Antigen-specific activation of autoreactive B cells in normal human individuals.

The purpose of our study was to determine if normal human B cells can be activated to autoantibody production using an antigen-specific system. For this purpose we investigated the in vitro antibody response to the autoantigen thyroglobulin (Tg) employing soluble or insolubilized Tg (i-Tg) and a B cell growth and differentiation factor (BDGF) to stimulate lymphocytes from healthy individuals. Similar experiments were carried out with the xenoantigen ovalbumin (OVA). The presence of Tg and OVA-reactive B cells was demonstrable by stimulating lymphocytes from tonsil, spleen and blood with a combination of pokeweed mitogen and formalinized Staphylococcus aureus: mitogen stimulation resulted in the generation of IgM anti-Tg and IgM anti-OVA antibody-forming cells (AFC) as detected in a spot enzyme-linked immunosorbent assay. Soluble antigen failed to induce autoantibody production. However, i-Tg or i-OVA did activate normal tonsil and spleen B cells. Differentiation of these activated B cells to IgM AFC required the presence of BGDF, derived from a human T hybrid clone. Preincubation experiments with the particulate autoantigen show that a specific activation signal is provided by the antigen which subsequently renders the B cells responsive to BGDF. i-Tg-dependent stimulation of B lymphocytes could be inhibited by adding free Tg to the cultures; the same applied to i-OVA stimulation. We conclude that the normal human B cell repertoire contains B cells that can be activated to autoantibody production by the autoantigen Tg if the necessary T cell signals are provided. Thus, these B cells are not in an inherently anergic state. Similar mechanisms seem to play a role in the activation of B cells responding to i-OVA and i-Tg.