IgG (Immunoglobulin G), Inflammation, Allergy, IgE, Food allergy tests, Food sensitivity

IgG Sensitivity Testing and Inflammation: Where and How Do IgE/IgG4 Fit?

By Andrea Gruszecki, ND

Introduction

The testing of immunoglobulin G (IgG) has been common in functional, naturopathic, and alternative clinical practices for years.¹ New research is shifting the conventional medical perspective on IgG measurements and human studies are proving that IgG-immune system interactions can result in chronic, delayed, inflammatory reactions.^2,3 An improved understanding of the inter-relationship between various IgG immunoglobulin subclasses and IgE highlights the necessity of separate assessments for IgG subclasses 1-3 and IgG4. One of the likely reasons that it has taken so long for the science to catch up to clinical practice is that the early research was unable to differentiate the function and contribution of each individual IgG subclass during immune system activation. It is now clear that the use of total IgG (_totIgG) in the evaluation of chronic inflammatory antigen (allergen) reactions is no longer appropriate. IgG subclass four (IgG4) is associated with immediate IgE-mediated reactions and has protective, anti-inflammatory properties, unlike the other potentially pro-inflammatory IgG 1-3 subclasses. The clinical management of IgG4/IgE differs from the management of the other IgG subclasses. To fully discern the nature of the immune system’s response to foods and environmental antigens, and to provide proper patient care, IgG4 must be evaluated independently from IgG 1-3, and not as _totIgG.⁴

IgG4, IgE and Immediate Hypersensitivity Reactions

Antigens are good inducers of IgG1, IgG4 and IgE. Type I immediate hypersensitivity reactions (or anaphylaxis) typically occur after antigen sensitization, when IgE antibodies are formed against the antigen. With additional exposures, the IgE binds to receptors on mast cells and basophils, which release histamine and pro-inflammatory mediators. Mast cell and basophil activation via IgE receptors cause the symptoms associated with type I sensitivity.⁵ In patients with IgE-mediated allergy symptoms, increased production of allergen-specific IgE antibodies is observed, but often, there may be low production or lack of allergen-specific IgG1 and IgG4 antibodies due to acquired or inherited subclass deficiencies.⁶ Approximately 2.5% of the general population has an IgG subclass deficiency which results in lower IgG levels and may exacerbate type I IgE reactions and symptoms.⁷

In the majority of individuals, IgG4 antibodies are induced by T-regulatory cells and are formed following repeated or long-term exposure to an antigen. IgG4 may become the dominant subclass during chronic exposures, raising IgG4 levels.⁸ IgG4 antibodies can prevent IgE reactions through several mechanisms³:

• IgG4 can bind with receptors on mast cells and basophils, blocking IgE access. Unlike IgE, IgG4 binding does not promote the release of histamine or pro-inflammatory cytokines by basophils or mast cells.

• IgG4 induces the secretion of tolerant, anti-inflammatory cytokines from T-regulatory cells, reducing local and systemic reactivity.

• Circulating antibodies may be bound into complexes with IgG4. IgG4 is unique in that it often dissociates into two separate, smaller, monovalent antibody “chains.” The monovalent IgG4-antigen complex is small enough to be filtered and excreted by the kidneys before it deposits into tissues.

• IgG4 receptor binding may prevent pro-inflammatory, antigen-specific IgG1 and IgG3 “priming” of mast cells and basophils that carry both IgG and IgE receptors.

IgG and Hypersensitivity Reactions

Both complement activation and hypersensitivity reactions require multiple cell signals to manifest either tolerance or proinflammatory reactions. There are three types of hypersensitivity reactions mediated by immunoglobulin-antigen (Ig) interactions. Traditionally, type I immediate hypersensitivity has been considered IgE-mediated, while type IV hypersensitivity is considered an antibody-independent process.⁵ The remaining two types of hypersensitivity have different mechanisms, but both types can be mediated by IgG 1-3 complement activation.

Type II hypersensitivity causes IgG antibody-mediated cell damage when normally tolerated environmental antigens are bound by IgG antibodies to the surface of circulating blood cells such as platelets or red blood cells.⁹ The coated cells become targets for white blood cells, and the bound antibodies can either activate natural killer cells and cytotoxic T-cells or induce pro-inflammatory complement cascades that destroy the coated cells.¹⁰ Immune system T-cells program antibodies for type II reactions during a first exposure, and reactions may then occur with subsequent exposures. Type II hypersensitivity can be involved in autoimmune reactions against cell surface proteins or extracellular matrix proteins if the environmental antigen is chemically similar to body tissues.³ Classical type II reactions begin within 24 hours of exposure; these reactions commonly occur due to medication use, or as a response to infections (fungal, bacterial, viral). Medical conditions associated with type II hypersensitivity include loss of platelets (immune thrombocytopenia), loss of red blood cells (autoimmune hemolytic anemia), and loss of white blood cells (autoimmune neutropenia). Removal of the causative antigen resolves the symptoms over time.

