Publish Date

March 24, 2023

Delves into immunoglobulins (IgGs) 5 different classes termed G, A, M, E, and D and an explanation of why Total IgG is important vs. IgG4 alone.

Immunoglobulins (Igs) consist of 5 different classes termed G, A, M, E, and D. IgG is broken into several subclasses termed 1, 2, 3, and 4. IgGs are composed of two heavy chain–light chain pairs (half-molecules), which are connected via inter–heavy chain disulfide bonds situated in the hinge region. IgG4 antibodies usually represent less than 6% of the total IgG antibodies. IgG4 antibodies differ functionally from other IgG subclasses in their anti-inflammatory activity, which includes a poor ability to induce complement and cell activation because of low affinity for C1q (the q fragment of the first component of complement). Consequently, IgG4 has become the preferred subclass for immunotherapy, in which recruitment of host effector function is undesirable.

IgG4 antibodies are dynamic molecules that exchange half of the antibody molecule specific for one antigen with a heavy-light chain pair from another molecule specific for a different antigen. The results in bispecific antibodies that are unable to form large cross-linked antibodies via complement binding thus producing inflammation. The production of large amounts of these IgG4 antibodies is the reason that immunotherapy with various antigens is used to reduce severe reactions caused by IgE mediated allergies. If antigens react with IgG4 antibodies, the antigens cannot react with IgE antibodies that might cause anaphylaxis or other severe reactions. Thus, IgG4 antibodies are often termed blocking antibodies. For example, in specific immunotherapy for allergic rhinitis, increases in allergen-specific IgG4 levels correlate with improved clinical responses. IgG4 antibodies not only block IgE mediated food allergies but also block the reactions of food antigens with other IgG subclasses, reducing inflammatory reactions caused by the other IgG subclasses of antibodies to food antigens.

[Structure of IgG Antibodies]

In IgG mediated food allergy testing, the goal is to identify foods that are capable of causing inflammation that can trigger a large number of adverse reactions. IgG1, IgG2, and IgG3 all are capable of causing inflammation because these antibodies do not exchange heavy and light chains with other antibodies to form bispecific antibodies. Thus, IgG1, IgG2, and IgG3 antibodies to food antigens can and do form large immune complexes or lattices that fix complement and increase inflammation. The presence of IgG4 antibodies to food antigens indicates the presence of antibodies to foods that will not usually cause inflammation even though high amounts of these antibodies do indicate the presence of immune reactions against food antigens. Testing only for IgG4 antibodies in foods limits the ability of the clinician to determine those foods that are causing significant clinical reactions that are affecting their patients. The importance of measuring other subtypes of IgG antibodies is highlighted in an article by Kemeny et al. They found that IgG1 antibodies to gluten were elevated in all 20 patients with celiac disease but none of the patients had elevated IgG4 antibodies to gluten.

Read a scientific article indicating that testing for IgG4 against foods is not recommended as a diagnostic tool.


Clinical Documentation of Use of Total IgG Food Allergy Test in Many Illnesses

Irritable Bowel Syndrome

W. Atkinson, et al Food elimination based on IgG antibodies in irritable bowel syndrome: a randomised controlled trial. Gut 2004;53:1459-1464.

Crohn’s Disease

Bentz S,Clinical relevance of IgG antibodies against food antigens in Crohn’s disease: a double-blind cross-over diet intervention study. Digestion. 2010;81(4):252-64. Epub 2010 Jan 30.

Migraine Headache

Huber A,et alInt Arch Allergy Immunol. 1998 Jan; 115(1):67-72. Diet restriction in migraine, based on IgG against foods: a clinical double-blind, randomised, cross-over trial.

Bipolar Disorder

Severance EG et al Immune activation by casein dietary antigens in bipolar disorder. Bipolar Disord 2010: 12: 834–842.


Severance EG, et al Subunit and whole molecule specificity of the anti-bovine casein immune response in recent onset psychosis and schizophrenia. Schizophr Res. 2010 May;118(1-3):240-7. Epub 2010 Jan 13.


Wilders-Truschnig M et al. IgG Antibodies Against Food Antigens are Correlated with Infl ammation and Intima Media Thickness in Obese Juveniles. Exp Clin Endocrinol Diabetes DOI 10.1055/s-2007-993165. Published online: 2007.

Juvenile-Onset Diabetes

Tahmeed Ahmed; et al Circulating antibodies to common food antigens in Japanese children with IDDM. Diabetes Care; Jan 1997; 20, 1; Research Library, pg. 74-76.


Vladimir Trajkovski et al Higher Plasma Concentration of Food-Specific Antibodies in Persons With Autistic Disorder in Comparison to Their Siblings.

Rheumatoid Arthritis

O’Farrelly, C., Price, R., McGillivray, A.J. and Fernandes, L. (1989), IgA rheumatoid factor and IgG dietary protein antibodies are associated in rheumatoid arthritis, Immunological Investigations, Vol. 18, pp. 753-64.


  • Marijn van der Neut Kolfschoten, et al Anti-Inflammatory Activity of Human IgG4 Antibodies by Dynamic Fab Arm Exchange. SCIENCE VOL 317 14 SEPTEMBER 2007 pgs1554-1555.
  • Volpi, Nicola and Maccari, Francesca(2009) ‘Serum IgG Responses to Food Antigens in the Italian Population Evaluated by Highly Sensitive and Specific ELISA Test’, Journal of Immunoassay and Immunochemistry, 30: 51 — 69.
  • Kemeny DM, et al Sub-class of IgG in allergic disease. I. IgG sub-class antibodies in immediate and non-immediate food allergy. Clin Allergy. 1986 Nov; 16(6):571-81.
  • Stapel SO, Testing for IgG4 against foods is not recommended as a diagnostic tool: EAACI Task Force Report.Allergy. 2008 Jul;63(7):793-6. Epub 2008 May 16.
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About the Author

William Shaw, PhD

William Shaw, PhD, is board certified in the fields of clinical chemistry and toxicology by the American Board of Clinical Chemistry. Before he founded The Great Plains Laboratory, Inc., Dr. Shaw worked for the Centers for Disease Control and Prevention (CDC), Children’s Mercy Hospital, University of Missouri at Kansas City School of Medicine, and Smith Kline Laboratories.