Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antigen-Presenting Cells / immunology*
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Apoptosis Regulatory Proteins / deficiency
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Apoptosis Regulatory Proteins / genetics
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Apoptosis Regulatory Proteins / immunology
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Apoptosis Regulatory Proteins / metabolism*
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Apoptosis*
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Autoantibodies / blood
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Autoimmunity*
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B-Lymphocytes / immunology
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Bcl-2-Like Protein 11
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Humans
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Kidney / immunology
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Kidney / pathology
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Lupus Erythematosus, Systemic / genetics
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Lupus Erythematosus, Systemic / immunology*
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Lupus Erythematosus, Systemic / metabolism
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Lupus Erythematosus, Systemic / pathology
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Lymphatic Diseases / immunology
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Macrophage Activation
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Macrophages / immunology
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Membrane Proteins / deficiency
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Membrane Proteins / genetics
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Membrane Proteins / immunology
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Membrane Proteins / metabolism*
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Mice
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Mice, Inbred MRL lpr
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Proto-Oncogene Proteins / deficiency
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / immunology
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Proto-Oncogene Proteins / metabolism*
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Splenomegaly / immunology
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T-Lymphocytes / immunology
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fas Receptor / deficiency
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fas Receptor / genetics
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fas Receptor / immunology
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fas Receptor / metabolism*
Substances
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Apoptosis Regulatory Proteins
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Autoantibodies
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BCL2L11 protein, human
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Bcl-2-Like Protein 11
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Bcl2l11 protein, mouse
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Membrane Proteins
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Proto-Oncogene Proteins
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fas Receptor