After the initial antigen exposure, Ig antibodies begin to form in 4-10 days.¹⁰ Type III hypersensitivity occurs when these antibodies combine with circulating antigens to form larger molecular complexes that can either bind to receptors on mast cells and leukocytes or induce pro-inflammatory complement cascades. When an antigen is in excess, these large circulating IgG 1-3 immune complexes eventually deposit into joints or tissues and result in local inflammation and tissue damage. Type III reactions may also occur if there is a failure by the immune system to remove the antibody-antigen complexes. Medical conditions associated with Type III reactions include joint inflammation, blood vessel inflammation (vasculitis), kidney inflammation (glomerulonephritis), systemic lupus erythematosus, and rheumatoid arthritis.⁵

IgG 1-3, Chronic Inflammation, and Complement Activation

The complement system is an important part of the innate immune system. Complement is a group of plasma and membrane-associated serum proteins that contribute to the local inflammatory response to antigens such as pathogens, damaged tissue, or foreign environmental proteins.³ Only IgG 1-3 can activate complement; once activated, the complement pathway produces anaphylotoxins – smaller molecules that promote inflammation, vascular permeability, and inflammatory white blood cell responses. Anaphylotoxins can trigger inflammatory responses from both mast cells and basophils.¹¹ Sustained activation of the complement system can result in a loss of tolerance and can contribute to chronic inflammation.¹² Over time, sustained activation of complement can increase the risk of autoimmunity.

In contrast, IgG4 does not activate complement or participate in chronic, complement-mediated, inflammatory reactions. Instead, IgG4 can prevent such reactions by blocking white blood cell receptors stimulated by other IgE or IgG subclasses, by binding antigen in circulation, or through the inhibition of immune complex precipitation into joints or tissues.³

Allergy, Sensitivity, or Tolerance – What to Measure?

Human studies have demonstrated that IgE and IgG4 trend together in adults, and that IgG4 levels tend to be higher in those with atopic (allergic) IgE-mediated diseases.¹³ This makes IgG4 an acceptable stand-in for IgE, as foods or aeroallergens with high IgG4 levels likely indicate the presence of an IgE-mediated type I hypersensitivity (classical “allergy”).¹⁴

This knowledge then creates a dilemma for clinicians trying to interpret total IgG (_totIgG) results. There is no way to discern from _totIgG which high values are driven by inflammatory IgG1, IgG2, or IgG3 and there is no way to determine which _totIgG values are elevated due to the presence of IgG4 blocking antibodies. IgG-mediated food antibodies commonly decrease when foods are eliminated, and many clinicians attempt food reintroductions after eliminating a food and “resting” the immune system from the antigen exposure for a period of time.^15,16 Since all of the IgG subclasses can be tested in either a serum or dried blood spot (fingerstick) format, it is a simple matter to run a separate test for IgG4 and IgG 1-3 when testing a sample.

When food testing is performed, it may not be appropriate to rotate or attempt the re-introduction of a food known to be IgE/IgG4-mediated, since the re-introduction may result in inflammatory symptoms or an anaphylactic reaction.¹⁷ But, if only _totIgG is measured, there is no way to know which foods are safe for attempted re-introduction (Figure 1).¹⁸ It may also be imperative to remove or manage environmental IgE-mediated exposures to minimize the risk of food cross-reactions or type I hypersensitivity reactions to pollens, molds, pets, etc.^16,19,20

The risk in re-introducing a food with a high IgG4 value lies in the fact that IgG levels can be variable.²¹ Depending upon inheritance, nutritional status, infection, comorbid diseases, or medical interventions, IgG levels may not be consistent or reliable and acquired IgG deficiency may occur at any time.^22,23 Acquired IgG deficiency may decrease IgG subclass levels, including protective IgG4 to the point where IgE blocking is no longer possible. The loss of protective IgG4 makes type I IgE-mediated symptoms, including anaphylaxis, much more likely with additional antigen exposures, such as food re-introduction or seasonal exposures.²⁴

Conclusion

An improved understanding of the inter-relationship between various IgG immunoglobulin subclasses and IgE highlights the necessity of separate assessments for IgG subclasses 1-3 and IgG4. If IgE-mediated allergens are incorrectly assumed to be IgG-mediated, then the measurement of total IgG can increase the risk of IgE-driven symptoms during food reintroduction, up to and including life-threatening anaphylactic reactions. Clinicians using IgG testing for food or aero-allergen (inhalant) sensitivity must be aware of the clinically relevant difference between IgG 1-3 and IgG4. With this increased awareness the measurement of IgG4 independently from the other IgG subclasses shall become the standard of care to correctly determine the proper treatment path for each antigen and each patient.

