifications suggested by the ELISA results are very successful in providing symptomatic relief from a variety of chronic conditions.

Ø The scientific literature world-wide was reviewed to find evidence for and against the role of IgG in food sensitivity.

Ø The review revealed evidence to support the view that food specific IgG may indeed serve as a useful diagnostic marker for food sensitivity related to chronic disease. However its role in the pathogenesis of these disease conditions is less clear.

Ø The occurrence of raised levels of IgG in food sensitive individuals, and their decrease when the offending food is removed from the diet, provides strong circumstantial evidence for the involvement of IgG in food sensitivities. This view is further supported when the elimination of offending foods also results in symptomatic improvement.

Ø Well designed clinical trials will be necessary to provide more convincing evidence for the role of food specific IgG in chronic disease. YNL is currently undertaking such studies.

2. INTRODUCTION

Over the past 2 years YNL Ltd have been conducting tests to detect raised IgG antibodies for food sensitivities. The test is an enzyme linked immunoassay or ELISA method consisting of a panel of food antigens, the pattern of serum IgG reactivities against these antigens is used to identify an individual programme of dietary modifications. They have evidence that the dietary modifications suggested are successful in providing symptomatic relief from a wide range of chronic illnesses. The identification of food sensitivities via this method is much easier and far more convenient for both patient and clinician than challenge/elimination diets. Until recently, a medically extracted blood sample was required for testing, now only 50ml, taken by the patient, is needed for the same test. This is a much faster and less inconvenient method for all parties involved as the laboratory not only returns the results of the clinical test, but also individual dietary modifications for each patient.

The role of IgE in adverse reactions to food is much more clearly defined than non-IgE responses, so the associated diagnostic testing traditionally involves the detection of IgE antibodies by skin prick tests and food challenge/elimination diets, (Salkie 1994). The skin tests are not well correlated with food allergens and are only diagnostic of IgE-mediated responses. The challenge/elimination diets are time consuming and rely heavily on the patient for both motivation and compliance, (Miller 1998). The theory behind testing for elevated levels of food specific IgG in the diagnosis of food sensitivities comes from the evidence that reports raised IgG titres in the serum of atopic individuals. Early studies show that IgE is not always detected in the sera of individuals who give an inflammatory response after skin pricking tests, however in many of these sera, IgG is observed, (Parish 1970 and Berry 1977). Significantly elevated levels of IgG have also been observed in the serum of individuals with certain food sensitivities (Shiner et al 1975, Dannaeus et al 1977, Berrens et al 1981, Dannaeus & Inganas 1981, Daul et al 1987, Burks et al 1988, Lilja et al 1991, Host et al 1992 and Germano et al 1993).

Adverse reactions to food can cause a range of symptoms throughout the body, which are thought to be immunologically or non-immunologically mediated. The two immunologically related responses differ in that food allergy (IgE mediated) usually occurs within 1 hour of ingestion and results in a variety of symptoms involving the skin, gastrointestinal tract (GIT) and lungs. Food sensitivity (elevated food specific IgG levels often observed) involves a delayed reaction, usually occurring between 24 to 120 hours after eating and is more of a recurrent/ongoing response. The symptoms are more generalised and may include bloatedness, cramps, nausea, rashes, migraine and general malaise.

The GIT contains the largest surface area of mucosal lymphoid tissue of any organ in the body; therefore it is the obvious choice for major antigen sensing and antibody production. The food antigens are sampled from the contents of the GIT by immune mediators, which are capable of recognising most of the food antigens; thus an individual is routinely sensitised to many of the foods ingested. An immune reaction in the GIT will induce an inflammatory response, leading to increased GIT permeability and demonstration of the associated symptoms of heartburn, nausea and vomiting. The increased permeability of the GIT allows incompletely digested food to enter the bloodstream and is then treated as a pathogen to be recognised by circulating antibodies, leading to the symptoms of other organs mentioned. This continual stress will eventually cause the immune system to weaken, leaving the individual much more susceptible to illness.

