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

TLDR

Anti‑FcepsilonRIalpha autoantibodies occur and may be pathogenetic in a subset of chronic urticaria patients. The study aimed to determine the prevalence and magnitude of the humoral anti‑FcepsilonRIalpha response in chronic urticaria versus other skin‑related autoimmune diseases. An ELISA assay for anti‑FcepsilonRIalpha autoantibodies was developed and validated against Western blotting. IgG anti‑FcepsilonRIalpha autoantibodies were present in 38 % of chronic urticaria patients and in 39 % of pemphigus vulgaris, 36 % of dermatomyositis, 20 % of systemic lupus erythematosus, and 13 % of bullous pemphigoid, with similar titers but only chronic urticaria sera inducing strong histamine release, predominantly via IgG1/3 complement‑activating subtypes, and complement blockade markedly reduced this activity, suggesting therapy should target both antibody levels and complement activation.

Abstract

Anti-FcepsilonRIalpha 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-FcepsilonRIalpha 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-FcepsilonRIalpha autoAbs in nonfractionated serum samples. Results obtained using this assay correlated well with those generated by Western blotting. We found IgG anti-FcepsilonRIalpha autoreactivity in 38% of CU patients but not in atopic dermatitis patients, psoriatics, or healthy individuals. We frequently detected anti-FcepsilonRIalpha 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-FcepsilonRIalpha+ CU serum specimens displayed pronounced histamine-releasing activity. The anti-FcepsilonRIalpha 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-FcepsilonRIalpha 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-FcepsilonRIalpha-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-FcepsilonRIalpha autoAbs.