Studies

IMMUNOLOGY INFLAMMATION

1) Increase in intranuclear 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, Abdo T, Tripathy D, Chaudhuri A, Dandona P. Am J Clin Nutr. 2004 Apr;79(4):682-90.Learn More

2) Mouse and human neutrophils induce anaphylaxis. Jönsson F, Mancardi DA, Kita Y, Karasuyama H, Iannascoli B, Van Rooijen N, Shimizu T, Daeron M, Bruhns P. J Clin Invest. (2011) Apr 1;121(4):1484-96.Learn More

3) IgG subclasses and allotypes: from structure to effector functions. GesturVidarsson, Gillian Dekkers and Theo Rispens. Frontiers in Immunology October 2014 | Volume 5 | Article 520 | 1.Learn More

4) 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.Learn More

5) Immunoglobulin G4: an odd antibody. Aalberse RC, Stapel SO, Schuurman J, Rispens T. Clin Exp Allergy, (2009) 39 (4):469-77.Learn More

Despite its well-known association with IgE-mediated allergy, IgG4 antibodies still have several poorly understood characteristics. IgG4 is a very dynamic antibody: the antibody is involved in a continuous process of half-molecules (i.e. a heavy and attached light-chain) exchange. This process, also referred to as ‘Fab-arm exchange’, results usually in asymmetric antibodies with two different antigen- combining sites. While these antibodies are hetero- bivalent, they will behave as monovalent antibodies in most situations. Another aspect of IgG4, still poorly understood, is its tendency to mimic IgG rheumatoid factor (RF) activity by interacting with IgG on a solid support. In contrast to conventional RF, which binds via its variable domains, the activity of IgG4 is located in its constant domains. This is potentially a source of false positives in IgG4 antibody assay results. Because regulation of IgG4 production is dependent on help by T-helper type 2 (Th2) cells, the IgG4 response is largely restricted to non-microbial antigens. This Th2-dependency associates the IgG4 and IgE responses. Another typical feature in the immune regulation of IgG4 is its tendency to appear only after prolonged immunization. In the context of IgE-mediated allergy, the appearance of IgG4 antibodies is usually associated with a decrease in symptoms. This is likely to be due, at least in part, to an allergen-blocking effect at the mast cell level and/or at the level of the antigen-presenting cell (preventing IgE-facilitated activation of T cells). In addition, the favourable association reflects the enhanced production of IL-10 and other anti-inflammatory cytokines, which drive the production of IgG4. While in general, IgG4 is being associated with non- activating characteristics, in some situations IgG4 antibodies have an association with pathology. Two striking examples are pemphigoid diseases and sclerosing diseases such as autoimmune pancreatitis. The mechanistic basis for the association of IgG4 with these diseases is still enigmatic. However, the association with sclerosing diseases may reflect an excessive production of anti- inflammatory cytokines triggering an overwhelming expansion of IgG4-producing plasma cells. The bottom line for allergy diagnosis: IgG4 by itself is unlikely to be a cause of allergic symptoms. In general, the presence of allergen-specific IgG4 indicates that anti-inflammatory, tolerance-inducing mechanisms have been activated. The existence of the IgG4 subclass, its up-regulation by anti- inflammatory factors and its own anti-inflammatory characteristics may help the immune system to dampen inappropriate inflammatory reactions.

Article Link: https://www.ncbi.nlm.nih.gov/pubmed/19222496

6) Independent audit of IgG food intolerance tested patient survey. Sheldon TA. British Allergy Foundation, 2000.Learn More

7) Inflammation and metabolic disorders. Hotamisligil G. S. Nature, (2006), 444, 860-867.Learn More

8) Food Allergy: Adverse Reactions to Foods and Food Additives. 4th edition page18
Edited by Dean D. Metcalfe, Hugh A. Sampson, and Ronald A. Simon c 2008 Blackwell Publishing, ISBN: 978-1-405-15129-0.Learn More

9) Gliadin IgG antibodies and circulating immune complexes. Eisenmann A1, Murr C,
Fuchs D, Ledochowski M.Scand J Gastroenterol. 2009; 44(2):168-71.Learn More

IBS

11) Food elimination based on IgG antibodies in irritable bowel syndrome: a randomised controlled trial. Atkinson W, Sheldon TA, Shaath N, Whorwell PJ. Gut. 2004 Oct, 53(10):1459-64. Learn More