References

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2. Piuri G, Ferrazzi E, Speciani AF. Blind Analysis of Food-Related IgG Identifies Five Possible Nutritional Clusters for the Italian Population: Future Implications for Pregnancy and Lactation. Nutrients. 2019;11(5):1096.

3. Scott-Taylor TH, et al. Immunoglobulin G; structure and functional implications of different subclass modifications in initiation and resolution of allergy. Immun Inflamm Dis. 2018;6(1):13-33.

4. Vidarsson G, Dekkers G, Rispens T. IgG subclasses and allotypes: from structure to effector functions. Front Immunol. 2014;5:520.

5. Vaillaint AAJ, Vashisht R, Zito PM. (2020) Immediate Hypersensitivity Reactions. StatPearls Publishing, Treasure Island, FL. https://www.ncbi.nlm.nih.gov/books/NBK513315/ Accessed 20 Aug 2020.

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7. Ayass MA, Jabeen A, Nowshad G. Prevalence and Correlates of Immunoglobulin IgA Deficiency in Adult Outpatient Population. J. Allergy Clin. Immunol. Feb 2015;135(2); Supp AB93.

8. Gocki J, Bartuzi Z. Role of immunoglobulin G antibodies in diagnosis of food allergy. Postepy Dermatol Alergol. 2016;33(4):253-256.

9. Janeway CA Jr, et al. (2001) Immunobiology: The Immune System in Health and Disease, 5th edition. Garland Science, New York.

10. Usman N, Annamaraju P. (2020) Type III Hypersensitivity Reaction. StatPearls Publishing, Treasure Island, FL. https://www.ncbi.nlm.nih.gov/books/NBK559122/ Accessed 20 August 2020.

11. Dunkelberger J, Song W. Complement and its role in innate and adaptive immune responses. Cell Res. Dec 2009;20;34–50.

12. Markiewski MM, Lambris JD. The role of complement in inflammatory diseases from behind the scenes into the spotlight. Am J Pathol. 2007;171(3):715-727.

13. Carballo I, et al. Serum Concentrations of IgG4 in the Spanish Adult Population: Relationship with Age, Gender, and Atopy. PLoS One. 2016;11(2):e0149330.

14. Smoldovskaya O, et al. Allergen-specific IgE and IgG4 patterns among patients with different allergic diseases. World Allergy Organ J. 2018;11(1):35.

15. Neuendorf R, et al. Impact of Food Immunoglobulin G-Based Elimination Diet on Subsequent Food Immunoglobulin G and Quality of Life in Overweight/Obese Adults. J Altern Complement Med. Feb 2019; 25(2):241-248.

16. Popescu FD. Cross-reactivity between aeroallergens and food allergens. World J Methodol. 2015;5(2):31-50.

17. Hourihane JO, Knulst AC. Thresholds of allergenic proteins in foods. Toxicol Appl Pharmacol. 2005;207(2 Suppl):152-156.

18. Versluis A, et al. Reintroduction failure after negative food challenges in adults is common and mainly due to atypical symptoms. Clin Exp Allergy. 2020;50(4):479-486.

19. Gautier C, Charpin D. Environmental triggers and avoidance in the management of asthma. Journal of Asthma and Allergy. 2017;10:47-56.

20. Geroldinger-Simic M, et al. Birch pollen-related food allergy: clinical aspects and the role of allergen-specific IgE and IgG4 antibodies. J Allergy Clin Immunol. 2011;127(3):616-22.e1.

21. Agarwal S, Cunningham-Rundles C. Assessment and clinical interpretation of reduced IgG values. Ann Allergy Asthma Immunol. 2007;99(3):281-283.

22. Faria A, et al.  Food components and the immune system: from tonic agents to allergens.  Front Immunol. 2013;4: 102.

23. Anogeianaki A, et al. Vitamins and mast cells. Int J Immunopathol Pharmacol. 2010;23(4):991-996.

24. Burnett M, et al. Relationship of dog- and cat-specific IgE and IgG4 levels to allergic symptoms on pet exposure. J Allergy Clin Immunol: In Practice. 2013;1:350-3.

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Figure 1. Which foods should be re-introduced?

The results in figure A give no indication that certain legume reactions are IgE/IgG4-mediated. IgE-mediated foods should be avoided because their re-introduction may risk a Type I hypersensitivity reaction (anaphylaxis). The results in figure B clearly indicate that the re-introduction of green bean, kidney bean, and pinto bean may be contraindicated.

BIO in July 2020