Measuring IgG4 specific antibodies against food allergens is important in the detection of food intolerances. 

With the term allergy we usually think of an acute inflammatory reaction caused by specific IgE antibodies (sIgE) directed against an invasive allergen. The foreign allergen may originate from pollen, trees or plants, animal epithelium, house dust mite, food, etc. This inflammation is initiated by activation of mast cells. Activation takes place through a strong binding of (relatively) large amounts of sIgE required (to the FCE receptor of the mast cells) combined with binding of the incoming allergen to these sIgE antibodies. After activation, large amounts of histamine are released that cause the inflammatory reactions. 

Role of IgG4

It has long been known that IgG4 antibodies have a protective effect in an IgE-meditated allergy. After all, during a successful immunisation the sIgE titre decreases, while the IgG4 antibody titre against that allergen increases. This is a natural process used by the body as a corrective mechanism against long-term allergy in which high doses of allergens enter the body on a daily basis (a kind of protective mechanism against overly severe allergy). The IgG4 antibodies bind very well to the FCE receptor (and prevent the binding of sIgE) without activating the mast cells. A nice natural allostatic response. But every allostatic reaction in the body has its downside.

Because of this, it has been thought for decades that IgG4 only has a protective effect and does not play a role in allergy and inflammatory processes (1). The views of the international immunology and allergy agencies are clear: "the measurement of IgG4 antibodies is strongly discouraged". However, since a few years it has been recognized that a (local or systemic) excess of IgG4 antibodies can also have negative effects and cause delayed inflammatory reactions (2).

IgG4 and inflammation

In 2003 the Japanese research group of Kamasawa (3) described for the first time that an excess of IgG4 prodcution is associated with inflammation in the pancreas (type I pancreatitis). Since 2003, hundreds of publications have appeared that describe the association between an excess of IgG4 in the body and fibrosating inflammation in all organs of the body: especially the pancreas, intestine, bile and liver are preferred organs where these inflammations can occur, but also the kidney and thyroid gland are frequently mentioned. In addition, it can also cause inflammations in the aorta, skin, etc. Recently some reviews about this have appeared (4,5).

As an entity, this syndrome is called the so-called IgG4 related disease (IgG4-RD). The complaints are often atypical and generally suitable for inflammations: tired, muscle pain, joint pain, abdominal pain, but usually no fever. Specific complaints can occur as a result of affected organs.

A relationship has been demonstrated between IgG4-RD and the prevention of allergy (6) and inflammatory bowel diseases, such as ulcerative collitis and Crohn's disease (7). This does not mean that there is a causal relationship, but it does mean that IgG4-RD is more common in these diseases.

IgG4 antibodies and food allergy

Very recently a relation has been made between the development of this IgG4-RD and the level of nutrient IgG4 antibodies (8). This relationship does not yet show a causal relationship either. However, it has been sufficiently proven that decreasing the IgG4 titre by (temporary) elimination of the relevant nutrients reduces or even completely eliminates complaints (7). The choice of the nutrients to be eliminated or restricted can be made on the basis of an IgG4 test in blood. This nutritional intervention can make an important contribution to the treatment or prevention of inflammatory diseases. IgG4 antibodies also seem to play a role in weight reduction (9).

From the above you could deduce that measuring the total amount of IgG4 would be a good diagnostic test to detect IgG4 related diseases. However, a recent study has shown that not the total IgG4 concentration, but rather high specific IgG4 (sIgG4) concentrations (with low sIgE titres) against cow's milk is strongly associated with the severity of esinophilic oesophagitis (10). This supports our recommendation for measuring sIgG4 antibodies against food allergens.

Use and interpretation of the IgG4 test

From the literature it has become clear that high titres of IgG4 antibodies against one specific food allergen (titre 4+ or higher) or multiple IgG4 antibodies positive (titre 2+ or higher) are needed for successful therapy (7,8,9). The local increase of IgG4 (in affected organ or tissue) in combination with the presence of IL10 and FGF-beta (fibroblasts growth factor) causes increased production of fibrous tissue (fibrosis) and ultimately to fibrosis inflammation. This seems to be a slow inflammatory reaction. 

In practice, it is therefore hardly possible to make a connection between certain foods and the effect it has in the body. This is because they are non-specific symptoms and these symptoms only occur 2 to 72 hours after ingestion of the food. Screening, using 24 nutrients (IgG4-24 screen test), is therefore recommended in individuals with few complaints and with 40 or 88 nutrients (IgG4-40 and IgG4-88 screen test) in individuals with moderate/numerous complaints. The latter two tests can also be used in individuals with a positive IgG4-24 screen test, in order to further optimize nutritional intervention.

Composition of the IgG4 tests

The IgG4-24 screen test includes the following allergens: apple, banana, carrot, potato, casein, kiwi, garlic, peach, rye, celery, mustard, soy, tomato, wheat, egg (egg yolk + protein), fish mixture, meat mixture, vegetable mixture, grain mixture1, grain mixture2, spice mixture, milk mixture, nuts/seed mixture, fruit mixture.