12) Food allergy in irritable bowel syndrome: The case of non-celiac wheat sensitivity. Mansueto P,D’Alcamo A, Seidita A1Carroccio AWorld J Gastroenterol. 2015 Jun 21;21(23):7089-109.Learn More

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

OBJECTIVE:
In Irritable Bowel Syndrome, the gut-associated immune system may be up- regulated resulting in immune complex production, low-grade inflammation, loss of Class I bacteria, and translocation of inflammatory mediators and macromolecules outside of the GI lumen. Since food intolerance may be one of the reasons for this upregulation, our goal was to investigate the role of food intolerance in IBS patients.

METHODS:
In this open label pilot study, we enrolled 20 patients with IBS by Rome II criteria (15 women, ages 24-81) who had failed standard medical therapies in a tertiary care GI clinic. Baseline serum IgE and IgG food and mold panels, and comprehensive stool analysis (CSA) were performed. Breath-hydrogen testing and IBS Quality-of-Life (QOL) questionnaires were obtained. Patients underwent food elimination diets based on the results of food and mold panels followed by controlled food challenge. Probiotics were also introduced. Repeat testing was performed at 6-months. We followed up with this cohort at 1 year after trial completion to assess the reported intervention and for placebo effect.

RESULTS:
Baseline abnormalities were identified on serum IgG food and mold panels in 100% of the study subjects with significant improvement after food elimination and rotation diet (p < 0.05). Significant improvements were seen in stool frequency (p < 0.05), pain (p < 0.05), and IBS-QOL scores (p < 0.0001).
Imbalances of beneficial flora and dysbiotic flora were identified in 100% of subjects by CSA. There was a trend to improvement of beneficial flora after treatment but no change in dysbiotic flora. The 1-year follow up demonstrated significant continued adherence to the food rotation diet (4.00 +/- 1.45), minimal symptomatic problems with IBS (4.00 +/- 1.17), and perception of control over IBS (4.15 +/- 1.23). The continued use of probiotics was considered less helpful (3.40
+/- 1.60).

CONCLUSION:
These data demonstrate that identifying and appropriately addressing food sensitivity in IBS patients not previously responding to standard therapy results in a sustained clinical response and impacts on overall well being and quality of life in this challenging entity.

Article Link: https://www.ncbi.nlm.nih.gov/pubmed/17229899

14) 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.Learn More

AIM:
To study the association between serum levels of milk protein IgG and IgA antibodies and milk-related gastrointestinal symptoms in adults.

METHODS:
Milk protein IgG and IgA antibodies were determined in serum samples of 400 subjects from five outpatient clinics in Southern Finland. Subjects were randomly selected from a total of 1900 adults undergoing laboratory investigations in primary care. All 400 participants had completed a questionnaire on abdominal symptoms and dairy consumption while waiting for the laboratory visit. The questionnaire covered the nature and frequency of gastrointestinal problems, the provoking food items, family history and allergies. Twelve serum samples were disqualified due to insufficient amount of sera. The levels of specific milk protein IgG and IgA were measured by using the ELISA technique. The association of the milk protein-specific antibody level was studied in relation to the milk-related gastrointestinal symptoms and dairy consumption.

RESULTS:
Subjects drinking milk (n = 265) had higher levels of milk protein IgG in their sera than non-milk drinkers (n = 123, P < 0.001). Subjects with gastrointestinal problems related to milk drinking (n = 119) consumed less milk but had higher milk protein IgG levels than those with no milk-related gastrointestinal symptoms (n = 198, P = 0.02). Among the symptomatic subjects, those reporting dyspeptic symptoms had lower milk protein IgG levels than non-dyspeptics (P < 0.05).
However, dyspepsia was not associated with milk drinking (P = 0.5). The association of high milk protein IgG levels with constipation was close to the level of statistical significance. Diarrhea had no association with milk protein IgG level (P = 0.5). With regard to minor symptoms, flatulence and bloating (P = 0.8), were not associated with milk protein IgG level. Milk protein IgA levels did not show any association with milk drinking or abdominal symptoms. The levels of milk protein IgA and IgG declined as the age of the subjects increased (P < 0.004).

