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ImuPro review: discussion with Dr Camille Lieners

ImuPro review: a discussion with Dr Camille Lieners

In this ImuPro review, Dr Lieners discusses the controversy around use of IgG tests, what the literature says and his own clinical experiences.

Camille F. J. Lieners PhD Luxembourg is director of and responsible for clinical laboratories; specialized in immunology, clinical chemistry, hormonology, microbiology and auto-immune diagnostics.; responsible for the development of food hypersensitivy tests and genetic polymorphism tests.

Undoubtedly food plays a major role in health and disease development in humans.

On one side it is essential for a normal development of the organism, on the other side it can alter normal functions, cause chronic diseases (best known is coeliac disease) and even lead to anaphylactic shock. This is an abnormal reaction of the immune system against a harmless protein. Generally this type of acute allergy is believed to be caused by IgE reactions.

However, little is known about the chronic inflammation induced by food. Determination of specific IgG to food seems to be the best marker to identify foods causing low grade chronic inflammation. Elimination diets based on IgG guided findings significantly ameliorate a range of chronic illnesses.

New evidence for the role of IgG mediated immune response

Jönnson et al. (1) showed and reproduced previous scientific findings (2, 3, 4, 5) that IgG can also be implicated in anaphylaxis. However, it appears that larger amounts of antigens and antibodies are required than in case of IgE. The assumption cited in all the past literature, which also is the basis of the arguments from immunologists, that IgG represents a “normal” reaction with no clinical impact must be rejected, even in type 1 allergy.

Calderon et al (6) showed that IgG and IgA isotypes were significantly detected, even in the absence of IgE, in the three allergic conditions. All allergic patients, including those showing only IgG and IgA antibodies, significantly ameliorated their symptoms. The levels of beef-specific antibodies were considerably reduced in response to a cow meat exclusion diet. Calderon further concluded that specific IgG and IgA antibodies coexist with IgE antibodies in sera from allergic patients and are significantly associated with the clinical course of allergic disorders, particularly with asthma.

It is likely that in humans IgG mediated reactions will predominantly cause milder reactions. Moreover, food is not injected, as in the model of Jönnsen, but resorbed from the gut mucosa. This will lead to a dilution of the antigen and the reaction will become dose dependent, a phenomenon observed in IgG positive food challenge.

ImuPro review: IgG vs IgG4

Mullin et al (7) describes the difference of food allergy mediated by IgE and delayed food allergy mediated by IgG. A major difference between several tests on the market is the type of IgG tested. IgG is divided in 4 subclasses, IgG1, IgG2, IgG3 and IgG4. IgG4 is related to a type 1 allergy and can be considered as the antidote of IgE. IgG4 does not opsonise the antigen and does not activate the complement (8), it is a scavenging antibody not inducing inflammation (9, 10).

IgG1, IgG2 and IgG3 have all opsonising properties and are able to activate the complement, necessary for an inflammatory response (8). IgG4 is not recommended for the detection of adverse food reactions, as also stated in the position paper of the EAACI (11). IgG4 is present in blood in much lower concentrations than the other subclasses. The sensitivity of ImuPro test towards IgG4 is adjusted in a way to only detect very high levels of IgG4, commonly reported as RAST class 6. This is important because lower values of IgG4 are irrelevant, but higher values of IgG4 could generate histamine, which could lead to pseudo-allergic symptoms in subjects with low DAO-activity (12). Therefore it is preferable to avoid these foods too.

Arguments brought forward by allergy societies

The statement and comments made in several publications (13, 14, 15, 16, 17,18,19, 20, 21) are misleading, as they all relate to type 1 allergy. Nobody in the field of IgG testing is referring to type 1 allergy; ImuPro is definitely not addressing allergy type 1 issues. The statements made are correct, in respect to type 1 allergy, but not to the delayed type 3 allergy.

Not all IgG positive food lead to specific symptoms

The main criticism brought forward in all papers denying the relevance of IgG is that not every positive IgG reaction leads to a symptom.

Therefore, these reactions are often qualified as « non-specific » or « false positive ». However, these allegations are also correct for the gold standard in type 1 allergy, IgE. Not every positive IgE is automatically related to a symptomatic allergic reaction. Provided the test system used has no technical reasons for such false positive results and that the presence of the detected IgG is real, this result should obtain the same attention than any food causing a specific symptom. We could observe that every IgG positive food was responsible for water retention, a sign of an inflammatory reaction.

