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Food reactivity testing: the leukocyte activation test.

Introduction

The world has advanced vastly in technology, but also in increasing prevalence of chronic illnesses.

For thousands of generations, we ate food shortly after it was harvested and when it was in season. Meat was occasionally consumed and much of it was caught in the wild. Fish was fresh, never frozen and shipped. All food was organic: there was no other choice. Then, starting right after World War II, our diet changed dramatically, especially in industrialized countries and in urban areas. What we eat now, as compared with the diet of even two or three generations ago and back to the beginning of human history, is vastly different.

Each person in America eats approximately 1 ton of food per year, including 220 pounds of protein. Add to this the chemical additives such as artificial food colorings, flavorings, preservatives, and sweeteners both in foods and liquids we consume. In this mixture of foods we eat are new strains of wheat, rice, soy, and corn; in the United States, we eat more GM crops than the rest of the world combined. Our vegetables and fruits contain residues of insecticides, pesticides, and fungicides. The cattle, hogs, chickens, and turkey in concentrated animal feeding operations (CAFOs) are fed and injected with antibiotics and hormones. CAFOs use ractopamine to increase the meat content in cattle and pork: it is a IS-agonist drug that is known to augment protein synthesis and is banned in 160 countries, including China, the European Union, Taiwan, and Russia. Our dairy products contain recombinant bovine growth hormone (rBGH), which is given to cows to increase their milk production; it is banned in the European Union, Canada, and other countries. We use plasticizers such as bisphenol A (BPA) in food and beverage containers that leach out and get into our bodies. Tally up with all this the medications that we take, the antibiotics, antacids, proton pump inhibitors, histamine 2 blockers, and other drugs, many of which are available over the counter--many of these are found in the water supply of most cities. The majority of Americans include processed food in their diet. Flow we cook has also changed: our ancestors did not have microwave ovens nor coated pots and pans. (1-3)

All of the above and more have contributed significantly to a dramatic increase in many chronic diseases, such as obesity, gastrointestinal disorders, cancer, stroke, and cardiovascular diseases, with inflammation as a predominant central cause. Part of this inflammation is due to the massive amounts of food and liquids along with their chemicals that our gastrointestinal tract is exposed to, which can bring on an immune reaction.

Our Defense Mechanism

Our defense mechanism against this relentless and incessant bombardment of xenobiotics is our immune system. It is divided into two parts: our innate immune system and our adaptive immune system, also known as the antibody mediated (specific) immune system. One main difference between the two is that the cells of the innate system recognize and respond to pathogens, whereas the adaptive immune system confers long-lasting protective immunity. The innate immune system is our first line of defense against invading organisms while the adaptive immune system acts as a second line of defense and affords protection against re-exposure to the same pathogen.

The innate immune system remains unchanged from birth and consists of neutrophils, dendritic cells, macrophages, natural killer cells, complement and various other neutralizing proteins, and physical epithelial barriers like the skin. It is our "firewall," is the first respondent, and is non-specific. The major functions include activation of inflammation, activation of NK cells, removal of antigen-antibody complexes, and complement activation, with its pathogen opsonization and membrane attack complex functions, among others.

The innate immune system responds to infection or irritation with inflammation via chemical factors released by injured cells. These include histamine, bradykinin, leukotrienes, and prostaglandins, and produce vasodilation of the blood vessels in the direct vicinity, as well as the attraction of neutrophils, which make up 60% to 75% of white blood cells in the circulation. These neutrophils migrate through the blood vessels, passing through interstitial tissue to the site of injury or infection via chemotaxis mediated by interleukin-8 (IL-8), C5a, fMLP, and leukotriene B4. The bone marrow of a healthy adult produces approximately 100 billion neutrophils daily, and 10 times that amount during an acute inflammatory reaction. Neutrophils phagocytize the offending substance and release factors that summon other leukocytes and lymphocytes. Cytokines produced by the innate immune system mediate the inflammatory response via TNF, IL-1, and others. The results of inflammation are well known classical signs: redness due to locally increased blood circulation; increased local temperature or internally a fever; swelling of the affected tissues; increased production of mucus; pain; and dysfunction of the affected tissues or organ. (4)

With all the above, we can readily see how a person may undergo inflammation as a result of intolerance or sensitivity to foods or other substances with the subsequent activation of the innate immune system followed by neutrophil reactions.