CONCLUSION:
Milk protein IgG but not milk IgA seems to be associated with self-reported milk- induced gastrointestinal symptoms

Article Link: https://www.ncbi.nlm.nih.gov/pubmed/19842221

15) Serological Investigation of Food Specific Immunoglobulin G Antibodies in Patients with
Inflammatory Bowel Diseases. Chenwen Cai, Jun Shen, Di Zhao, Yuqi Qiao, Antao Xu, Shuang Jin, Zhihua Ran, and Qing Zheng*PLoS One. 2014 Nov 13;9(11).Learn More

16) The value of eliminating foods according to food-specific immunoglobulin G antibodies in irritable bowel syndrome with diarrhea. Hong Guo, Tao Jiang, Jinliang Wang, Yongchao Chang, Hai Guo, Weihong Zhang. J.Int.Med.Res.2012; 40 (1):204-10.Learn More

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

BACKGROUND:
Post-prandial worsening of symptoms as well as adverse reactions to one or more foods are common in the patients with functional gastrointestinal diseases, such as irritable bowel syndrome (IBS) and functional dyspepsia (FD). However, the role played by true food allergy in the pathogenesis of these diseases is still controversial and there are no well-established tests to identify food allergy in this condition.

OBJECTIVE:
To investigate serum food antigen-specific IgG, IgE antibody and total IgE antibody titres in controls and patients with IBS and FD, and to correlate symptoms with the food antigen-specific IgG titres in IBS and FD patients.

METHODS:
Thirty-seven IBS patients, 28 FD patients and 20 healthy controls participated in this study. Serum IgG and IgE antibody titres to 14 common foods including beef, chicken, codfish, corn, crab, eggs, mushroom, milk, pork, rice, shrimp, soybean, tomatoes and wheat were analysed by ELISA. Serum total IgE titres were also measured. Last, symptomatology was assessed in the study. Results IBS patients had significantly higher titres of IgG antibody to crab (P=0.000), egg (P=0.000), shrimp (P=0.000), soybean (P=0.017) and wheat (P=0.004) than controls. FD patients had significantly higher titres of IgG antibody to egg (P=0.000) and soybean (P=0.017) than controls. The percentage of individuals with detectable positive food antigen-specific IgE antibodies of the three groups did not show any significant differences (P=0.971). There were no significant differences between IBS patients, FD patients and controls in the serum total IgE antibody titres (P=0.978). Lastly, no significant correlation was seen between symptom severity and serum food antigen-specific IgG antibody titres both in IBS and FD patients.

CONCLUSION:
Serum IgG antibody titres to some common foods increased in IBS and FD patients compared to controls. But there is no significant correlation between symptom severity and elevated serum food antigen-specific IgG antibodies in these patients.

Article Link: https://www.ncbi.nlm.nih.gov/pubmed/17517095

18) Immune Activation in patients with irritable bowel syndrome. Liebregts T, Adam B, Bredack C, Röth A, Heinzel S, Lester S, Downie-Doyle S, Smith E, Drew P, Talley NJ, Holtmann G. Gastroenterology. 2007 Mar;132(3):913-20. Epub 2007 Jan 26.Learn More

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

MIGRAINE

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

21) IgG-mediated allergy: a new mechanism for migraine attacks? Pascual J, Oterino A. Cephalalgia. 2010 Jul;30(7):777-9. doi: 10.1177/0333102410364856. Epub 2010 Mar 26.Learn More

Despite recent advances offered by modern neuroimaging and genetic techniques, the pathophysiology of migraine has not been fully clarified. As pointed out by Selby and Lance 50 years ago, a relevant proportion of patients report that their migraine attacks are usually precipitated by dietary items (1). In a survey analysing the prevalence of dietary migraine in 500 new migraine patients, Peatfield et al. found in 1984 that 19.2% of migraine patients reported sensitivity to cheese, 18.2% to chocolate ad 11.1% to citrus fruit (2). The same year, Monro et al. published a paper in the Lancet with the categorical title ‘Migraine Is a Food- Allergic Disease’, describing the treatment of just nine patients with severe refractory migraine with either sodium cromoglycate or placebo after the patients ate foods previously identified as provocants (3). Sodium cromoglycate exerted a protective effect, which made the authors conclude that a food-allergy reaction is the cause of migraine, at least in this group of patients with dietary precipitants.
Definite proof that this is a reproducible fact, however, has proved elusive. In other studies objective evidence of hypersensitivity was found in very few cases, and those reporting a reduction in migraine during formal diets not only include a low number of patients, but mostly make no serious attempt to conceal the dietary strategy from the patients, pay insufficient attention to placebo effect and include an incredible prevalence of atopic diseases in migraine patients.

