Potential Mechanisms for IgG4 Inhibition of Immediate Hypersensitivity Reactions

Abstract

IgG4 is the least abundant IgG subclass in human serum, representing less than 5 % of all IgG. Increases in IgG4 occur following chronic exposure to antigen and are generally associated with states of immune tolerance. In line with this, IgG4 is regarded as an anti-inflammatory antibody with a limited ability to elicit effective immune responses. Furthermore, IgG4 attenuates allergic responses by inhibiting the activity of IgE. The mechanism by which IgG4 inhibits IgE-mediated hypersensitivity has been investigated using a variety of model systems leading to two proposed mechanisms. First by sequestering antigen, IgG4 can function as a blocking antibody, preventing cross-linking of receptor bound IgE. Second IgG4 has been proposed to co-stimulate the inhibitory IgG receptor FcγRIIb, which can negatively regulate FcεRI signaling and in turn inhibit effector cell activation. Recent advances in our understanding of the structural features of human IgG4 have shed light on the unique functional and immunologic properties of IgG4. The aim of this review is to evaluate our current understanding of IgG4 biology and reassess the mechanisms by which IgG4 functions to inhibit IgE-mediated allergic responses.

Changes in Phosphoinositide Turnover in Airway Smooth Muscles and Blood Lymphocytes in Ova Sensitized Guinea Pig Model of Asthma

“…33,34 Allergic sensitization results from the formation of antigen-specific IgE in response to common inhalant allergens. 35,36 In our present study, on day 9 after sensitization the animals in the experimental group showed a significant positive response in i.d. which indicate that allergen-specific IgE were synthesized in enough amounts which could respond to the antigen as early as day 9.…”

Ratios of specific IgG4 over IgE antibodies do not improve prediction of peanut allergy nor of its severity compared to specific IgE alone

“…32 Recently, the LEAP intervention study 25 showed that in young children in the early introduction intervention group exposed to peanut protein, decreased development of peanut allergy was associated with increased IgG 4 levels and IgG 4 /IgE ratios. 20 We observed that in patients with peanut allergy, similar to IgE, specific IgG and IgG 4 levels against peanut Ara h 2 were higher in allergic than tolerant subjects and increased with symptom severity. This would inhibit IgE-facilitated antigen presentation and activation of effector cells and could thus explain why some sensitized subjects do not have allergic symptoms to peanut.…”

“…With the advent of component-resolved diagnosis (CRD), the potential of serum IgE testing to distinguish between tolerance and allergy, and beyond that, to better assess the risk of severe reactions, has significantly increased. 20 Whether identical epitopes for IgE, IgG, and IgG4 are a prerequisite for blocking activity is still not fully understood. 9 More recently, IgE against Ara h 6 has been reported to perform similarly well as Ara h 2 as biomarker for peanut allergy.…”

Schistosoma mansoni‐specific immune responses and allergy in Uganda

“…Typically, these cytokines influence the profile of antibodies involved in helminth infection and allergy. Helminth‐induced IL‐10 may drive immunoglobulin class switching to IgG4 which, akin to the Th2 cytokine‐induced polyclonally stimulated IgE, may inhibit development of allergen‐specific effector responses, leading to inverse helminth‐allergy associations. Conversely, helminth‐induced protein‐specific IgE may promote strong, cross‐reactive helminth‐ and allergen‐specific responses, resulting in positive helminth‐allergy associations …”