Combined deficiency of proapoptotic regulators Bim and Fas results in the early onset of systemic autoimmunity.
Alterations in the stoichiometric balance between members of Bcl-2 and Fas apoptotic pathway could lead to the pathogenesis of systemic lupus erythematosus (SLE). We showed that patients with SLE displayed increased expression in antiapoptotic members of the Bcl-2 and Fas apoptotic pathways in isolated mononuclear cells. Further, mice (Bcl2l11(-/-)Fas(lpr/lpr)) lacking the Bcl-2 pro-apoptotic member, Bim (Bcl2l11(-/-)) and and with an lpr mutation in the gene encoding Fas (Fas(lpr/lpr)) developed severe SLE-like disease by 16 weeks of age unlike Bcl2l11(-/-) or Fas(lpr/lpr) mice. Bcl2l11(-/-)Fas(lpr/lpr) antigen-presenting cells (APCs) were markedly activated, and their numbers were increased in lymphoid tissues and in kidneys, yet numerous TUNEL-positive cells were observed in glomeruli of Bcl2l11(-/-)Fas(lpr/lpr) mice. These data demonstrate that dysregulation of the Bcl-2 or Fas pathways can alter the function of APCs, thereby leading to SLE pathogenesis.
Hutcheson
Jack
J
Department of Molecular Microbiology & Immunology, School of Medicine, Saint Louis University, Saint Louis, MO 63104, USA.
Scatizzi
John C
JC
Siddiqui
Akbar M
AM
Haines
G Kenneth
GK
Wu
Tianfu
T
Li
Quan-Zhen
QZ
Davis
Laurie S
LS
Mohan
Chandra
C
Perlman
Harris
H
D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology*; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D001323:Autoantibodies / Q000097:blood; D015551:Autoimmunity; D001402:B-Lymphocytes / Q000276:immunology; D000072224:Bcl-2-Like Protein 11; D006801:Humans; D007668:Kidney / Q000276:immunology / Q000473:pathology; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008206:Lymphatic Diseases / Q000276:immunology; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D019463:Mice, Inbred MRL lpr; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D013163:Splenomegaly / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D019014:fas Receptor / Q000172:deficiency / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
D051017:Apoptosis Regulatory Proteins; D001323:Autoantibodies; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D019014:fas Receptor