One of the obstacles to acceptance of the dietary hypothesis is the lack of a clear scientific explanation of the mechanisms implicated in the development of migraine attacks supposedly precipitated by food. The first obvious proposed mechanism was an allergy mediated by IgE antibodies. Theoretically, the interaction of a food constituent with a specific IgE antibody would produce a response by activation of complement or degranulation of mast cells. Several independent studies have failed to find elevated IgE levels or complement activation during migraine attacks, even in patients with a history of food- precipitated headaches (4,5).

These results, together with the finding that diet-sensitive patients are usually sensitive to several and different foods, led to the next proposal for a common pathogenic mechanism: antigenic similarities between these disparate foods seemed less likely than sharing a common chemical constituent (2). Investigators tried to confirm the so-called ‘amine hypothesis’ first by clinical challenge tests with substances like tyramine or β-phenylethylamine. As elegantly reviewed by Peatfield (5), the results of these studies can be interpreted as inconsistent. The next step was to investigate the amines’ metabolic routes. Could the elimination pathways of such amines be deficient in dietary migraine patients? There are two major breakdown pathways for these substances in humans: oxidation by monoamine oxidase (MAO) to parahydroxyphenylacetic acid and sulphation by phenosulphotransferase to water-soluble conjugates. MAO, a mitochondrial enzyme, exists in two forms in humans, with different substrate specificities. MAO A predominates in gut mucosa and liver and preferentially inactivates catecholamines and serotonin. The human platelet contains only MAO B, which metabolises phenylethylamine, benzylamine and methylhistamine. Tyramine and dopamine are substrates for both forms (6). The easy availability of platelets led to MAO B being the only form to be studied in migraine patients. Most studies have found a low platelet MAO B activity but only during migraine attacks, both in dietary and non-dietary patients (5). The significance of these findings remains uncertain. The sulphation route has also been explored in migraine patients. A reduced urinary output of sulphated tyramine metabolites after an oral tyramine load in subjects with food-sensitive migraine has been reported.
Phenolsulphotransferase, the enzyme responsible for sulphate conjugation, has been found to exist in two forms: the phenosulphotransferase M, which sulphates the amines, including tyramine, dopamine and catecholamines, and the phenosulphotransferase P, for which no endogenous substrate has been identified (7). In studies of these two enzymes in migraine patients, only in the case of P type was this deficiency statistically significant, which would hypothetically implicate an unidentified substrate in the pathophysiology of dietary migraine (8). Finally, still within the frame of the ‘amine hypothesis’, the possibility that dietary patients could absorb more of the substances due to a deficiency or a change in sensitivity of one or more intestinal-wall enzymes has also been tested (9). Again, results have not consistently confirmed this possibility.

With all these negative results, there has been almost no interest in studying, clinically or pathophysiologically, the relationship between migraine and diet in the last two decades. As just one significant example, both the aminergic hypothesis and IgE-mediated allergy hypothesis have totally disappeared as potential
explanations for the pathophysiology of migraine attacks in the last edition of The Headaches (10), even though we do continue to see many patients who experience migraine attacks when they eat certain foods or whose migraine improves on some diets (11). In this issue of Cephalalgia, Alpay and co-workers report the results of an interesting randomised, double-blind, cross-over, headache diary–based trial with 30 patients having migraine without aura (12).
Following a six-week baseline, IgG antibodies against 266 food antigens were determined. Then the investigators randomised the patients to a six-week individualised diet either including or excluding specific foods associated with raised IgG antibodies. Following a two-week diet-free interval after the first period, the same patients were given the opposite diet. Both patients and physicians were blind to the type of diet and IgG tests. Interestingly, most patients seemed to be IgG-positive for several foods and in more than half of these cases titres were graded at least as moderate. Compared to baseline, there was a statistically significant reduction both in the number of headache days and in the number of migraine attacks in the elimination diet period. The results of this Turkish trial are in line with those of a recent Mexican study in which IgG antibodies against 108 food allergens were measured in 56 migraine patients and 56 controls without migraine. IgG antibodies were statistically more frequent in the migraine patients, who then improved on an elimination diet without the need of medication (13).

