Dermal Mast Cell Activation by Autoantibodies Against the High Affinity IgE Receptor in Chronic Urticaria

Previous studies identified autoantibodies against the IgE high affinity receptor α -chain, Fc ϵ RI α , in sera of selected patients with severe chronic idiopathic urticaria. We have now determined the incidence of anti-Fc ϵ RI α autoantibodies in a group of 163 patients. Intradermal injection of autologous serum caused skin reactions indicative of mast cell degranulation in 98 (60%) patients. Based on histamine release from IgE-sensitized and nonsensitized basophil leukocytes of healthy donors, we detected anti-Fc ϵ RI α autoantibodies in sera from 38 (23%) urticaria patients and evidence for anti-IgE antibodies in a further nine patients. The sera that released histamine from basophils induced histamine release (4−34%, n=12) from mast cells in incubated skin slices. Protein-G affinity chromatography of sera demonstrated that mast cell histamine release was IgG-mediated. Preincubation of sera or the IgG fraction with a recombinant α -chain of Fc ϵ RI α inhibited histamine release from mast cells and basophils. Further studies with the mouse anti-human Fc ϵ RI α antibody 29C6 showed that mast cells and basophils were similarly sensitive to IgG-mediated direct cross-linking of Fc ϵ RI α , with 0.01–1.0 μ /ml 29C6 evoking histamine release in each case. These studies demonstrate that circulating levels of anti-Fc ϵ RI α autoantibodies mediate histamine release from skin mast cells in vitro and, taken together with in vivo evidence of mast cell degranulation following intradermal injection of autologous serum, support the concept that anti-Fc ϵ RI α autoantibodies are relevant to the pathogenesis of severe chronic urticaria in about 25% of patients.