Autism/IgG4 levels, Food allergies, Mucus membrane/IgA, IgG reactions, IgA reactions,Depression, Ankylosing spondylitis, Migraine, Arthritis, Sleep, Irritable bowel syndrome

Testing for IgG, IgG4, and IgA-Mediated Reactions: Beneficial Implications for GI Health, Mood Disorders, Respiratory Health, and More

By Chris D. Meletis, ND

Exposure to food antigens can result in the production of different classes of antibodies, including immunoglobulin G (IgG), IgA, and IgE. IgE-mediated reactions are true allergies that can lead to hives and anaphylactic type reactions. These IgE-mediated reactions are obvious and occur soon after eating a particular food. In contrast, IgG reactions are delayed-type hypersensitivity reactions. The symptoms can occur hours or even days after consuming the problematic food and therefore can masquerade behind other apparent causes. IgE has a half-life of only two to three days, whereas IgG has a much longer half-life of 23 days.¹ Typically, these types of IgG reactions have been associated with gastrointestinal symptoms such as diarrhea, constipation, and abdominal bloating. However, newer research shows that IgG-mediated hypersensitivity reactions may be to blame for a more expansive number of health concerns, including nasal congestion, chronic sinus infections, joint pain, and headaches.²

IgG testing has long been used to pinpoint these delayed hypersensitivity reactions. However, there is a relative newcomer in the testing arena that can paint a more detailed picture of a patient’s health: IgA testing. This article will address the newest research on IgG testing, explain the benefits of testing specifically for IgG4, and discuss the importance of IgA testing and which groups of patients can benefit the most from it. These testing options can be used together to yield clinically meaningful results.

New Research on IgG Testing’s Role in Health

One of the most abundant proteins in circulation, IgG comprises approximately 10% to 20% of the plasma protein.³ IgG testing is an important means of identifying delayed hypersensitivity reactions to food and other environmental irritants. IgG1-IgG3 trigger complement, leading to an inflammatory response associated with a number of health concerns. For example, IgG-mediated reactions are associated with the following:

Depression. In 184 adolescent patients with depressive disorder, markedly higher serum food antigen-specific IgG positive rates were detected compared to healthy controls.⁴ Food antigens can enter the systemic circulation and create an immune complex with food antigen-specific IgG. Macrophages can remove the larger complexes, but the smaller ones can escape into the central nervous system (CNS), leading to neuroinflammation, or are deposited in blood vessels, joints, glomeruli, and other tissues, resulting in tissue damage, inflammation, and metabolic problems.⁴ In the study of adolescents, the depressive disorder patients also had higher levels of histamine. A higher level of histamine indicates hypersensitivity mediated by food antigen-specific IgG, which suggests that the resulting blood brain barrier leakage may play a potential role in the pathogenesis of adolescent depression.⁴

Ankylosing spondylitis (AS). AS is a chronic autoimmune disease characterized by arthritis and inflammation at the sites where tendons and ligaments connect with the bone. Compared to healthy controls, people with AS have markedly higher serum concentrations of beef-, crab-, and pork-specific IgG.⁵ In one study, serum concentrations of pork-specific IgG were significantly and positively associated with the inflammatory marker C-reactive protein (CRP).⁵ This suggests that food intolerances induce inflammation, and this inflammation can in turn disrupt the gut microbiome.⁵ According to the researchers, “These results suggest that α-Gal, the predominant natural antigen in mammalian red meat, might play a potential role in the pathogenesis of AS, and therefore, AS patients should exclude such allergenic foods, including beef, crab and pork, from their daily diet.”

Migraines. In 30 patients with migraines, IgG antibodies against 266 food antigens were measured by ELISA.⁶ The patients were randomized to a group participating in a six-week diet that either excluded or included specific foods that were shown to raise IgG antibodies. After the first diet period, the patients underwent two weeks of no dieting and then were put on the opposite diet for six weeks. When the participants were consuming an elimination diet (excluding foods to which they tested IgG positive), they experienced significantly reduced number of headache days and number of migraine attacks.

Asthma. In a case report of two patients, a diet that eliminated foods that demonstrated reactivity to IgG in serum testing such as wheat, dairy, and eggs led to less asthma symptoms, decreased dependence on medications, and improved quality of life.⁷

Sleep. In a randomized controlled trial of overweight and obese adults, participants were randomly divided to either a group eating an elimination diet based on IgG test results for three months or a waitlist group.⁸ The people eating the elimination diet were told to eliminate up to 10 foods for which they had high IgG levels. Health coaches also provided nutritional counseling to this group. The waitlist group were not informed of their IgG test results and did not receive health coaching. The group eating the elimination diet experienced an improvement in sleep during the study.

Irritable bowel syndrome (IBS). A number of studies have shown that IgG is associated with ulcerative colitis and Crohn’s disease.⁹ In a double-blind, randomized, controlled parallel study, patients with IBS had a significant decline in severity of symptoms and improved quality of life after they were put on an IgG-testing-based elimination diet compared to a sham diet. In an open label pilot study, IBS patients who had failed standard medical treatments demonstrated improvement in pain, stool frequency, and quality of life after they began eating a food elimination and rotation diet based on the results of IgG testing.¹⁰

Effectiveness of IgG Testing

Research indicates that when measuring IgG levels, ELISA testing is a highly effective means.² Hodsdon and Zwickey sent blood samples to U.S. BioTek lab to measure IgG concentrations to various foods.² The researchers then determined results according to test repeatability on a split sample and test variability during a week. In the samples undergoing U.S. BioTek ELISA IgG testing, of 96 foods tested, 91 foods (95%) were identical between split samples. The reported results were consistent on both a split sample over one day and during a week. The researchers found that ELISA IgG testing is a reliable and reproducible way to detect delayed hypersensitivity reactions. The study authors stated, “While the sample size was small, these tests are completed for individual patients in a clinical setting and thus, variability must be minimal for the test to be clinically valid.”

