ANTIGEN-RECEPTOR CROSS-LINKING INDUCES PERITONEAL B-CELL APOPTOSIS IN NORMAL BUT NOT AUTOIMMUNITY-PRONE MICE

Background: Programmed cell death (apoptosis) is an essential process in the development of various tissues and seems to be involved in the elimination of self-reactive immature T and B lymphocytes when they interact with self antigens. Indeed, signaling through the antigen receptor of immature T cells induces their apoptotic cell death. Immature B cells have also been shown to be eliminated when they interact with antigens, although the involvement of apoptosis has yet, to be demonstrated. In contrast, little is known about the elimination of mature lymphocytes upon interaction with antigens. We have previously demonstrated that Ly1 B cells in the peritoneal cavity of transgenic mice undergo apoptotic cell death upon interaction with antigens. As Ly1 B cells constitute a B-cell lineage distinct from conventional B cells, it is important to know whether conventional B cells also undergo apoptosis upon antigen-receptor cross-linking. Results: Our experiments shaw that, in vivo, strong cross-linking of cell-surface immunoglobulins induced apoptotic death of normal, mature B cells in the peritoneal cavity, regardless of whether they were conventional or Ly1 B cells. The same treatment did not kill, but rather activated, B cells in bcl-2-transgenic, apoptosis-resistant mice. Peritoneal B cells from autoimmune-disease-prone New Zealand mouse strains were also found to be resistant to cell death induced by surface immunoglobulin cross-linking. Conclusion: Self-reactive B cells are eliminated by the binding of antigen at both mature and immature stages. B-cell activation appears to require, in addition to antigen binding, a second signal that induces expression of rescue molecules such as the bcl-2 gene product. Resistance to B-cell apoptosis induced by antigen receptor cross-linking may play a crucial role in the production of autoantibodies and in the pathogenesis of the autoimmune diseases found in the strains of mice used here.