Functional experiments have provided evidence of a pathogenic role for IgG as well as IgE in food sensitivities. IgE mediated histamine release is well documented, but other studies have shown that IgG may also be involved, (Hindocha & Wood 1985 and Beauvais et al 1990). A study looking at the passive transfer of milk sensitivity to non-sensitised guinea pig epithelium demonstrated an involvement of IgG and not IgE, (Baird et al 1987). One study has shown that IgG directed antibody dependent cell mediated cytotoxicity (mechanism where antibodies interact with cytotoxic cells) may be of pathogenic importance in certain diseases associated with adverse GIT symptoms in cow’s milk protein sensitive individuals. Sera from children with GIT symptoms as oppose to coeliacs patients was shown to efficiently mediate ADCC to cells coated with b-lactoglobulin. Deliberate depletion of IgG 1, 3 and 4 caused a marked decrease in ADCC mediating capacity. Thus IgG is of pathogenic importance in cow’s milk protein sensitive patients with GIT symptoms, (Saalman 1995).

As the theory behind testing is unclear and the reliability and validity of the test has not been fully evaluated, this methodology is still argued against in terms of diagnostic value. Therefore, it is the aim of this review to present evidence and key arguments in support of a role for IgG in food sensitivity.

3. THE CASE AGAINST IgG AND FOOD SENSITIVITY IN CHRONIC DISEASE

Many studies have reported food specific IgG in the serum of normal subjects, this review cites a few examples. Food specific IgG containing immune complexes were observed in adult and children non-atopics, (Haddad et al 1983, Paganelli et al 1983, and Lessof & Kemeny 1991). Food specific IgG has been observed in healthy subjects (Husby et al 1985 and Kruszewski et al 1994). It has been demonstrated by ELISA that the levels of food specific IgG in control subjects and food sensitive patients were not significantly different, (Portnoy et al 1988 and Burks et al 1989 and 1990). Specific IgG was significantly raised in shrimp sensitive individuals, but the IgG response was not significantly predictive of an adverse reaction to food challenge (Morgan et al 1990). It has been demonstrated that food specific IgG levels don’t seem to be predictive of certain diseases such as inflammatory bowel disease and eczema, (Zvetckenbaum 1988 and Sloper et al 1991).

4. THE CASE FOR IgG AND FOOD SENSITIVITY IN CHRONIC DISEASE

Although elevated levels of food specific IgG seems to be a good marker of food sensitivities, the exact role played by IgG remains unclear. There is however considerable evidence that argues in favour of the involvement of food specific IgG in individuals who suffer from adverse reactions to foods. This includes the demonstration of an independent behaviour of food specific IgG compared to IgE in food sensitive individuals and the observation of elevated levels of food specific IgG in various diseases. A search of the relevant literature associated with food sensitivity reveals evidence supporting a role for food specific IgG in the pathogenesis of various diseases and ailments. Probably the most common is a general sensitivity to cow’s milk producing various symptoms including those associated with the GIT, respiratory tract and the skin.

4.1 INDEPENDENT BEHAVIOUR OF FOOD SPECIFIC IgG

In many individuals who suffer from an immunologically related adverse reaction to food, the food specific IgG behaves independently of the IgE, suggesting that there is more than one immunopathogenic mechanism involved, (Brighton 1980).

In orally challenged food sensitive individuals two components of the complement pathway were utilised in the specific immune response, the IgE levels were unchanged from normal, suggesting IgG may have triggered complement leading to inflammation, and the adverse effects, (Trevino et al 1981). Sera from eczema patients contained high levels of milk specific IgG, A and E whereas cow’s milk allergy patients had high levels of IgE only, indicating two possible different pathogenic mechanisms, IgE mediated mast cell degranulation and the eczema skin lesions were probably the result of chronic antigen exposure, leading to immune complex deposition and local inflammatory response in the skin, (Firer et al 1982). In egg allergic individuals, elevated ovalbumin specific IgG showed no relationship with IgE and in some patients IgG was observed in the absence of IgE, (Nakagawa 1986). Individuals with late onset food allergies of the skin, respiratory tract and GIT mostly had elevated IgG compared with IgE and in some a food induced IgE response was absent altogether, (el Rafei et al 1989). In food allergic children, 77% had elevated IgG and only 37% had IgE, in non-allergic individuals there was no response. Elimination and re-introduction of offending food lead to remission and relapse of symptoms respectively, (Hoffman 1995).