The adaptive immune system develops later on and consists primarily of lymphocytes and their products, including antibodies and cytokines. It adapts as new substances are encountered and has memory for antigens it has come across before. The adaptive immune system is a specific response, induced by an antigen that targets that specific antigen. It has memory, and provides long-lasting protection, as when a person recovers from measles and is now protected against measles for their lifetime. There are two main responses, the antibody responses and the cell-mediated immune response that are carried out by B cell lymphocytes and T cell lymphocytes. In the first, B cells are activated to produce antibodies, also known as immunoglobulins, and bind to the foreign antigen inactivating it or rendering it more accessible to phagocytes. Various cytokines and chemokines mediate this process, where there is collaboration between antigen presenting cells and CD4 T lymphocytes and B-lymphocytes.

Classical allergies are part of the adaptive immune system, are an IgE antibody hypersensitivity reaction, and include atopic dermatitis, asthma, hay fever, food allergies, and anaphylaxis. Common symptoms are itchy rash, runny nose, and wheezing. These occur quickly and very shortly after exposure. However, food intolerance and sensitivities are not part of classical allergies.

Testing for Food Reactivity

The challenge is to find the right way to test for food reactivity. Hippocrates is quoted as saying: "Let food be thy medicine and medicine be thy food." Maimonides, the 13th-century physician and scholar, is believed to have said, "Anything that can be treated by diet should be treated by diet." Each person is unique, and their immune system is unique; therefore diets should be personalized.

In searching to elucidate which food or foods could be causing an adverse reaction or intolerance in a patient, the gold standard still remains the double-blind, placebo-controlled oral challenge test, with each challenge of food separated by 3 days. This method is cumbersome, impractical for clinical practice, and would take months if not years to test all the foods that we eat today. Furthermore, this would be a very costly undertaking. However, there is another method that correlates very well with oral challenges and is cost efficient and convenient.

The Leukocyte Activation Test

The leukocyte activation test, known as the ALCAT (antigen leukocyte cellular antibody test), is a laboratory method to identify immune reactions by leukocytes, mainly neutrophils, to food and other substances. Leukocytes are stimulated by foods, chemicals, herbs, food additives, common medications, molds, and others. These reactions are mediated by the innate immune system rather than by the adaptive immune system, therefore the testing is done on live leukocytes rather than on serum. This is a functional response test, rather than an antibody test, and therefore is not subject to cross-reactivity with other substances, nor is it affected by molecular mimicry, both of which yield false-positive results. An important notable factor of the ALCAT is that it uses organic food processed in house rather than purchasing reagents from a supplier. This assures purity of the food, as well as not having pesticides or other chemical contaminants, which would perhaps give false-positive results. The ALCAT measures changes in cell size and volume after incubation with foods or other substances, including the swelling of the cell, the decrease in cell numbers with degranulation of neutrophils, and the respiratory burst, releasing activated NADPH oxidase, generating superoxide anion and hydrogen peroxide, which then give rise to reactive oxygen species. These free radicals can damage tissues and induce apoptosis in other immune cells, leading to inflammation and disease processes. These changes to neutrophils and a histogram of the reaction, with the cell size on the x-axis and the number of cells on the y-axis, are shown in the 2 figures above (p. 89).

