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

Abstract

Circulating IgG autoanti-IgE is detectable in a large proportion of individuals with allergic asthma where it is suggested to be potentially involved in the removal of IgE-allergen complexes. Since such a putative role will largely be determined by the subclass profile of complexed (i.e. IgE-bound) IgG anti-IgE, a study was undertaken to determine the subclass distribution of complexed IgG anti-IgE antibody in the sera of asthmatic patients. The study exploits the heat-labile property of IgE by heating (30 min at 56°C) serum to liberate bound anti-IgE, pre- and post-heated sera are then assayed for IgG subclass anti-recombinant human Fcε (rFcε) activities by ELISA and any heat-induced increase in antibody activity is taken as a measure of complexed anti-IgE. This has revealed a disproportionately high amount of IgG4 in complexed (but not free) IgG anti-IgE. The propensity of IgG4 to form complexes with IgE has important biological consequences, particularly with regard to the activation of C1q and FcγR by other subclasses.

Domain-Specific Anti-IgE Antibodies Interfere with IgE Binding to FcεRII

“…free anti-IgE antibodies [8], This makes their measurement difficult [31] and may explain why there is a general lack o f correlation between antibody levels or IgE levels and clinical status [7]. Dissolution o f immune complexes by heating recently dem onstrated a disproportionate increase in the amount of IgG4 in complexed (but not free) IgG anti-IgE [32], However, a recent paper indicating an elevation in the IgG 1 and lgG4 anti-IgE response in atopies compared to controls failed to show a correlation between isotype and disease severity or duration [33]. The isotype of anti-IgE antibodies may still be of potential pathological relevance since the mechanisms of removal of immune complexes from the circulation may well depend on the isotype distribution [34], However, in view of our results indicating opposing functions of antiIgE mAbs related to their domain specificity, it now be comes important to type human anti-IgE autoantibodies both in free and complexed form according to their Call epitope specificities in order to assess the ratio o f these dif ferent anti-IgE antibodies in different patient groups.…”

IgE-Dependent Activation of T cells by Allergen in Atopic Dermatitis: Pathophysiologic Relevance

“…In some experiments, the culture medium contained serum that was either unmodified or heated at 561C for 60 min, conditions that irreversibly denature IgE amongst other molecules (Geha et al, 1985;Ishizaka et al, 1986), but not IgG (Shakib et al, 1992). Atopic sera specifically depleted of IgE were prepared by immunoprecipitation using protein G Dynabeads (Dynal, Bromborough, UK).…”

In vitro basophil histamine‐releasing activity of circulating IgG1 and IgG4 autoanti‐IgE antibodies from asthma patients and the demonstration that anti‐IgE modulates allergen‐induced basophil activation

“…asthma) [1][2][3][4] and parasite (hookworm and schistosomes) infections [5]. Our studies of human IgG anti-lgE have mostly focused on allergic asthma [3][4][5][6][7], where IgG anti-lgE is highly prevalent [1][2][3][4]. In terms of subclass distribution, the IgG anti-lgE activity is restricted to IgGl and lgG4, with IgG4 displaying a disproportionately high percentage of the activity [I], particularly in lgE:anti-IgE complexes [7].…”

“…Our studies of human IgG anti-lgE have mostly focused on allergic asthma [3][4][5][6][7], where IgG anti-lgE is highly prevalent [1][2][3][4]. In terms of subclass distribution, the IgG anti-lgE activity is restricted to IgGl and lgG4, with IgG4 displaying a disproportionately high percentage of the activity [I], particularly in lgE:anti-IgE complexes [7]. The subclass nature of IgG anti-lgE is of potential physiological and pathological relevance because IgG subclasses exhibit considerable variation in their ability to Correspondence: Dr F. Shakib, Department of Immunology, University Hospital, Queen's Medieal Centre, Nottingham NG7 2UH.…”