Another point of criticism is that IgG guided elimination diets lead to the elimination of too many foods, which causes malnutrition.

In the ImuPro concept we have two important factors avoiding such malnutrition:

  1. Rotation diet: Each person should rotate the food on a 4 – 5 days basis, meaning only eating the same food every 5th day. So automatically he or she has to eat different foods every day, avoiding a monotonous diet and malnutrition. The average daily Western diet is by definition more monotonous than a rotation diet.
  2. Provocation test: After 5-8 weeks of elimination, when inflammation has decreased, we start the reintroduction of foods. One by one, we can then identify the food causing specific symptoms. This principle is also used in IgE mediated allergy and is the final proof for a clinically relevant allergy.

Once passed the gut barrier, the reaction between an antigen and an antibody (IgG) will lead to the formation of an immune complex which is destroyed by the immune cells. In most cases it will take place in circulation and will not provoke a specific symptom, other than water retention. Aljada et al (22) showed the pro-inflammatory effect of a mixed meal. In some individuals, it will lead to reduced insulin sensitivity, which on the long term could lead to insulin resistance and related weight problems. The impact of chronic low-grade inflammation on insulin resistance and obesity has been largely documented by Hotamisligil (23, 24, 25).

Interpretation of scientific literature

Papers brought forward by the Allergy Society to show the uselessness of IgG is strictly dealing with type 1 allergy. None of the papers cited (13, 14, 15, 16, 17, 18,19, 20, 21, 26) rely on scientific works of IgG mediated immune response. No published scientific papers are in support of the claims of allergy societies. All statements done are polemic and represent the personnel opinion of some individuals without support of scientific works. Old statements of certain medical societies are repeated which have been refuted in the past years and which are strictly related to type 1 allergy.

A scientifically conducted discussion must also consider all published papers in favour of IgG, which have become numerous in the past years. Increasing evidence for the role of IgG to food in IBS (27, 28, 29, 30, 31,44), inflammation and hypertension (32) migraine (33, 34, 35), respiratory diseases (36) Crohn’s disease (37), behaviour problems like schizophrenia (38, 39) and asthma (6, 36, 40, 45) is described.

Example of inappropriate interpretation

I would also like to comment on the paper of Pelsser (41) who concluded « that the prescription of diets on the basis of IgG blood tests should be discouraged ». Firstly this statement is inappropriate because Pelsser didn’t conduct an IgG based elimination diet – so how can she predict any possible outcome? You can only postulate the above statement when you compare an IgG based elimination diet to a control or other elimination diet. Neither has been performed. Pelsser justifies her statement with a non-significant challenge between IgG positive and IgG negative food. Both showed a high percentage of relapse of ADHD by 63%.

This result is not surprising if you know the way she performed the challenge that had strong technical mistakes. Instead of using single food items for the challenge, the children were allowed to choose from complex, processed food, like peanut butter, pizza, ketchup, and so on. The food was not selected and provided by the therapist, but could be bought in the supermarket. A challenge with these foods is inappropriate when you want to challenge IgG negative food, as you cannot rule out that these processed foods contain IgG positive food.

In practice, a significant improvement of ADHD in children and adults equally could be observed, by adjusting their diet according to IgG-findings.

Clinical observation

In practice, it could be observed that in weight problems, every positive food was relevant. When a specific symptom was concerned, in most cases only 1 or 2 foods were responsible for the symptom. It could also observed that a certain food, which was positive and did not cause symptoms at the time of testing, became relevant after some time, then causing a new symptom.

ImuPro review case report:

A middle-aged man was positive to milk, yeast and some other food including gluten. Milk and yeast were eventually linked to two individual symptoms, while gluten and the rest were responsible for water retention. After one year the man developed tendinitis after excessive workout, which would normally disappear after 1-2 weeks. However, in this case tendinitis sustained, even after anti-inflammatory treatment. Subsequently, it turned out that by avoiding gluten, his tendinitis disappeared. A challenge with gluten caused a relapse of the joint pain.

This case demonstrates that one needs a sensitized tissue that is coated with adhesion molecules to attract and fix circulating immune complexes, which are then destroyed locally. If the food is eaten regularly, the chronic inflammation will soon or later occur locally and lead to a specific symptom.

Not every food causes a specific symptom or the same symptom. Rather, it is strictly dependent of the individual predisposition. Food is not the primary cause but is the ongoing trigger for inflammation and related diseases in presence of an IgG response. Therefore the identification and avoidance of such a food is extremely important for a possible cure.