Analysis of blood instead of serum offers a significant advantage in that it contains not only all the cellular elements, but also the immune system elements. There is always some mediator release in a reaction to a food or other substances, so if a leukocyte begins to swell or progresses to a respiratory burst of reactive oxygen species, which is a crucial reaction to degrade internalized particles, these morphological changes can be accurately measured by the ALCAT. These measurements are of the immune reaction to a specific food or substance by live leukocytes and denote what that patient is reacting to. It's worth noting that the resulting symptoms from the reaction may not occur quickly, as this test is does not measure allergic reactions. Rather, the symptoms may be delayed by a few hours to a few days, and tend to be vague, such as fatigue, bloating, muscle and joint aches and pains, and abdominal discomfort. The sustained activation of leukocytes by substances leads to chronic inflammation, giving rise to common problems such as: gastrointestinal complaints, skin diseases, metabolic disorders, obesity, neurological disorders, and musculoskeletal disorders. The ALCAT is therefore a valuable tool for practitioners for identifying dietary and environmental triggers of inflammation. A review paper by Pietschmann showed how the ALCAT is a useful clinical screening tool to identify substances at the root of inflammatory disorders and how the diet provided by the results can restore immune homeostasis. (5)

A recent study by researchers at Harvard University, including Dr. Alessio Fasano, and the National Institutes of Health, reported real-time microscopic observations of gluten-induced neutrophil activation in the duodenal tissues of laboratory animals. (6) Other research has yielded important facts regarding the ALCAT. Researchers at Yale School of Medicine have discovered immunological specific markers associated with food intolerance using the ALCAT method. They found that severe intolerance on the ALCAT was linked with an upregulation of the CDllb on CD4+ and CD8+ T cells, a known inflammatory marker. (7)

In a controlled study, carried out at Baylor Medical College, analyzing 100 overweight patients, an 80% decrease in body fat was observed in the group following a diet based on ALCAT results when compared with the control group. Furthermore, there was a significant improvement reported by the ALCAT group on a 20-item Disease Symptom Inventory Self-Report. (8)

There have been a number of studies showing improvement in gastrointestinal diseases such as IBS, as well as arthritis, skin problems, and others. Double-blind studies have shown the clinical usefulness of the ALCAT in identifying food additives and food sensitivities in patients. (9-15)

IgG Antibodies to Food

With IgG food testing, there can be a lack of correlation between results and actual symptoms. This increases the risks of unnecessary food avoidance and thereby developing a lack or deficiencies of certain nutrients, escalating the potential harm from the results of this test. In addition, there is no published clinical evidence to support the use of IgG tests to determine the need for vitamins or supplements. IgG antibodies indicate exposure to foods, not allergy, and may be markers of food tolerance rather than intolerance or adverse reactivity. IgG is a "memory" antibody; it is normal for the adaptive immune system to make IgG antibodies to foreign proteins, and IgG antibodies to a food is a sign of a normal adaptive immune system. IgG antibodies to food is a test that relies on only proteins; antibodies cannot be made against any other substance. Due to molecular mimicry, there can be high antibody levels to foods that do not provoke any clinical symptoms. (16) For example, a patient's diet might be strictly kosher, but may react to pork and other nonkosher food due to cross-reactivity.

Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder with prevalence rates in the US of 10% to 15%, with annual physician visits between 2.4 and 3.5 million. Two-thirds of subjects with IBS relate their symptoms to the foods in their diet. Many of these patients modify their diet after getting their IgG test for foods, and, as a result, some of them have an inadequate diet. (17) However, IgG antibodies to food antigens may be detected in the serum of normal healthy individuals as well as patients with IBS. In a case-controlled study in the general population with abdominal complaints and their intake of common food items, IgG and IgG4 antibodies were measured. There were 269 subjects and 277 controls. The study concluded that there was no evidence that the use of IgG or IgG4 antibody to food testing is a method to diagnose food hypersensitivity. (18)

In another example, 42 bakers and 20 controls were measured for IgG antibodies to wheat flour. IgG antibodies were significantly higher in the bakers than in the unexposed group, but none had symptoms. The conclusion of the study was that IgG antibodies reflect exposure, but are not related to any specific clinical situation. (19)

