Anti-FcεRIα autoantibodies in autoimmune-mediated disorders. Identification of a structure-function relationship

Abstract

Anti-FcεRIα autoantibodies (autoAbs) occur and may be of pathogenetic relevance in a subset of chronic urticaria (CU) patients. To analyze the prevalence and magnitude of the humoral anti-FcεRIα response in cohorts of CU patients compared with individuals suffering from classic skin-related (auto)immune diseases, we developed an ELISA system for the measurement of anti-FcεRIα autoAbs in non-fractionated serum samples. Results obtained using this assay correlated well with those generated by Western blotting. We found IgG anti-FcεRIα autoreactivity in 38% of CU patients but not in atopic dermatitis patients, psoriatics, or healthy individuals. We frequently detected anti-FcεRIα autoAbs in pemphigus vulgaris (PV, 39%), dermatomyositis (DM, 36%), systemic lupus erythematosus (SLE, 20%), and bullous pemphigoid (BP, 13%). While the autoAb titers in DM, SLE, BP, and PV were similar to those encountered in CU patients, only anti-FcεRIα+ CU serum specimens displayed pronounced histamine-releasing activity. The anti- FcεRIα autoAbs in CU patients belong predominantly to the complement- fixing subtypes IgG1 and IgG3, whereas in DM, PV, and BP, they were found to be mainly of the IgG2 or IgG4 subtype. Complement-activating properties of anti-FcεRIα autoAbs can indeed be of pathogenetic relevance, because C5a receptor blockade on basophils as well as decomplementation reduced drastically the histamine-releasing capacity of most anti-FcεRIα-reactive CU sera. As a consequence, therapeutic efforts in CU should aim at altering not only the quantity but also the complement-activating properties of IgG anti-FcεRIα autoAbs.