The apoptotic ligands TRAIL, TWEAK, and Fas ligand mediate monocyte death induced by autologous lupus T cells.
Individuals with systemic lupus erythematosus show evidence of a significant increase in monocyte apoptosis. This process is mediated, at least in part, by an autoreactive T cell subset that kills autologous monocytes in the absence of nominal Ag. We have investigated the apoptotic pathways involved in this T cell-mediated process. Expression of the apoptotic ligands TRAIL, TNF-like weak inducer of apoptosis (TWEAK), and Fas ligand on lupus T cells was determined, and the role of these molecules in the monocyte apoptotic response was examined. We report that these apoptotic ligands mediate the autologous monocyte death induced by lupus T cells and that this cytotoxicity is associated with increased expression of these molecules on activated T cells, rather than with an increased susceptibility of lupus monocytes to apoptosis induced by these ligands. These results define novel mechanisms that contribute to increased monocyte apoptosis characterizing patients with lupus. We propose that this mechanism could provide a source of potentially antigenic material for the autoimmune response and interfere with normal clearing mechanisms.
Kaplan
Mariana J
MJ
Department of Internal Medicine, University of Michigan, 1150 West Medical Center Drive, 5220 Medical Science Research Building I, Ann Arbor, MI 48109, USA. makaplan@umich.edu
Lewis
Emily E
EE
Shelden
Eric A
EA
Somers
Emily
E
Pavlic
Robert
R
McCune
William J
WJ
Richardson
Bruce C
BC
D000328:Adult; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D051017:Apoptosis Regulatory Proteins; D001379:Azathioprine / Q000494:pharmacology; D002352:Carrier Proteins / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D002478:Cells, Cultured; D002738:Chloroquine / Q000494:pharmacology; D000074049:Cytokine TWEAK; D003601:Cytotoxicity Tests, Immunologic; D053222:Fas Ligand Protein; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000494:pharmacology; D007113:Immunity, Innate; D007213:Indomethacin / Q000494:pharmacology; D008024:Ligands; D008180:Lupus Erythematosus, Systemic / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology*; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D008297:Male; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects / Q000276:immunology* / Q000473:pathology*; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D048069:Tumor Necrosis Factors; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology
D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; D000074049:Cytokine TWEAK; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008024:Ligands; D008562:Membrane Glycoproteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; C109743:TNFSF12 protein, human; D014409:Tumor Necrosis Factor-alpha; D048069:Tumor Necrosis Factors; D002738:Chloroquine; D001379:Azathioprine; D006854:Hydrocortisone; D007213:Indomethacin