A study conducted in China on 5394 participants and published in 2013 looked at IgG antibodies to 14 foods and the symptoms associated with these positive antibodies. The authors concluded: "Although testing for the presence of food-specific IgGs has been regarded as a potential tool of the diagnosis of food allergy/ intolerance, it's the accuracy and clinical utility of such testing [that] remain unclear." Also: "Chronic symptoms were negatively associated with the concentrations of a few food-specific IgGs, and were positively associated with the concentrations of other food-specific IgGs." This large study indicates that IgG testing for foods is not clinically relevant in regard to symptoms, and that the clinical utility of this type of testing is uncertain. (20) In a study titled "Blood Testing for Sensitivity, Allergy or Intolerance to Food," the author concluded: "Immunoglobulin G antibodies directed at specific foods can be found in healthy children as well as adults." (21) In a randomized controlled trial of food elimination diet based on IgG antibodies to see if this would reduce migraine headaches, the authors concluded: "Use of ELISA test with subsequent diet elimination advice did not reduce the disability or impact on daily life of migraine like headaches or the number of migraine like headaches at 12 weeks." (22)

In the Diabetes Autoimmunity Study in the Young (DAISY), 260 participants were tested for IgG4 antibodies to dietary foods. The conclusion of the study showed: "Our examination of the individual dietary IgG4 antibody concentrations, as well as our composite measure of [beta]-lactoglobulin, gluten, and ovalbumin IgG4 antibodies in childhood, provided no evidence of a greater generalized immune response in children developing IA (Islet Autoimmunity) or progressing to T1D." (23)

Conclusion

The clinician looking for answers to treat his patient's complaints such as fatigue, aches and pains, gastrointestinal issues, migraine and other neurological complaints, short-term memory loss, malaise, tremors, sleep disturbance, skin rashes, and others should consider if foods might be the causal factor. The ALCAT can determine this in a reproducible and accurate manner, and has done so for the last 29 years, and in over 1 million patients in the last 10 years alone, throughout the world.

Notes

(1.) Campbell AW. Pesticides: our children in jeopardy. Alt Ther Health Med. 2013;(19):1.

(2.) Campbell AW. Autoimmunity and the gut. Autoimmune Dis. 2014:152428. Epub 2014 May 13. Review.

(3.) Campbell AW. Neurotoxicity: better living through chemistry. Adv Mind Body Med. 2012 Fall;26(2):6--7.

(4.) Abbas A, Lichtman A, Pillai S. Cellular and Molecular Immunology. 8th ed. Philadelphia: Elsevier; 2015.

(5.) Pietschmann N. Food intolerance: immune activation through diet-associated stimuli in chronic disease. Alt Ther Health Med. 2015;21;42-52.

(6.) Lammers KM, Chieppa M, Liu L, et al. Gliadin induces neutrophil migration via engagement of the formyl peptide receptor, FPR1. PLoSONE. 2015;10(9):e0138338.

(7.) Ayaz G, Wajahat M, Ather A. Food reactivity on the ALCAT leukocyte activation test is associated with upregulation of CDllb on T cells. J Altern Complement Med. 2014;20(5):A35A36.

(8.) Kaats GR, Pullin D, Parker LK. The short-term efficacy of the ALCAT test of food sensitivities to facilitate changes in body composition and self-reported disease symptoms: a randomized controlled study. Bariatrician. Spring 1996:18-23.

(9.) Fell PJ, Soulsby S, Brostoff J. Cellular responses to food in irritable bowel syndrome--an investigation of the ALCAT test. J Nutr Med. 1991;2:143-149.

(10.) Mylek D. ALCAT test results in the treatment of respiratory and gastrointestinal symptoms, arthritis, skin and central nervous system. Rocz Akad Med Bialymst. 1995;40(3):625-629.

(11.) Brostoff J, Fell PJ, Pasula M. High correlation of the ALCAT test results with double blind challenge (DBC) in food sensitivity. Paper presented at: 45th Annual Meeting of the American College of Allergy and Immunology; November 12-16, 1988; Los Angeles, CA.