These particular studies emphasise that elevated food specific IgE is not always involved in adverse reactions to food, as there is evidence of a high occurrence of elevated IgG in association with symptomology this suggests that there are at least two immunological mechanisms involved in the pathogenesis of food sensitivity.

4.2 COW’S MILK SENSITIVITY

An infant with anaemia and chronic bronchitis associated with cow’s milk showed elevated levels of cow’s milk specific IgG measured by ELISA. When milk was removed from the diet there was symptomatic improvement and a decrease in cow’s milk IgG was observed in the absence of IgE. The investigators hypothesised that the initial formula feeding sensitised the infant to cow’s milk protein, which caused a slight intestinal illness leading to increased gut permeability and when whole cow’s milk was introduced into the diet a marked immune response involving IgG occurred, (Cohen et al 1985). It has been demonstrated that anti-b-lactoglobulin IgG correlates well with delayed onset cow’s milk sensitivity and that antibodies against b-lactoglobulin may be useful in the diagnosis of cow’s milk protein sensitivity, (Fallstrom et al 1986 and Shakib et al 1986). Significantly higher levels of anti b-lactoglobulin IgG were observed in infants with persistent cow’s milk allergy, (Host et al 1992).

In children from atopic families, elevated levels of cow’s milk specific IgG was detected by enzyme immunoassay. The ingestion of milk caused significant increases in milk specific IgG in the patients with sensitivity to cow’s milk, (Hamburger et al 1987). In a later study an ELISA designed to detect cow’s milk protein specific IgG revealed the presence of milk specific IgG in the serum of cow’s milk protein sensitive children. The levels of IgG were significantly higher than those found in control individuals, which consisted of those with ‘toddler diarrhoea’, atopic individuals and normal healthy subjects. The ELISA was highly sensitive and specific for the diagnosis of cow’s milk protein sensitivity when differentiating between that and general infant diarrhoea, (Taylor et al 1988). When anti-b-lactoglobulin IgG levels were measured by an enzyme immunoassay, marked differences in IgG levels were apparent in cow’s milk protein sensitive individuals compared with healthy controls and those with GIT symptoms not associated with food sensitivity. The investigators stated that the enzyme immunoassay test could be used to confirm the diagnosis of cow’s milk protein sensitivity, (Iacona et al 1995). Patients with gastroesophageal reflux (GER) plus cow’s milk sensitivity were significantly positive for anti-b-lactoglobulin IgG compared with those with GER only, suggesting that tests that detect elevated anti-b-lactoglobulin IgG are specific and sensitive methods for the diagnosis of GER with cow’s milk sensitivity, (Cavataio et al 1996).

It has been shown that preferential recognition of some epitopes of an antigen can be observed for IgG in children with cow’s milk sensitivity. Specific anti-b-lactoglobulin IgG specificity to native and pepsin digested b-lactoglobulin was measured by ELISA. In cow’s milk sensitive individuals there was significant binding to the native compared with the digested b-lactoglobulin, in the controls there was no difference in binding (weak). The binding of IgG to native b-lactoglobulin was significantly higher in the sensitives compared with controls and levels of b-lactoglobulin specific IgG declined with elimination of milk from the diet, this was not the case for the healthy controls where the low-level IgG was independent of milk consumption. The direct relationship between levels of anti-b-lactoglobulin IgG and the success of elimination of milk demonstrated that milk specific IgG is a useful indicator of food sensitivities, which may be used in dietary modifications, (Duchateau et al 1998).