Why choose ImuPro and not any other test?

  • Processed in IVDR certified laboratories.
  • Used by doctors in more than 44 countries. To our knowledge it is the only test with an external quality and proficiency testing worldwide.
  • Certified antigen production by R-Biopharm AG, an ISO certified diagnostic provider, also providing antigens for FDA approved IgE tests.
  • All reagents have CE labelling and every individual food allergen is registered according to strict IVDR (In Vitro Diagnostic Regulations) in Europe.
  • ImuPro tests are performed with venous blood serum samples, the gold standard for quantitative measurements.
  • Quantifies the specific IgG, allowing a follow up of evolution of antibody concentrations.
  • Very high reproducibility, a criterion extremely important to me.

ImuPro review summary

To sum up, I believe the main reason for the present controversy is that the allergy societies confuse specific total IgG testing with IgG4 testing, considered as useless in allergic diseases. In most publications in allergy research IgG4 was used as marker. As described above, the main indications for total specific IgG testing are not classical allergic diseases, as treated by immunologists, but chronic pro-inflammatory diseases, where no guideline medical treatment is successful.

It is also critical to see that publications of allergy societies do not treat the topic scientifically by citing the pro and contra literature. Only the contra literature publications, which are most of the time not actually scientific papers. Another issue could be that in the past the reliability of available IgG tests offered was not sustainable.

However, since over ten years things have changed. The high consistency and the reproducibility of the ImuPro Complete test have made IgG testing reliable and a new powerful tool to fight chronic inflammatory diseases by an individualized elimination diet. Certainly more studies are needed for complete acceptance in the medical society.

ImuPro review references:

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(2) Basophils play a pivotal role in immunoglobulin-G-mediated but not immunoglob- ulin-E-mediated systemic anaphylaxis. Tsujimura Y, et al. Immunity. (2008);28(4):581–589

(3) Pathways of anaphylaxis in the mouse. Strait RT, Morris SC, Yang M, Qu XW, Finkelman FD. J Allergy Clin Immunol. (2002);109(4):658–668.

(4) IgG-mediated systemic anaphylaxis to protein antigen can be induced even under conditions of limited amounts of antibody and antigen. Ishikawa R, Tsujimura Y, Obata K, Kawano Y, Minegishi Y, Karasuyama H. Biochem Biophys Res Commun. (2010) Nov 26;402(4):742-6.

(5) Anaphylaxis: lessons from mouse models. Finkelman FD. Department of Medicine, Cincinnati Veterans Affairs Medical Center, Ohio, USA. J Allergy Clin Immunol. (2007) Sep; 120(3): 506-15

(6) Meat-specific IgG and IgA antibodies coexist with IgE antibodies in sera from allergic patients: clinical association and modulation by exclusion diet. Calderon TE, Ferrero M, Marino GM, Beltramo D, Rabinovich GA, Romero MD. J.Biol.Regul.Homeost.Agents (2010) Jul-Sept: 24 (3): 261-71

(7) Testing for Food Reactions : The Good, the Bad, and the Ugly Gerard E. Mullin, Kathie M. Swift, Liz Lipski, Laura K. Turnbull and S. Devi Rampertab. Nutr Clin Pract (2010) 25: 192

(8) Immunologie, textbook Charles Janeway, Paul Travers, Mark Walport, Mark Shlomchick, Spektrum akademischer Verlag 5th edidtion (2002) 388-389 ISBN 3-8274-1079-7

(9) Inhibition of complement activation by IgG4 antibodies. Van der Zee JS, van Swieten P, Aalberse RC. Clin. Exp. Immunol. (1986) May: 64 (2):415-22
(10) Immunoglobulin G4: an odd antibody. Aalberse RC, Stapel SO, Schuurman J, Rispens T. Clin Exp Allergy, (2009) 39 (4):469-77.