Even taking into account the limitations of the Turkish trial—the rather low number of patients, relatively short follow-up, potential carry-over effect of a cross-over design, that the positive effects of the diet could be due to non- immunological mechanisms, the specificity and sensitivity of the enzyme-linked immunosorbent assay (ELISA) test and the fact that, due to the short duration of the trial, the authors were unable to correlate the clinical response with a decrease in the level of IgG antibodies—it is true that they offer a rather convincing explanation for dietary migraine, which should be tested in future larger and longer trials.

The interest in a role for IgG antibodies in food allergy has been recently driven by the findings in irritable bowel syndrome (IBS) and functional dyspepsia.
Concurring with migraine results, the levels of IgG, and not IgE, antibodies have been shown to be increased in IBS patients and recent studies have found a significant improvement in IBS on elimination diets (14–16). Interestingly, many of the clinical characteristics of IBS are conceptually similar to those of migraine, and subjects with IBS are at higher risk than controls to suffer from migraine (17). One further proof of a role of IgG antibodies against food antigens in the development of migraine attacks is the known association between migraine and celiac disease and the improvements of celiac sufferers’ migraine after changing to a gluten-free diet (18).

The mechanisms of IgG-mediated food allergy have not been fully elucidated and remain speculative. It has been proposed that food-allergy antigens transported by way of mast cells activate T helper and B lymphocytes, increasing the production of IgG antibodies and cytokines (19). Then the increased IgG antibodies and cytokines would lead to an inflammation response, which, as pointed out by Alpay and co-workers (11), seems to play an important role in the pathophysiology of migraine attacks. Supporting this hypothesis, a recent study has shown that anti-food IgG antibodies in obese juveniles are associated with systemic inflammation (20). These data are interesting, as obesity seems to be a risk factor in the development of chronic migraine (21). Alternatively, however, elevated IgG antibodies to food could be secondary to ‘inflammation’ and therefore be more of an epiphenomenon rather than a true delayed allergic reaction. In any case, Alpay and co-workers’ results, if fully confirmed in future trials, may be important not only in terms of their obvious consequences for the management of our migraine patients, but also conceptually, as the clarification of the mechanisms through which IgG antibodies are able to lead to development of migraine attacks would improve the knowledge of migraine pathophysiology. But consequences of these findings could be even more extensive. For instance, the dramatic differences in diet between the Occidental countries, where migraine prevalence is high and almost identical, and African or Asiatic countries, where migraine prevalence is clearly lower, could theoretically explain, at least in part, these epidemiological findings.

Article Link: http://journals.sagepub.com/doi/10.1177/0333102410364856

22) Randomised controlled trial of food elimination diet based on IgG antibodies for the prevention of migraine like headaches. Natasha Mitchell et al, Nutrition Journal 2011.Learn More

23) 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.

24) 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. Learn More

AUTOIMMUNITY

26) Molecular mimicry as a mechanism for food immune reactivities and autoimmunity. Vojdani A .Altern Ther Health Med. 2015;21 Suppl 1:34-45.Learn More

The mucosal immune system is constantly exposed to challenges from the antigenic substances found in food and released from the body’s own microbial flora. The body’s normal tolerance to friendly antigenic substances can be disrupted by a number of factors, such as disease, injury, shock, trauma, surgery, drugs, blood transfusion, environmental triggers, etc. When this disruption happens, the ingestion of foods containing antigenic substances that have compositions similar to those of the body’s autoantigens can result in the production of antibodies that react not only against the food antigens but also the body’s own tissues. This response is known as food autoimmune reactivity.
Between 7% and 10% of the world’s population suffers from some form of autoimmune disease. Each patient’s antibodies, both immunoglobulin A (IgA) + immunoglobulin M (IgM) in the saliva and immunoglobulin G (IgG) and IgA in the blood must be examined to give a complete picture of food immune reactivity. A host of health problems and autoimmune disorders have increasingly become associated with some of the most commonly consumed foods in the world, such as wheat and milk. Many of these problems can be traced to molecular mimicry.
The peptide sequences of foods such as milk and wheat are similar to those of human molecules, such as myelin oligodendrocyte glycoprotein, human islet cell tissue, and human aquaporin 4 (AQP4). This similarity can result in cross- reactivity that leads to food autoimmunity and even autoimmune disorders, such as multiple sclerosis (MS), celiac disease (CD), and neuromyelitis optica. Further research is needed to determine what other foods have dangerous sequence similarities to human tissues and what methods are available to test for the autoantibodies resulting from these molecular, mimicry-induced misfires of the immune system. The identification and removal of corresponding food triggers can then be used as the basis of therapy

