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In healthy individuals, a substantial proportion of circulating Abs exhibit polyreactivity and self-reactivity. These Abs are referred to as natural autoantibodies (NAAs). As part of the innate immunity, NAAs play an important role in eliminating pathogens. However, inherent to their poly/autoreactivity is the potential for NAAs to differentiate to high-affinity autoantibodies during an immune response. We recently generated site-directed transgenic mice that express a prototypic NAA, ppc1-5, which binds a variety of self- and non-self-Ags including DNA and phosphocholine. We have shown previously that B cells expressing the ppc1-5 NAA are positively selected during their primary development. In this study, we demonstrate that following immunization with the T-dependent Ag, phosphocholine conjugated to keyhole limpet hemocyanin, ppc1-5 NAA B cells mounted a quick IgM Ab response and entered germinal centers, but they failed to differentiate to IgG-producing cells during late primary and memory responses. Hybridomas and cDNA clones derived from the immunized mice included many IgM NAA-producing cells, but IgG NAA clones were extremely rare. Instead, many of the IgG B cells replaced their IgH transgene with an endogenous V(H) gene and produced non-autoreactive Abs. These results indicate that although NAA B cells are positively selected in the preimmune repertoire and can participate in early IgM Ab response, they are subjected to regulatory mechanisms that prevent them from developing to high-affinity IgG autoantibody production. This would explain, at least in part, why NAAs do not cause autoimmunity in most individuals.

Exclusion of Natural Autoantibody-Producing B Cells from IgG Memory B Cell Compartment during T Cell-Dependent Immune Responses