The mechanisms of therapeutic action of IVIg are still unclear in most autoimmune and inflammatory diseases. IVIg have been shown to bind to a variety of human proteins including BAFF, amyloid beta peptide and GM-CSF. It has been suggested that this autoreactivity could contribute to the therapeutic immunomodulatory effects of IVIg. In this work, we showed that native IgG purified from plasma under non-denaturing conditions were much less autoreactive than IVIg. However the native IgG autoreactivity with BAFF, amyloid beta peptide and GM-CSF was significantly increased by short incubation under the slightly denaturing conditions used during industrial plasma fractionation. We conclude that the relatively mild conditions used in industrial plasma fractionation are sufficiently denaturing to activate a significant amount of cryptic autoreactive plasma IgG which could be involved not only in the therapeutic immunomodulatory effects of IVIg but also in the adverse "allergic" reactions often observed in IVIg-infused patients.