Article Link: https://www.ncbi.nlm.nih.gov/pubmed/25599184

27) Cross-Reaction between Gliadin and Different Food and Tissue Antigens. Aristo Vojdani1,2*, Igal Tarash1 Food and Nutrition Sciences, 2013, 4, 20-32. Learn More

28) Anti-Saccharomyces cerevisiae autoantibodies in autoimmune diseases: from bread baking to autoimmunity. Rinaldi M1, Perricone R, Blank M, Perricone C, Shoenfeld Y.Clin Rev Allergy Immunol.2013 Oct;45(2):152-61. Learn More

29) Gastrointestinal disease in Sjogren’s syndrome: related to food hypersensitivities. Kim-Lee C, Suresh L, Ambrus JL Jr.Springerplus. 2015 Dec 12;4:766. Learn More

30) Lectins, agglutinins, and their roles in autoimmune reactivities.. Vojdani A.Altern Ther Health Med. 2015;21 Suppl 1:46-51. Learn More

31) The gut–joint axis: cross reactive food antibodies inheumatoid arthritis. M Hvatum†,
L Kanerud, R Hällgren, and P Brandtzaeg, Gut. 2006 Sep; 55(9): 1240–1247. Learn More

Background and aims
Patients with rheumatoid arthritis (RA) often feel there is an association between food intake and rheumatoid disease severity. To investigate a putative immunological link between gut immunity and RA, food antibodies were measured in serum and perfusion fluid from the jejunum of RA patients and healthy controls to determine the systemic and mucosal immune response.

Go to: Methods
IgG, IgA, and IgM antibodies to dietary antigens were measured in serum and jejunal perfusion fluid from 14 RA patients and 20 healthy subjects. The antigens originated from cow’s milk (α‐lactalbumin, β‐lactoglobulin, casein), cereals, hen’s egg (ovalbumin), cod fish, and pork meat.

Go to: Results
In intestinal fluid of many RA patients, all three immunoglobulin classes showed increased food specific activities. Except for IgM activity against β‐lactoglobulin, all other IgM activities were significantly increased irrespective of the total IgM level. The RA associated serum IgM antibody responses were relatively much less pronounced. Compared with IgM, the intestinal IgA activities were less consistently raised, with no significant increase against gliadin and casein.
Considerable cross reactivity of IgM and IgA antibodies was documented by absorption tests. Although intestinal IgG activity to food was quite low, it was nevertheless significantly increased against many antigens in RA patients. Three of the five RA patients treated with sulfasalazine for 16 weeks had initially raised levels of intestinal food antibodies; these became normalised after treatment, but clinical improvement was better reflected in a reduced erythrocyte sedimentation rate.

Go to: Conclusions
The production of cross reactive antibodies is strikingly increased in the gut of many RA patients. Their food related problems might reflect an adverse additive effect of multiple modest hypersensitivity reactions mediated, for instance, by immune complexes promoting autoimmune reactions in the joints.

Article Link: https://www.ncbi.nlm.nih.gov/pmc

32) The pathogenesis of rheumatoid arthritis is associated with milk or egg allergy..Li J, Yan H, Chen H, Ji Q, Huang S, Yang P, Liu Z, Yang B. North Am J Med Sci 2016;8:40-6. Learn More

33) Correlation of Tissue Antibodies and Food Immune Reactivity in Randomly Selected Patient Specimens. J Lambert J, Vojdani A (2017) Clin Cell Immunol 8: 521. Doi: 10.4172/2155-9899.1000521. Learn More

CROHN’s DISEASE

34) Higher titers of anti-Saccharomyces cerevisiae antibodies IgA and IgG are associated with more aggressive phenotypes in Romanian patients with Crohn’s disease. Gologan S1, Iacob R, Preda C,Vadan R, Cotruta B, Catuneanu AM, Iacob S, Constantinescu I, Gheorghe L, Iobagiu S, Gheorghe C, Diculescu M. J Gastrointestin Liver Dis. 2012 Mar;21(1):39-44.Learn More

