Is IgE‐mediated hypersensitivity an autoimmune disease?

Abstract

It is now weO established that IgE plays a key role in the complex interaction between humoral and cellular components of the hypersensitivity response in allergy. A pre-requisite to such a role is the binding of IgE to high-affinity Fcreceptors (Fc,R) on mast cells and basophils and the subsequent cross-linking of receptorbound IgE molecules witi\ the allergen (antigen). Cross-linking of membrane-bound IgE antibodies can also be effected in vitro with allergen, concanavalin A (binds to the carbohydrate moieties of IgE) and heterologous antiIgE antiserum. The pharmacokinetics and dynamics of mediator production by anti-IgE or its F(ab')2 fragment are relatively comparable to release induced by allergen (for review see 17). Panicularly striking is the overlap between the concentrations of antigen (1-3 ng/ml) and antiIgE (3 ng/ml) required for optimum release of histamine from human basophils. Cross-linking of mast cell-and basophil-bound IgE by a specific ligand (allergen or anti-IgE) initiates a chain of events culminating in mediator release. These include activation of proteolytic enzymes, rise in cAMP concentration, increased phospholipid metabolism, mobilisation and influx of calcium ions, generation of arachidonic acid metabolites and protein phosphorylation. Anti-IgE antisera have, therefore, been (Extensively utilised in elucidating the mechanism of IgE-dependent mediator release from basophils and mast cells. Injection of anti-IgE antibody into human skin produces a mast cell-dependent weal and flare response followed by a latephase response mediated by eosinophils and neutrophils. That these inflammatory cells are activated (i.e. show enhanced receptor expression and effector function) by histamine and leukotrienes (LTB^) liberated by an IgE-dependent mechanism has been clearly demonstrated using an in vitro system in which basophils were challenged with anti-IgE and changes in the activity of bystander eosinophils and neutrophils were recorded (17).It is, therefore, not surprising that there has recendy been a surge of interest in elucidating the pathophysiological role of autoantibodies to IgE (for a thorough review see 22). The demonstration of these autoantibodies in the sera of allergic patients raises some very important questions, the most critical of which is whether IgE-mediated hypersensitivity can be caused by autoimmunity. The purpose of this contribution is to bring into focus the biological significance of circulating autoanti-IgE antiglobulins and their clinical implications. Data from experimental animal models will also be incorporated whfere appropriate.

The Recognition of a Recombinant Human Fcε Fragment by the Subclasses of IgG Autoanti-lgE: Disproportional Subclass Distribution of Complexed Autoantibody

“…Fey) for effector function molecules (i.e. Clq and FcyR) [3], However, the efficiency with which such effector functions are con ducted, or indeed whether they occur or not, would largely depend on the subclass profile of the complexed IgG antiIgE. The general consensus from most published studies is that the IgGl and IgG3 subclasses are recognized by Clq and all three FcyRs (i.e.…”

“…Circulating IgG autoanti-IgE is found in a large pro portion of individuals with allergic asthma [1,2] where it is suggested to be potentially involved in modulating IgEmediated hypersensitivity [3]. We have recently shown, us ing a series of overlapping recombinant human e-chain peptides, that IgG anti-IgE antibodies recognize at least two autoantigenic epitopes located within the Ce2 (i.e.…”

“…uncomplexed) anti-IgE, since anti-IgE complexed to IgE escapes detection by the anti-IgE antibody assay [3], The presence of IgE/IgG anti-IgE complexes in the sera of atopic patients was originally demonstrated when heating sera at 56°C for 30 min resulted in a striking increase in IgG anti-IgE titre [9]; an effect which was interpreted as being due to disruption of the heat-labile autoantigcnic site on IgE and the consequent detachment of anti-IgE molecules. Since then the presence of such complexes in the sera of atopic patients has been confirmed using a range of chromatographic procedures [10], IgG anti-IgE may potentially be involved in the remov al of IgE-allergen complexes via the complement receptor (CR1) on red cells and by activating one or more of the three classes of IgG Fc receptors (FcyR) found on phago cytic cells [11].…”

Disproportional Distribution of Isotype and Non-lsotype-Specific IgG Subclass Anti-lgE Autoantibodies in Human Cord Serum

“…In it self, cord serum is interesting because the IgG is mainly of maternal origin [27] and the IgE levels are very low [28] minimizing problems encountered by immunocomplexed a-E Ab [1, 6,8,10]. In addition, it seems important to estab lish suitable methods that discriminate specificities o f a-E Ab before any physiological roles can be ascribed to IgG subclass a-E Ab in cord serum.…”

“…6,8]. Increased levels of IgG a-E Ab have been demonstrated in atopic [I, 2,[8][9][10] and parasiteinfested individuals [6. 11,12] also with regard to individual IgG subclasses [13 16].…”