Conditional autoimmunity mediated by human natural anti‐FcεRIα autoantibodies?

Abstract

Natural antibodies provide an early defense mechanism against pathogens, show a frequent self-reactivity, and are present throughout life. Two questions concern the physiological control of self-reactivity and the pathogenetic link to autoimmune disease. Here we propose a concept of conditional autoimmunity involving natural antibodies against the alpha chain of the high-affinity receptor for IgE (Fc(epsilon)RIalpha ). Like other natural antibodies, anti-Fc(epsilon)RIalpha antibodies are found in sera of healthy donors. We now report the first human recombinant anti-Fc(epsilon)RIalpha autoantibodies isolated by repertoire cloning from a human tonsillar IgM library. These high-affinity antibodies recognize Fc(epsilon)RIalpha on cells and trigger histamine release from freshly isolated blood basophils. However, the latter effect requires IgE removal from the Fc(epsilon)RI. The same conditional histamine release is seen when using sera from individual normal donors and affinity-purified anti-Fc(epsilon)RIalpha antibodies isolated from multidonor therapeutic IgG preparations. We propose that such anti-Fc(epsilon)RIalpha antibodies can become pathogenic and that this is dependent on the state of occupancy of the Fc(epsilon)RIalpha by its natural ligand IgE. We suggest that an imbalance between Fc(epsilon)RIalpha occupancy and natural anti-Fc(epsilon)RIalpha antibodies may be implicated in the pathogenesis of autoimmune urticaria.

A High-Affinity Natural Autoantibody from Human Cord Blood Defines a Physiologically Relevant Epitope on the FcεRIα

“…The anti-phage Abs (raised in our laboratory) were conjugated with HRP (Sigma-Aldrich; P-8375) as previously described (31). LTM␣15 and LTM␣35 were previously produced in our laboratory as IgG Abs (11). Human monoclonal IgE-SUS11 was purified (29) from hybridomas generated in our laboratory (32).…”

“…1). UG␣8, and an Ab identical with LTM␣15, previously described as UM␣16, were isolated from libraries generated from blood of CU patients (11). The most similar Ab to CBM␣8 is LTM␣35.…”

“…The most similar Ab to CBM␣8 is LTM␣35. The LTM␣15 and LTM␣35 Abs were previously isolated from a library constructed from tonsils of healthy children (11). Among the human anti-Fc⑀RI␣ Abs isolated to date, CBM␣8 had a unique CDR3 of the H chain.…”

“…Using phage display technology, we have recently isolated autoantibodies to the high-affinity IgE receptor (Fc⑀RI␣) from tonsils of healthy children and from blood of chronic urticaria (CU) 3 patients (11). These widespread Abs are particularly interesting because they cross-link the Fc⑀RI␣ on basophils leading to cell degranulation and release of inflammatory mediators in vitro and may thus have a role in the pathogenesis of CU (12).…”

“…The interaction between IgE and Fc⑀RI␣ is of high affinity; consequently, the autoepitope on the receptor is physiologically masked by IgE. Occasional dissociation of IgE from the receptor has been suggested (11) and could lead to an immune response and selection of specifically reacting B lymphocytes. According to current knowledge, Abs of predetermined specificities mutate and are selected for increased affinity, but against selfrecognition.…”