(11) Testing for IgG4 against foods is not recommended as a diagnostic tool: EAACI Task Force Report. Steven O. Stapel , R. Asero , B. K. Ballmer-Weber 3 , E. F. Knol , S. Strobel, S. Vieths , J. Kleine-Tebbe Allergy (2008) 63:793–796

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(13) Keine Empfehlung für IgG und IgG4-Bestimmungen gegen Nahrungsmittel. Leitlinie der Deutschen Gesellschaft für Allergologie und klinische Immunologie (DGAKI), des Ärzteverbandes Deutscher Allergologen (ÄDA), der Gesellschaft für Pädiatrische Allergologie und Umweltmedizin (GPA), der Österreichischen Gesellschaft für Allergologie und Immunologie (ÖGAI) und der Schweizerischen Gesellschaft für Allergologie und Immunologie (SGAI) nach Übernahme des Task Force Report der European Academy of llergology and Clinical Immunology (EAACI). Kleine-TebbeJ,ReeseI,Ballmer-WeberBKetal Allergo J (2009)18:267– 273

(14) Unproven diagnostic procedures in IgE-mediated allergic diseases. Niggemann B, Gruber C Allergy (2004) 59:806–808

(15) In-vitro Allergiediagnostik. Leitlinie der Deutschen Gesellschaft für Allergologie und Klinische Immunologie (DGAKI) unter Beteiligung des Ärzteverbandes Deutscher Allergologen (ÄDA), der Gesellschaft für Pädiatrische Allergologie und Umweltmedizin (GPA) und der Deutschen Dermatologische Gesellschaft (DDG). Renz H, Biedermann T, Bufe A et al Allergo J (2010)19:110–128

(16) Allergenfamilien und molekulare Diagnostik IgE-vermittelter Nahrungsmittelallergien: von der Theorie zur Praxis. Kleine-TebbeJ, MeißnerAM, JappeU, HeroldDA Allergo J (2010)19:251–263

(17) In-vitro-Diagnostik und molekulare Grundlagen von IgE-vermittelten Nahrungsmittelallergien. Leitlinie der Deutschen Gesellschaft für Allergie und Klinische Immunologie (DGAKI), des Ärzteverbandes Deutscher Allergologen (ÄDA) und der Gesellschaft für Pädiatrische Allergologie und Umweltmedizin (GPA), der Österreichischen Gesellschaft für Allergologie und Immunologie (ÖGAI) und der Schweizerischen Gesellschaft für Allergologie und Immunologie (SGAI). Kleine-TebbeJ, Ballmer WeberB,BeyerKetal Allergo J (2009)132–146

(18) Bioresonanz – diagnostischer und therapeutischer Unsinn. Stellungnahme der Fachkommisssion der Schweizerischen Gesellschaft für Allergologie und Immunologie (SGAI) zu den Bioresonanz- und Elektroakupunkturgeräten zur Diagnostik und Therapie von (vermeintlichen) Allergien. WüthrichB, FreiPC, BircherAJetal. Akt Dermatol (2006)32:73–77

(19) Sinnlose Allergietests. Eine Stellungnahme der Fachkommission der Schweizerischen Gesellschaft für Allergologie und Immunologie (SGAI) zur IgG/IgG4-Bestimmungen gegen Nahrungsmittel. WüthrichB,FreiPC,BircherAJetal Allergologie (2005) 465–468

(20) Sinnlose diagnostischeTestsund Therapieverfahren in der Allergologie – ein zunehmendes Problem. Wüthrich B Dermatology (2010) 16:103–118

(21) AllergenspezifischeT-Zell-Antwortbei Ekzemkrankheiten (Habilitationsschrift). Werfel T. (2000) Fortschritte der Allergologie und Immunologie. Dustri, Deisenhofen München

(22). Increase in intra- nuclear nuclear factor kappaB and decrease in inhibitor kappaB in mononuclear cells after a mixed meal: evidence for a proinflammatory effect. Aljada A, Mohanty P, Ghanim H, et al. Am J Clin Nutr (2004); 79:682–690.

(23) Increase adipose tissue expression of tumor necrosis factor-alpha in human obesity and insulin resistance. Hotamisligil GS, Arner P, Caro JF, Atkinson RL, Spiegelman BM.. J Clin Invest (1995); 95: 2409-2415.

(24) Adipose expression of tumor necrosis factor- direct role in obesity-linked insulin resistance. ) Hotamisligil GS, Shargill NS, Spiegelman BM. .Science (1993); 259: 87-91.

(25) Inflammation and metabolic disorders Hotamisligil GS,Nature, (2006), 444, 860-867 (26) Ungeeignete Testverfahren in der Allergologie J. Kleine-Tebbe. D. A. Herold Hautarzt (2010) 61: 961-966

(27) Food allergy in irritable bowel syndrome: new facts and old fallacies. Isolauri E, Rautava S, Kalliomaki M, (2004) Gut; 53 (10):1391-3

(28) Food elimination based on IgG antibodies in irritable bowel syndrome: a randomised controlled trial. Atkinson W, Sheldon TA, Shaath N and Whorwell PJ. (2004) Gut 53(10):1459-1464.

