Bcl-2 and Fas, molecules which influence apoptosis. A possible role in systemic lupus erythematosus?
Polyclonal B cell activation and the production of antibodies against a variety of autoantigens are features of systemic lupus erythematosus (SLE). Autoreactive B cells are found in healthy individuals but their numbers are probably regulated by cell death, after a few days, in the absence of proliferative stimuli. The process which achieves this regulation is known as apoptosis or programmed cell death. It has been postulated that in SLE patients dysfunction of apoptosis could result in the inappropriate longevity of autoreactive B cells, allowing autoantibody levels to reach pathogenic thresholds. This hypothesis has arisen as a result of studies revealing links between autoimmunity and two molecules which influence apoptosis. These are bcl-2 which enhances cell survival by inhibiting or delaying apoptosis and Fas, a cell surface molecule involved in the induction of apoptosis. Transgenic mice over expressing bcl-2 in their B cells showed polyclonal B cell expansion and their B cells showed extended survival in vitro. After a few months these mice developed an autoimmune syndrome resembling SLE. Mice that carry the lpr disorder have defects in the Fas gene. These mice, which do not express functional Fas molecules, suffer from an SLE-like autoimmune syndrome. Thus inappropriate expression of both bcl-2 and Fas can result in SLE-like autoimmune disease in mice. Research is now in progress to ascertain whether quantitative or functional abnormalities in these molecules exist in human SLE patients and contribute to the pathogenesis of the disease in some or all cases.
Rose
L M
LM
Department of Molecular Pathology, University College London Medical School.
Latchman
D S
DS
Isenberg
D A
DA
D000818:Animals; D000954:Antigens, Surface / Q000502:physiology*; D017209:Apoptosis / Q000502:physiology*; D002470:Cell Survival / Q000502:physiology; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000276:immunology*; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2; D011956:Receptors, Cell Surface / Q000502:physiology*; D019014:fas Receptor
D000954:Antigens, Surface; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011956:Receptors, Cell Surface; D019014:fas Receptor