(12.) Hoj L. Diagnostic value of ALCAT test in intolerance to food additives compared with double-blind placebo-controlled (DBPC) oral challenges. J Allergy Clin Immunol. 1996;97(1, pt 3):336.

(13.) Berardi L, De Amici M, Castello M, et al. ALCAT test results in the treatment of gastrointestinal symptoms. Paper presented at: 30th Congress of the European Academy of Allergy and Clinical Immunology; June 11-15, 2011; Istanbul, Turkey.

(14.) Berardi L, De Amici M, Vignini A, Torre C, Mosca M. Food intolerance in patients with cutaneous diseases: diagnostic value of the ALCAT test. Allergy. 2009;64(suppl 90):490.

(15.) De Amici M, Berardi L, Castello M, et al. Evaluation of ALCAT test results in the non IgE-mediated pathology of the skin. Paper presented at: 30th Congress of the European Academy of Allergy and Clinical Immunology; June 11-15, 2011; Istanbul, Turkey.

(16.) Mullen G, Swift K, Lipski L, et al. Testing for food reactions: the good, the bad, and the ugly. Nutr Clin Proc. 2010;25(2):192-198.

(17.) Monsbakken KW, Vandvik PO, Farup PG. Perceived food intolerance in subjects with irritable bowel syndrome etiology, prevalence and consequences. Eur J Clin Nutr. 2006;60:667-672.

(18.) Ligaarden S, Lydersen S, Farup P. IgG and IgG4 antibodies in subjects with irritable bowel syndrome: a case control study in the general population. BMC Gastroenterology. 2012;12:166.

(19.) Tiikkainen U, Klockars M. Clinical significance of IgG subclass antibodies to wheat flour antigens in bakers. Allergy. 1990 Oct;45(7):497-504.

(20.) Zeng Q, Dong S-Y, Wu L-X, et al. Variable Food-Specific IgG Antibody Levels in Healthy and Symptomatic Chinese Adults. Krauss-Etschmann S, ed. PLoS ONE. 2013;8(1):e53612.

(21.) Lavine E. Blood testing for sensitivity, allergy or intolerance to food. CMAJ. 2012;184(6):666-668.

(22.) Mitchell N, Hewitt CE, Jayakody S, et al. Randomised controlled trial of food elimination diet based on IgG antibodies for the prevention of migraine like headaches. Nutr J. 2011;10:85.

(23.) Lamb MM, Simpson MD, Seifert J, Scott FW, Rewers M, Norris JM. The association between IgG4 antibodies to dietary factors, islet autoimmunity and type 1 diabetes: the Diabetes Autoimmunity Study in the Young. PLoS ONE. 2013;8(2):e57936.

by Andrew W. Campbell, MD

Dr. Campbell was born of an American father and a Swiss mother in Beirut, Lebanon. He graduated from a Swiss preparatory school at age 14, first in his class. He completed college in 3 years and then graduated from medical school. Dr. Campbell trained at the Orlando Regional Medical Center in Florida and at the Medical College of Georgia before moving to Houston, Texas, where he was the medical director of the Medical Center for Immune and Toxic Disorders for over 20 years. He has held various leadership positions in hospitals in Houston. Dr. Campbell served on the admissions committee for the University of Texas Medical School and as a faculty member. He founded the St. John Vianney Clinic for the indigent 27 years ago. He has served as president or vice president of a number of medical organizations, both national and international. He has also been editor-in-chief, coeditor, associate editor, and on the editorial board of several medical journals. He is currently the editor-in-chief of two peer-reviewed and indexed medical journals. Dr. Campbell has received awards from many organizations, both medical and consumer, national and international. He is fluent in French, Spanish, Arabic, Hungarian, and English. He has been on several television shows, including 20/20, the Montel Williams Show, 24 Hour Investigative News and has been interviewed by NBC, ABC, and CBS affiliates throughout the United States as well as television programs in Canada and Mexico. Dr. Campbell has published over 70 peer-reviewed journal articles and medical textbook chapters.

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Date:May 1, 2016
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