The IgG4-40 test contains the following allergens: goat's milk, α-lactalbumin, β-lactoglobulin, casein, chicken protein, chicken egg yellow, wheat, mango, orange, carrot, strawberry, shrimp, cod, blue mussel, banana, cocoa, tomato, date, kiwi, apricot, peanut, cashew nut, pecan, walnut, sesame, coconut, eggplant, almond, gluten, oats, vanilla, yoghurt, pineapple, pistachio, hazelnut, soybean, cabbage, pea, okra, mustard.

The IgG4-88 test contains the following allergens: pineapple, anise, apple, apricot, baker's yeast, banana, basil, pear, cauliflower, broccoli, buckwheat, camembert, cashew, dill, spelt, pea, strawberry, peanut, trout, golden cheese, grapefruit, green bean, cucumber, oats, hazelnut, herring, raspberry, millet, chicken, cod, chamomile, tea, carrot, potato, casein, cherry, kiwi, garlic, kohlrabi, coconut, lettuce, shrimp, raw milk, caraway, salmon, lamb, leek, lentil, bay leaf, corn, mackerel, almond, mango, nutmeg, orange, paprika, parsley, mint, peach, plum, mushroom, radish, rice, beef, rye, sprouts, sheep milk, black pepper, pork, celery, mustard, soy, asparagus, spinach, tuna, thyme, tomato, grapefruit, turkey meat, vanilla, egg, (egg yolk + protein), walnut, white beans, wheat, goat's milk, cinnamon, lemon, zucchini, onion.

Literature

1. Steven O. Stapel, R. Asero, B. K. Ballmer Weber, E. F. Knol, S. Strobel, S. Vieths, J. Kleine-Tebbe. Testing for IgG4 against foods is not recommended as a diagnostic tool: EAACI Task Force Report. Allergy 2008: 63: 793–796
2. http://www.uptodate.com/contents/overview-of-igg4-related-disease
3. Kamisawa T1, Funata N, Hayashi Y, Eishi Y, Koike M, Tsuruta K, Okamoto A, Egawa N, Nakajima H. A new clinicopathological entity of IgG4-related autoimmune disease. J Gastroenterol. 2003; 38(10): 982-984.
4. Vasaitis L. IgG4-related disease: A relatively new concept for clinicians. Eur J Intern Med. 2016;27:1-9.
5. A. Khosroshahi, ZS Wallace, JL Crowe, T Akamizu, A Azumi, MN Carruthers, ST Chari, E Della-Torre, L Frulloni, H Goto, PA Hart, T Kamisawa, S Kawa, M Kawano, MH Kim,Y Kodama, K Kubota, MM Lerch, M Löhr, Y Masaki, S Matsui, T Mimori, S Nakamura,T Nakazawa, H Ohara, K Okazaki, JH Ryu, T Saeki, N Schleinitz, A Shimatsu, T Shimosegawa, H Takahashi, M Takahira, A Tanaka, M Topazian, H Umehara, GJ Webster, TE Witzig, M Yamamoto, W Zhang, T Chiba and JH Stone. International Consensus Guidance Statement on the Management and Treatment of IgG4-Related Disease. Arthritis & Rheumatology 2015; 67(7): 1688–1699.
6. Iago Carballo, Lucía Alvela, Luis-Fernando Pérez, Francisco Gude, Carmen Vidal, Manuela Alonso, Bernardo Sopeña, Arturo Gonzalez-Quintela. Serum Concentrations of IgG4 in the Spanish Adult Population: Relationship with Age, Gender, and Atopy. Plos One. DOI:10.1371/ journal.pone. 0149330 February 24, 2016.
7. S. Bentz, M. Hausmann, H. Piberger, S. Kellermeier, S. Paul, L. Held, W. Falk, F. Obermeier, M. Fried, J. Schölmerich, G. Rogler. Clinical Relevance of IgG Antibodies against Food Antigens in Crohn’s Disease: A Double-Blind Cross-Over Diet Intervention Study. Digestion 2010;81:252–264.
8. Emma L Culver, Ellen Vermeulen, Mateusz Makuch, Astrid van Leeuwen, Ross Sadler, Tamsin Cargill, Paul Klenerman, Rob C Aalberse, S Marieke van Ham, Eleanor Barnes, Theo Rispens. Increased IgG4 responses to multiple food and animal antigens indicate a polyclonal expansion and differentiation of pre-existing B cells in IgG4-related disease. Ann Rheum Dis 2015;74:944–947.
9. John E. Lewis, Judi M. Woolger, Angelica Melillo, Yaima Alonso, Soyona Rafatjah, Sarah. Eliminating Immunologically-Reactive Foods from the Diet and its Effect on Body Composition and Quality of Life in Overweight Persons. J Obes Weig los Ther 2012, 2:1.
10. Schuyler AJ, Wilson JM, Tripathi A, Commins SP, Ogbogu PU, Kruzsewski PG, Barnes BH, McGowan EC, Workman LJ, Lidholm J, Rifas-Shiman SL, Oken E, Gold DR, Platts-Mills TAE, Erwin EA. Specific IgG antibodies to cow's milk proteins in pediatric patients with eosinophilic esophagitis. J Allergy Clin Immunol. 2018 Jul;142(1):139-148.e12. doi: 10.1016/j.jaci.2018.02.049. Epub 2018 Apr 18.