35) The effects of provocation by foods with raised IgG antibodies and additives on the course of Crohn’s disease: A pilot study. Hulya Uzunismail et al. Turk J Gastroenterol 2012; 23 (1): 19-27.Learn More

36) 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.Scholmerich, G. Rogler Digestion (2010);81:252–264.Learn More

ASTHMA

37) Food-specific IgG Antibody–guided Elimination Diets Followed by Resolution of Asthma
Symptoms and Reduction in Pharmacological Interventions in Two Patients: A Case Report Kulveen Virdee,Glob Adv Health Med. 2015 Jan; 4(1): 62–66.Learn More

38) 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.Learn More

39) 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.Learn More

Current understanding of the use of exclusion diets in the management of asthma in children is limited and controversial. The aim of this study was to examine the effects of excluding eggs and milk on the occurrence of symptoms in children with asthma and involved 22 children aged between three and 14 years clinically diagnosed as having mild to moderate disease. The investigation was single blind and prospective, and parents were given the option of volunteering to join the ‘experiment’ group, avoiding eggs, milk and their products for eight weeks, or the ‘control’ group, who consumed their customary food. Thirteen children were recruited to the experimental group and nine to the control group. A trained paediatrician at the beginning and end of the study period assessed the children.
A seven-day assessment of food intake was made before, during and immediately after the period of dietary intervention in both groups. A blood sample was taken from each child for determination of food specific antibodies and in those children who could do so, the peak expiratory flow rate (PEFR) was measured. Based on the recommended nutrient intake (RNI), the mean percentage energy intake of the children in the experimental group was significantly lower (p < 0.05) in the experimental group. After the eight-week study period and compared with baseline values, the mean serum anti-ovalbumin IgG and anti-beta lactoglobulin IgG concentrations were statistically significantly reduced (p < 0.05) for both in the experimental group. In contrast, the values for anti-ovalbumin IgG in the control group were significantly increased and those for anti-beta lactoglobulin IgG were practically unchanged. The total IgE values were unchanged in both groups. Over the study period, the PEFR in those children in the experimental group able to perform the test was significantly increased, but no such change was noted in the children in the control group who could do the test. These results suggest that even over the short time period of eight weeks, an egg- and milk-free diet can reduce atopic symptoms and improve lung function in asthmatic children.

Article Link: https://www.ncbi.nlm.nih.gov/pubmed/15067979

BRAIN-Psychosis

40) IgG dynamics of dietary antigens point to cerebrospinal fluid barrier or flow dysfunction in firstepisode schizophrenia. Emily G. Severance,a,* Kristin L. Gressitt,a Armin Alaedini,b Cathrin Rohleder,c Frank Enning,c,d J. Malte Bumb,c Juliane K. Muller,c Emanuel Schwarz,c Robert H. Yolken,a and F. Markus Leweke . Brain Behav Immun. 2015 Feb; 44: 148–158.Learn More

41) The humoral response in the pathogenesis of gluten ataxia. M. Hadjivassiliou, MD, Neurology April 23, 2002 vol. 58 no. 8 1221-1226.Learn More

42) Disruption in the Blood-Brain Barrier: The Missing Link between Brain and Body Inflammation in Bipolar Disorder? Jay P. Patel1 and Benicio N. Frey Neural Plasticity Volume 2015, Article ID 708306, 12 pages.Learn More

43) The role of IgG hypersensitivity in the pathogenesis and therapy of depressive disorders.
Karakuła-Juchnowicz H, Szachta P, Opolska A, Morylowska-Topolska J, Gałęcka M, Juchnowicz D, Krukow P, Lasik Z. Nutr Neurosci. 2014 Sep 30.Learn More

44) Evidence for an immune response in major depression: a review and hypothesis.Maes M. Progress in Neuro-Psychopharmacology and Biological Psychiatry 1995 Volume 19, Issue1, Pages11-38.Learn More

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

46) 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.Learn More

47) Complement C1q formation of immune complexes with milk caseins and wheat glutens in
Schizophrenia. Emily G. Severancea, Kristin Gressitta, Meredith Hallinga, Cassie R. Stallingsb, Andrea E. Origonib, Crystal Vaughanb, Sunil Khushalanib, Armin Alaedinic, Didier Dupontd, Faith B. Dickersonb, and Robert H. Yolkena Neurobiol Dis. 2012 December ; 48(3): 447–453.Learn More

