APOPTOSIS AND ITS RELEVANCE TO AUTOIMMUNITY
EXTRINSIC DEATH RECEPTOR PATHWAYS 1 DEATH RECEPTOR SIGNALING AND ITS FUNCTION IN THE IMMUNE SYSTEM 18 INHERITED AND ACQUIRED DEATH RECEPTOR DEFECTS IN HUMAN AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME 37 TUMOR NECROSIS FACTOR LIGAND RECEPTOR SUPERFAMILY AND ARTHRITIS HSU H C WU Y MOUNTZ J D BIRMINGHAM ALA INTRINSIC DEATH PATHWAYS 55 MITOCHONDRIA APOPTOSIS AND AUTOIMMUNITY 74 ROLE OF BIM AND OTHER BCL 2 FAMILY MEMBERS IN AUTOIMMUNE AND 95 MITOCHONDRIA CELL DEATH AND B CELL TOLERANCE APOPTOTIC CELL CLEARANCE 120 ROLE OF COMPLEMENT AND OTHER INNATE IMMUNE MECHANISMS IN THE REMOVAL OF APOPTOTIC CELLS 143 COLLECTINS OPSONINS FOR APOPTOTIC CELLS AND REGULATORS 162 MFG E8 DEPENDENT CLEARANCE OF APOPTOTIC CELLS AND AUTOIMMUNITY CAUSED BY ITS FAILURE HANAYAMA R MIYASAKA K NAKAYA M NAGATA S OSAKA 173 CLEARANCE OF APOPTOTIC CELLS IN HUMAN SLE 188 APOPTOSIS AND GLOMERULONEPHRITIS DEATH RECEPTOR SIGNALING AND ITS FUNCTION IN THE IMMUNE SYSTEM DEATH RECEPTORS BELONG TO THE TNF TUMOR NECROSIS FACTOR NGF NERVE GROWTH FACTOR RECEPTOR SUPERFAMILY SIGNALING VIA DEATH RECEPTORS PLAYS A DISTINCT ROLE E G IN THE IMMUNE SYSTEM WHERE IT CONTRIBUTES TO REGULATION OF THE ADAPTIVE IMMUNE RESPONSE IN VARIOUS WAYS MOST NOTABLY BY TRIGGERING ACTIVATION INDUCED CELL DEATH AICD OF T CELLS THUS DYSREGULA TION OF DEATH RECEPTOR SIGNALING EITHER ALLOWING TOO MUCH OR TOO LITTLE APOPTOSIS CAN LEAD TO AUTOIMMUNE DISORDERS AND ALSO IMPACTS ON TUMORIGENESIS OR OTHER DISEASES IN THIS CHAPTER WE ADDRESS COMPONENTS MOLECULAR MECHANISMS AND REGULATION OF DEATH RECEPTOR SIGNALING WITH PARTICULAR FOCUS ON CD95 APO 1 FAS WE DISCUSS THE ROLE OF DEATH RECEPTOR MEDIATED AICD IN REGULATION OF THE ADAPTIVE IMMUNE RESPONSE AGAINST FOREIGN AND SELF ANTIGENS IN COMPARISON TO CYTOKINE DEPRIVATION MEDIATED DEATH BY NEGLECT FINALLY THE CONTRIBUTION OF DYSREGULATED DEATH RECEPTOR LIGAND SYSTEMS TO AUTOIMMUNE DISEASES SUCH AS DIABETES MUL TIPLE SCLEROSIS AND HASHIMOTO S THYROIDITIS IS DISCUSSED COPYRIGHT 2006 S KARGER AG BASEL DEATH RECEPTOR SIGNALING PLAYS A DISTINCT ROLE E G IN THE IMMUNE SYSTEM WHERE IT CONTRIBUTES TO THE REGULATION OF THE ADAPTIVE IMMUNE RESPONSE BUT ALSO IN OTHER PHYSIOLOGICAL AND PATHOPHYSIOLOGICAL STATES SUCH AS DEVELOPMENT DIF FERENTIATION AND TUMORIGENESIS DEATH RECEPTORS BELONG TO THE TNF TUMOR NECROSIS FACTOR NGF NERVE GROWTH FACTOR RECEPTOR SUPERFAMILY MEMBERS OF THIS FAMILY ARE TYPE I TRANSMEMBRANE RECEPTORS CONTAIN 1 5 CYSTEINE RICH DOMAINS IN THEIR EXTRACELLULAR DOMAIN AND AN 80 AMINO ACID DEATH DOMAIN DD IN THE CYTOPLASMIC TAIL WHICH IS ESSENTIAL FOR TRANSDUCTION OF THE DEATH SIGNAL SIX MEMBERS OF THIS DEATH RECEPTOR SUBFAMILY ARE KNOWN SO FAR FIG NAMELY TNF R1 TUMOR NECROSIS FACTOR RECEPTOR 1 ALSO KNOWN AS CD120A CD95 FAS FRITZSCHING SURI PAYER KRAMMER ALSO KNOWN AS APO 1 AND FAS DR3 ALSO KNOWN AS APO 3 LARD TRAMP AND WSL1 TRAIL R1 TNF RELATED APOPTOSIS INDUCING LIGAND RECEPTOR ALSO KNOWN AS APO 2 AND DR4 TRAIL R2 ALSO KNOWN AS DR5 KILLER AND TRICK2 AND DR6 1 IN ADDITION THE ECTODYSPLASIN A RECEPTOR EDA R AND THE NERVE GROWTH FACTOR RECEPTOR NGF R P75 NTR ARE SOMETIMES REFERRED TO AS DEATH RECEPTORS BECAUSE THEY CONTAIN CYTOPLASMIC REGIONS SIMILAR TO DEATH DOMAINS HOWEVER THEIR DEATH DOMAINS SHOW STRIKING STRUCTURAL AND FUNCTIONAL DIFFERENCES FROM THE CLASSICAL DEATH DOMAIN AND NO BINDING TO FADD OR TRADD HAS BEEN DETECTED DEATH RECEPTORS ARE ACTIVATED BY THEIR NATURAL LIGANDS WHICH HAVE CO EVOLVED AS MEMBERS OF THE TNF FAMILY FIG 1 EXCEPT FOR LYMPHOTOXIN LT THEY ARE TYPE II TRANSMEMBRANE PROTEINS AND ALL DEATH LIGANDS FORM HOMOTRIMERS OR TRIMERIC COMPLEXES OF HIGHER ORDER SUCH AS HEXAMERS TNF CD95L CD178 FASL APO 1L AND TRAIL APO 2L HAVE ALSO BEEN REPORTED TO EXIST IN A SOLUBLE FORM CLEAVED FROM THE MEMBRANE BY METALLOPROTEASES THE FIG 1 DEATH RECEPTORS DRS DECOY RECEPTORS DCRS DEATH LIGANDS AND THEIR INTERACTIONS MEMBERS OF THE DEATH RECEPTORS ARE CHARACTERIZED BY EXTRACELLULAR CYSTEINE RICH DOMAINS DEPICTED AS DIAMONDS AND BY AN INTRACELLULAR DEATH DOMAIN APOPTOSIS AND ITS RELEVANCE TO AUTOIMMUNITY