Allergen-specific IgE levels and the ability of IgE-allergen complexes to cross-link determine the extent of CD23-mediated T-cell activation

Abstract

Background: CD23 mediates IgE-facilitated allergen presentation and subsequent allergen-specific T-cell activation in allergic patients. Objective: We sought to investigate key factors regulating IgEfacilitated allergen presentation through CD23 and subsequent T-cell activation. Methods: To study T-cell activation by free allergens and different types of IgE-Bet v 1 complexes, we used a molecular model based on monoclonal human Bet v 1-specific IgE, monomeric and oligomeric Bet v 1 allergen, an MHC-matched CD23-expressing B-cell line, and a T-cell line expressing a human Bet v 1-specific T-cell receptor. The ability to cross-link Fcε receptors of complexes consisting of either IgE and monomeric Bet v 1 or IgE and oligomeric Bet v 1 was studied in human FcεRI-expressing basophils. T-cell proliferation by monomeric or oligomeric Bet v 1, which cross-links Fcε receptors to a different extent, was studied in allergic patients' PBMCs with and without CD23-expressing B cells. Results: In our model non-cross-linking IgE-Bet v 1 monomer complexes, as well as cross-linking IgE-Bet v 1 oligomer complexes, induced T-cell activation, which was dependent on the concentration of specific IgE. However, T-cell activation by cross-linking IgE-Bet v 1 oligomer complexes was approximately 125-fold more efficient. Relevant T-cell proliferation occurred in allergic patients' PBMCs only in the presence of B cells, and its magnitude depended on the ability of IgE-Bet v 1 complexes to cross-link CD23. Conclusion: The extent of CD23-mediated T-cell activation depends on the concentration of allergen-specific IgE and the cross-linking ability of IgE-allergen complexes.

The role of IgE, IgG, and IgA in tolerance, sensitization, and targeted treatment of allergic disease

“…These findings suggest that the number of IgE molecules bound per allergen may play an essential role in this complex formation and binding. This was confirmed recently in a study by Villazala-Merino et al 70 where non-FcεRI cross-linking monoclonal IgE-monomeric allergen complexes, i.e. (one IgE molecule binding two Bet v1 molecules) could enhance T cell activation.…”

Filling the Antibody Pipeline in Allergy: PIPE Cloning of IgE, IgG1 and IgG4 against the Major Birch Pollen Allergen Bet v 1

“…However, the formation of allergen multimers would not only theoretically allow crosslinking of monoclonal antibodies [ 8 ], but was recently shown in detail in a study with Timothy grass pollen allergen [ 48 ]. Recent degranulation studies with an engineered Bet v 1 trimer confirm this notion [ 44 ]. Additional studies of our group with monoclonal antibodies against the major cow’s milk allergen BLG confirm these findings [ 49 ].…”

“…The findings of our internalisation studies were rather surprising: Bet v 1 internalisation appeared to be strictly antibody-dependent in the case of U937 monocytes, and unspecific and antibody-independent in the case of RPMI-8866 B cells. Based on the nature of these cell types and previous findings in B cells showing their IgE-dependent allergen internalisation and presentation to T cells, we would have assumed opposite results [ 44 , 45 , 46 ]. To our knowledge, only one study exists, which investigates Bet v 1 internalisation by monocytes and B cells [ 47 ].…”

The role of IgE, IgG, and IgA in tolerance, sensitization, and targeted treatment of allergic disease

“…Shamji validated the IgE-FAB assay and showed that serum IgE-FAB increased in a time-and dose-dependent fashion after grass pollen AIT 119,120 and correlated more closely with clinical response than accompanying elevated IgG4 levels This raised the possibility for IgE-FAB inhibition to predict individual responses to AIT 105 . Such blocking antibodies could also prevent captured allergen from stimulating IgE-producing cells thereby reducing boosts of IgE production caused by allergen exposure 70,121,122 .…”