Natural autoantibodies and complement promote the uptake of a self antigen, human thyroglobulin, by B cells and the proliferation of thyroglobulin-reactive CD4(+) T cells in healthy individuals

Serum from normal individuals contains substantial amounts of natural antib odies (NA) capable of recognizing self antigens. However, the physiological implications of this autoreactivity remain unclear. We have examined the r ole of self-reactive NA and complement in mediating the uptake of human thy roglobulin (Tg) by human peripheral B cells in reconstituted whole blood. S ignificant binding of fluorescein isothiocyanate-conjugated-Tg to B cells w as observed, and absorption of Tg-reactive antibodies from serum markedly r educed this uptake, as did inactivation of serum complement or blockade of complement receptor types 1 (CR1, CD35) and 2 (CR2, CD21). T cell responsiv eness to Tg was examined in a preparation of peripheral blood mononuclear c ells (PBMC) cultured in the presence of autologous serum. A subset of CD4() T cells exhibited a dose-dependent proliferative response to Tg, which wa s strongly inhibited by complement inactivation and by immunoabsorption of Tg-reactive antibodies. Furthermore, this T cell response was abrogated by depletion of B cells from the PBMC culture. These data imply that uptake of complement-opsonized Tg/ anti-Tg complexes and subsequent presentation of Tg by B cells are prerequisites for the proliferation of Tg-reactive CD4(+) T cells, suggesting a novel role for natural autoantibodies and complement in the regulation of autoreactivity under physiological conditions.