Conditional autoimmunity mediated by human natural anti-Fc epsilon RI alpha autoantibodies?

Natural antibodies provide an early defense mechanism against pathogens, sh ow a frequent self-reactivity, and are present throughout life. Two questio ns concern the physiological control of self-reactivity and the pathogeneti c link to autoimmune disease. Here we propose a concept of conditional auto immunity involving natural antibodies against the alpha chain of the high-a ffinity receptor for IgE (Fc epsilon RI alpha). Like other natural antibodi es, anti-Fc epsilon RI alpha antibodies are found in sera of healthy donors . We now report the first human recombinant anti-Fc epsilon RI alpha autoan tibodies isolated by repertoire cloning from a human tonsillar IgM library. These high-affinity antibodies recognize Fc epsilon RI alpha on cells and trigger histamine release from freshly isolated blood basophils. However, t he latter effect requires IgE removal from the Fc epsilon RI. The same cond itional histamine release is seen when using sera from individual normal do nors and affinity-purified anti-Fc epsilon RI alpha antibodies isolated fro m multidonor therapeutic IgG preparations. We propose that such anti-Fc eps ilon RI alpha antibodies can become pathogenic and that this is dependent o n the state of occupancy of the Fc epsilon RI alpha by its natural ligand I gE. We suggest that an imbalance between Fc epsilon RI alpha occupancy and natural anti-Fc epsilon RI alpha antibodies may be implicated in the pathog enesis of autoimmune urticaria.