(29) R. Treating irritable bowel syndrome with a food elimination diet followed by food challenge and probiotics. Drisko J, Bischoff B, Hall M and McCullum (2006). J of the Am college of Nutrition. Vol25 (6) 514-522

(30) Alterations of food antigen-specific serum immunoglobulins G and E antibodies in patients with irritable bowel syndrome and functional dyspepsia X. L. Zuo, Y. Q. L, W. J. Li, Y. T. Guo, X. F. Lu, J. M. Li and P. V. Desmond Clinical and Experimental Allergy, (2007) 37, 823–830

(31) Dietary Treatment of the Irritable Bowel Syndrome Peter Whorwell, MBChB, MRCP and Richard Lea, BSc, MD, FRCP Current Treatment Options in Gastroenterology (2004), 7:307-316

(32) IgG antibodies against food antigens are correlated with inflammation and intima media thickness in obese juveniles. Wilders-Truschnig M, Mangge H, Lieners C, Gruber HJ, Mayer C and Marz W. (2007). Exp Clin Endocrinol Diabetes

(33) A prospective Audit of food intolerance among migraine patients in primary care clinical practice. Trevor Rees, David Watson, Susan Lipscombe, Helen Speight, Peter Cousins, Geoffrey Hardman, Andrew Dowson. (2005) Headache, Vol 2 No.1 11-14

(34) Food allergy mediated by IgG antibodies associated with migraine in adults. Arroyave Hernandez CM, Echevarria Pinto M, Hernandez Montiel HL. Rev Alerg Mex (2007); 54: 162–168

(35) Diet restriction in migraine, based on IgG against foods: a clinical double-blind, randomised, cross-over trial. Alpay K, Ertas M, Orhan EK, Ustay DK, Lieners C and Baykan B. (2010) Cephalgia 1-9.

(36) Treatment of delayed food allergy based on specific immunoglobulin G RAST testing. Dixon H. (2000). Otolaryngology- Head Neck Surgery Vol 123:48-54

(37) Clinical relevance of IgG antibodies against food antigen in Crohn’s Disease – A double blind cross over diet intervention study S. Bentz, M. Hausmann, S. Paul, W. Falk, F. Obermeier, J. Schölmerich, G. Rogler Digestion (2010);81:252–264

(38) Subunit and whole molecule specificity of the anti-bovine casein immune response in recent onset psychosis and schizophrenia. Severence EG, Dickerson FB, Halling M, Krivogorsky B, Haile L, Yang S, Stallings CR, Origini AE, Bossis I, Xiao J, Dupont D, Haasnoot W, Yolken RH. Schizophr.Res.(2010) May 118(1-3):240-7

(39) Association between bovine casein antibody and new onset schizophrenia among US military personnel. Niehbur DW, Li Y, Cowan DN, Weber NS, Fisher JA, Ford GM, Yolken R. (2011) Schizophr.Res. Mar2. (Epub ahead of print)

(40) 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. Vance, G.H.S., Thornton, C.A., Bryant, T.N., Warner, J.A. and Warner, J.O. Clinical and Experimental Allergy,(2004) 34, (10), 1542-1549.

(41) Effects of a restricted elimination diet on the behaviour of children with attention-deficit hyperactivity disorder (INCA study): a randomised controlled trial. Pelsser LM, Frankena K, Toorman J, et al. Lancet (2011); 377: 494- 503

(42) Lebensmittelunverträglichkeit, Allergie Typ 3 erkennen und richtig behandeln. Hans J. Schwyn, Camille Lieners AT-Verlag, (2009) ISBN-10: 3038004154

(43) L’Immuno-nutrition, se nourir selon son immunité Dominique Rueff Edition Xavier de Guibert (2007) ISBN 978-2-7554-0107-3

(44) Milk protein IgG and igA : the association with milk-induced gastrointestinal symptoms in adults. Anthoni S, Savilahti E, Rautelin H, Kolho KL World J. (2009) Gastroenterol. Oct 21 ; 15 (39) 4915-8

(45) The effect of exclusion of dietary egg and milk in the managment of asthmatic children : a pilot study. Yussof NA, Hampton SM, Dickerson JW, Morgan JB, (2004) J.R.Soc Health 124(2) 74-80

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