Opinion

Classically, as we define reactions to antigens, either environmental or foods, we have broken the immune reaction down and divided them based on specific activity. This definition allows us to describe the difference between Type I IgE Medicated Hypersensitivity and Type II IgG mediated activity, and Type III driven by complement activation as well as Type IV Cell-Mediated Hypersensitivity. While these descriptions are not wrong, they are not the whole picture. While it is true IgE and IgG maintain distinct activity, it is also true that IgG, particularly type 1-3 will increase the activity of IgE[1]. Patterns of immune response can be seen for other reasons as well. For example, someone who is in general, more up regulated in terms of IgE reactions, may be low in sIgA. A decrease in sIgA creates a deficiency in a first line of defense, the 85% of the immune system that lines the mucosa. Because of this low level of defense or sIgA, the immune system works to compensate. One way the immune system will compensate is by up regulatingIgE activity, relying on a higher level of response in that pathway to overcome short comings created by low sIgA[2].When we look at various immunoglobulin’s responses together, rather than in isolation, we will get a deeper understanding into what is truly happening with immune function(Figure 1).

While IgE and complement are shown as distinct in the above figure, this is not always physiologically the case. Many studies show that complement is involved in IgE driven anaphylaxis and that IgG1 and IgG4 may also play a role. IgG is not limited to the action of delayed sensitivities, but can directly amplify IgE becoming a player in anaphylaxis[3].Other pathways of anaphylaxis involve complement alone, with no IgE. The Journal of Allergy and Clinical Immunology published in 2009 that complement is involved in the anaphylactic activation of the immune system to peanut, and other studies have shown the same to be true for allergic pathology in general[4].Further studies have demonstrated IgE-independent anaphylaxis. These pathways involved IgG4, complement, and total IgG[5,6].When these antibodies are measured contiguously, observation of amplification across immunoglobulin class, points to a result that is likely associated with more aggressive symptoms, increasing clinical value. Complement amplifies IgG reactions, which in turn, may increase the activity of IgE.

Complement and the complement system continue to demonstrate particular importance in allergies and human disease. Complement has 31 proteins and is involved not only in the lysis of bacteria and protecting humans from infectious microorganisms but also in its ability to drive anaphylatoxin which is produced in and responsible for allergies. C3d is a fragment of C3a anaphylatoxin which creates allergies. By measuring C3d you can measure whether C3a anaphylatoxin is being activated in response to various foods (Figure.2)

Complement is involved in producing a wheal-and-flare response in the skin, like immediate hypersensitivity responses found when induced by allergy extracts in the skin. Measuring complement helps to isolate allergic triggers that are not mediated by IgE. By measuring complement, the ability to isolate a distinct pathway by which a patient may have anaphylactic potential, is identified. This increases the sensitivity of IgE testing, and reduces false negatives.Complement, when bound to IgG, can increase its potential to increase histamine from 1000 to 10,000-fold[7].Complement will activate basophils known to release histamine and drive allergic or atopic conditions such as urticaria, angioedema and asthma(Table1).

Over the past 30 years, complement proteins have been cloned and sequenced. Complement-mediated tissue destruction occurs as part of the allergic process. By measuring complement we can detect underlying inflammatory mediators that augment the activity of IgG and IgE. Just as complement is measured to help diagnose many conditions, complement production specific to food can be looked at to know which dietary triggers are the most detrimental in relation to certain pathologies (Table 1). Identification of foods that trigger complement, allows for removal of foods, decreasing complement improving outcomes not only in allergies, but many other conditions as well.

In addition to certain IgG antibodies increasing reactivity, IgG4, when in the right ratio, can decrease risk of anaphylaxis. IgG4 increases as a way of developing tolerance to various allergies. Our body does not wish to remain anaphylactic to foods and so our immune system works to overcome the issue. IgG4 has a distinct mechanism of action, very different from subtype’s I-III. IgG4 is smaller and has more thiol groups allowing it to easily slot into receptor sites where IgE binds. By doing this it blocks IgE from binding sites, keeping IgE from triggering degranulation or a mast cell or eosinophil resulting in release of histamine. Therapies designed to desensitize allergens, in the form of injections or sublingual drops are intended to increase IgG4, not in fact decrease IgE. The mechanism by which desensitization therapies work is to increase IgG4 over IgE, blocking its ability to cause anaphylaxis. By looking at IgG4 distinct from the rest of subtypes of IgG, you will be able to detect if tolerance has been achieved [8].

If IgG4 gets high enough, it can result in other issues. High levels of IgG4 precipitate out into tissue causing structural and histologicalproblems. IgG4 antibodies are known to infiltrate into tissue such as the thyroid, resulting in thyroiditis, the esophagus resulting in eosinophilic esophagitis and the skin resulting in eczema. The ovaries and prostate are also at risk of IgG4 damage as it likes to lodge in reproductive tissue decreasing fertility and hormonal balance[9] (Table 2).

Figure 1: Types of Hypersensitivity.

Figure 2: This figure shows that C3d is a byproduct of activation of C3a, an analphyltoxin involved in increasing risk of anaphylactic symptoms. 

Table 1: Other conditions that complement is involved in, but not limited to.

Table 2: IgG4 Conditions.

1. Shakoor Z, AlFaifi A, AlAmro B, AlTawil LN, AlOhaly R (2016)Prevalence of IgG-mediated food intolerance among patients with allergic symptoms. Ann Saudi Med 36: 386-390.
2. Calderon T, Ferrero M, Marino G, Cordoba A, Beltramo D, et al. (2010) Meat-specific IgG and IgA antibodies coexist with IgE antibodies in sera from allergic patients: clinical association and modulation by exclusion diet. J Biol Regul Homeost Agents 24: 261-271.
3. Bergamaschini L, Santangelo T, Faricciotti A, Ciavarella N, Mannucci PM, et al.(1996) Study of complement-mediated anaphylaxis in humans. The role of IgG sublasses in the complement-activating capacity of immune complexes. J Immunonol156: 1256-1261.
4. Khodoun M, Strait R, Orekov T, Hogan S, Karasuyama H, et al. (2009) Peanuts can contribute to anaphylactic shock by activiating complement. J Allergy ClinImmunol 123: 342-351.
5. Finkelman FD, Khodoun MV, Strait R(2016) Human IgE-independent systemic anaphylaxis. J Allergy ClinImmunol 137: 1674-1680.
6. Muñoz-Cano R, Picado C, Valero A, Bartra J (2016) Mechanisms of Anaphylaxis Beyond IgE. J InvestgAllergolClinImmunol 26: 73-82
7. Dempsey PW, Allison ME, Akkaraju S, Goodnow CC, Fearon DT (1996)C3d of complement as a molecular adjuvant: bridging innate and acquired immunity.Science 271: 348-350
8. (1996, Feb 1). Study of complement-mediated anaphylaxis in humans. The role of IgG subclasses (IgG and/or IgG4) in the ccomplementactivating capacity of immune complexes. J Immunol 156: 1256-61.
9. Ebbo M , Grados A, Bernit E, Vely F , Boucraut J, et al. (2012) Pathologies Associated with Serum IgG4 Elevation. International Journal of Rheumatology 2012:1-6.