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.