48) Dietary antigens, epitope recognition, and immune complex formation in recent onset psychosis and long-term schizophrenia. Severance EG1, Lin J, Sampson HA, Gimenez G, Dickerson FB, Halling M, Gressitt K, Haile L,Stallings CR, Origoni AE, Dupont D, Yolken RH.Schizophr Res. 2011 Mar;126(1-3):43-50.Learn More

49) Seroreactive marker for inflammatory bowel disease and associations with antibodies to dietary proteins in bipolar disorder. Emily G. Severancea, Kristin L. Gressitta, Shuojia Yanga, Cassie R. Stallingsb, Andrea E. Origonib, Crystal Vaughanb, Sunil Khushalanib, Armin Alaedinic, Faith B. Dickersonb, and Robert H. YolkenaBipolar Disord. 2014 May ; 16(3):230–240.Learn More

50) Gastrointestinal inflammation and associated immune activation in schizophrenia.
Emily G. Severancea, Armin Alaedinib, Shuojia Yanga, Meredith Hallinga, Kristin L. Gressitta, Cassie R. Stallingsc, Andrea E. Origonic, Crystal Vaughanc, Sunil Khushalanid, F. Markus Leweked,e, Faith B. Dickersonc, and Robert H. Yolkena Schizophr Res. 2012 June ; 138(1): 48–53.Learn More

51)Breaking down the barriers: the gut microbiome, intestinal permeability and stress-related psychiatric disorders. John R. Kelly,Paul J.,.John F. Cryan, Timothy G. Dinan, Gerard Clarke, Niall P. Hyland Front. Cell. Neurosci., 14 October 2015 Learn More

52)Gut Uptake, Brain and Behaviour Tveiten D. Bioeng1 and K. L. Reichelt Journal of Scientific Research &Reports 3(22): 2834-2847, 2014;Learn More

Excema

53) Circulating immunoglobulins, leucocytes and complements in childhood-onset atopic eczema. Hon KL1, Wang SS, Pong NH, Leung TF.Indian J Pediatr. 2013 Feb;80(2):128-31. Learn More

OBESITY

54) Baker’s yeast (Saccharomyces cerevisiae) antigen in obese and normal weight subjects. Salamati S1, Martins C, Kulseng B. Clin Obes. 2015 Feb;5(1):42-7.Learn More

55) IgG Receptor FcγRIIB Plays a Key Role in Obesity-Induced Hypertension.
Nathan C. Sundgren, Wanpen Vongpatanasin, Brigid-Meghan D. Boggan, Keiji Tanigaki, Ivan S. Yuhanna, Ken L. Chambliss, Chieko Mineo, and Philip W. Shaul Hypertension. 2015 February ; 65(2): 456–462.Learn More

56) 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. IgG.(2007). Exp Clin Endocrinol Diabetes.Learn More

57) Increase adipose tissue expression of tumor necrosis factor-alpha in human obesity and insulin resistance. Hotamisligil G. S., Arner P., Caro J. F., Atkinson R. L., Spiegelman B. M.. J Clin Invest (1995); 95: 2409-2415.Learn More

58) Adipose expression of tumor necrosis factor- direct role in obesity-linked insulin resistance. Hotamisligil G. S., Shargill N. S., Spiegelman B. M.. Science (1993); 259: 87-91.Learn More

Autism

59) Food allergy investigations and ist significance in autism spectrum disorders. Anath N Rao, Minakshi Koch, Sabyasachi Ghosh and Suresh Kumar V. International Journal of Pharma and Bio Sciences Vol.1/Issue-4/Oct-Dec.2010.Learn More

60) Antibodies against Food Antigens in Patients with Autistic Spectrum Disorders. Laura de Magistris, Annarita Picardi, Dario Siniscalco, Maria Pia Riccio, Anna Sapone, Rita Cariello, Salvatore Abbadessa, Nicola Medici, Karen M. Lammers, Chiara Schiraldi, Patrizia Iardino, Rosa Marotta, Carlo Tolone, Alessio Fasano, Antonio Pascotto, and Carmela Bravaccio BioMed Research International Volume 2013, Article ID 729349, 11 pages.Learn More