Natural anti-FcepsilonRIalpha autoantibodies isolated from healthy donors and chronic idiopathic urticaria patients reveal a restricted repertoire and autoreactivity on human basophils.

The role of autoantibodies against the alpha-subunit of the human high-affinity IgE receptor (FcepsilonRIalpha) in the pathogenesis of chronic idiopathic urticaria (CIU) is controversial. We have shown that these antibodies are widespread, apparently non-pathogenic and belong to the natural antibody repertoire. To clarify this controversy, we constructed antibody libraries from both healthy donors and CIU patients with active disease. Here we describe the first three high affinity IgM anti-FcepsilonRIalphaautoantibodies isolated from normal and urticaria libraries. Sequence analysis revealed germline VH in both cases paired with a slightly mutated VL, thus supporting their classification as natural antibodies. Strikingly, one major IgM clone was present in both CIU patients and normal donors. The anti-FcepsilonRIalpha autoantibodies recognize FcepsilonRIalpha on cells, but are non-anaphylactogenic on blood basophils, except when IgE is removed from the receptor. Based on their functional activities we propose a concept of "conditional autoimmunity" where natural anti-FcepsilonRIalphaautoantibodies can become pathogenic dependent on the state of occupancy of the FcepsilonRIalpha by its natural ligand IgE.