Table 1: Reliability and Reproducibility of U.S. BioTek ELISA IgG Testing.²

The Clinical Usefulness of Testing for IgG4

In addition to IgG testing, patients can be tested specifically for IgG4. This IgG subclass does not bind to complement and therefore does not trigger inflammation.¹¹ IgG4 blocks more serious IgE-mediated allergic reactions through competing with IgE for the binding of an allergen to the same epitopes.^11,12 Thus, it can suppress the activation of mast cells and basophils.¹² It also blocks IgE-mediated antigen presentation to T cells.¹¹ IgG4 antibodies are produced after long-term exposure to an antigen. Consequently, IgG4 serves as an indicator of the extent of allergen exposure.¹² Furthermore, IgG4 antibodies are able to influence the immune response to an allergen.^11,12

IgG4 testing is useful in a number of applications. For example, it can be used to monitor the effectiveness of Allergen Specific Immunotherapy. As immunotherapy progresses, the IgG4/IgE ratio increases.¹² Immunotherapy regulates IgG4’s blocking ability of IgE-mediated allergic responses.¹² Additionally, there is a relationship between increased IgG4 blocking activity and successful immunotherapy.¹²

IgG4 and Autism

Autism spectrum disorders (ASD) are associated with higher IgG4 levels, probably on account of the altered immune response that occurs in this disorder.¹³ Researchers determined circulating plasma levels of IgG1, IgG3, and IgG4 in 241 children participating in the Childhood Autism Risks from Genetics and the Environment (CHARGE) trial.¹³ The study included 114 children with ASD, 31 children with developmental delays, and 96 normally developing controls. Compared with developmental delay children and with healthy controls, significantly higher concentrations of IgG4 were detected in children with ASD. The study authors concluded, “These results may suggest an underlying immunological abnormality in AU [autism disorder] subjects resulting in elevated IgG4 production.” Some studies have also indicated there is a relationship between high IgG4 levels in children with autism and behavioral symptoms.¹⁴

IgG4 and Irritable Bowel Syndrome

IBS patients have high IgG4 reactivity to certain foods. Compared to 43 controls, in 108 IBS patients, IgG4 antibodies to wheat, beef, pork, and lamb were higher.¹⁵ Another study showed that IgG4 antibodies to milk, eggs, wheat, beef, pork, and lamb were often higher in 25 people with IBS.¹⁶ After an elimination diet, pronounced improvement was noted at three months in pain severity, pain frequency, bloating severity, satisfaction with bowel habits, and effect of IBS on quality of life. The improvements continued at six months. Furthermore, other researchers have found that compared to controls, IgG4 antibodies to wheat, leek, and taro were significantly higher in patients with IBS.¹⁷ Serum IgG4 antibodies to ginger, cocoa, walnut, white radish, onion, and lettuce tended to be higher in IBS patients than controls.¹⁷ In a subgroup of IBS patients with diarrhea, IgG4 antibodies to wheat, gluten and gliadin tended to be higher compared with controls.¹⁷

IgG4 and Allergic Rhinitis

In 46 children with allergic rhinitis, IgG4 testing revealed 89.1% of participants had a strong reaction to egg white IgG4.¹⁸ More than half the patients were significantly reactive to egg yolk, milk, peanuts, almonds, wheat, and soybeans. In examining the association between specific IgE and specific IgG4, the study authors found that egg whites, milk, peanuts, and almonds had significant correlations. Cod, shrimp, and crab yielded very significant correlations. The researchers concluded, “Food allergy generates highly concentrated IgG4 and may play a role in children with allergic rhinitis.”

The Significance of IgA Testing

IgA is the second most abundant primary immunoglobulin antibody in circulation after IgG.¹⁹ It is a seromucosa antibody and protects the mucous membranes such as the eyes, nose, throat, lungs, GI tract, and female urogenital tract from pathogens in the outside world. ¹⁹ It triggers an immune response to viruses and bacteria and other pathogens.^19,20

Unlike IgG1-3, IgA does not activate complement, which would trigger inflammation.²⁰ This prevents the mucous membranes from remaining in a constant inflammatory state due to daily exposure to foreign substances.²⁰ IgA reactions to foods may result from inflammatory damage to the intestinal mucous membranes and the resulting intestinal permeability (leaky gut). Stress, alcohol, a diet filled with sugar and processed food, or even certain medications such as non-steroidal anti-inflammatory drugs (NSAIDS), oral contraceptives, and proton pump inhibitors are all implicated in this damage.^21-26

Elevated IgA to specific foods indicates mucosal membrane damage. Measurement of this antibody is useful in patients with Chron’s disease, ulcerative colitis, or celiac disease as well as to verify the presence of leaky gut. In the presence of overt symptoms of mucous membrane impairment, measuring IgA-related responses is essential.

Conclusion

Testing for IgG, IgG4, and IgA antibodies against specific foods can be used effectively to develop a regimen for patients with gastrointestinal issues, mood disorders, allergic rhinitis, and asthma, among other conditions. IgA testing is especially meaningful in patients who have irritable bowel syndrome, celiac disease, or symptoms of leaky gut. U.S. BioTek is currently the only lab that offers all three tests.

References

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18. Liu PJ, et al. Specific Immunoglobulin G4 and Immunoglobulin E Titers to Common FoodAntigens in Sera of Children With Allergic Rhinitis. Altern Ther Health Med. 2018 Nov;24(6):38-45.

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