The Fas signaling connection between autoimmunity and embryonic lethality.
The first gene to cause systemic autoimmune disease in mice was identified as the fas gene, which is mutated in lymphoproliferative (lpr) mice. These mice exhibited a defect in activation-inducted cell death of T cells and B cells in vivo, causing a failure of proper clearance of immune cells and defective down-modulation of an immune response. This led to the speculation that apoptosis defects may play a role in defective down-modulation of the hyperimmune response observed in human autoimmune diseases. More recently, scientists have generated different mouse lines with defects in Fas-apoptosis-associated molecules such as FADD and Apaf-1. These mice, however, died during embryonic development and did not develop autoimmune disease. These findings suggest that molecules associated with Fas apoptosis signaling can be important at the most limited levels for development of the immune system but also have more global apoptosis roles in other systems. We propose that the more global role of Fas-associated apoptosis molecules should be considered when evaluating their role in autoimmune disease.
Hsu
H C
HC
Department of Medicine, University of Alabama at Birmingham, 35294, USA.
Matsuki
Y
Y
Zhang
H G
HG
Zhou
T
T
Mountz
J D
JD
D000818:Animals; D017209:Apoptosis; D053477:Apoptotic Protease-Activating Factor 1; D029681:Arabidopsis Proteins; D001327:Autoimmune Diseases / Q000209:etiology*; D020964:Embryo Loss / Q000209:etiology*; D053222:Fas Ligand Protein; D044943:Fatty Acid Desaturases / Q000502:physiology*; D006801:Humans; D007107:Immune System / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000502:physiology; D011506:Proteins / Q000502:physiology; D011948:Receptors, Antigen, T-Cell / Q000502:physiology
C506592:APAF1 protein, human; C506593:Apaf1 protein, mouse; D053477:Apoptotic Protease-Activating Factor 1; D029681:Arabidopsis Proteins; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D011506:Proteins; D011948:Receptors, Antigen, T-Cell; D044943:Fatty Acid Desaturases; C084083:Fad7 protein, Arabidopsis; C509249:PTPN6 protein, human; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases; C509248:Ptpn6 protein, mouse