Autoimmune disease results from multiple interactive defects in apoptosis induction molecules and signaling pathways.
Activation induced cell death (AICD) plays a critical role in eliminating autoimmune cells and limiting inflammation after activation. The two major signaling molecules for AICD are the Fas and TNF-R pathways of apoptosis. Defective Fas apoptosis in lpr/lpr mice results in a compensatory increase in TNF-R/TNF-mediated apoptosis. TNF/TNF-R has been shown to be a compensatory pathway of apoptosis in T cells and macrophages of lpr/lpr mice. Therefore, early production of TNF/TNF-R limit an immune response by inducing AICD in the absence of an intact Fas/Fas ligand apoptosis pathway. However, increased TNF production in lpr mice also lead to increased susceptibility to septic shock and autoimmune disease such as arthritis. Therefore TNF production during an inflammatory response can downmodulate this response, but this also results in the failure to downmodulate TNF production leading to septic shock and arthritis. A second pathway of AICD is mediated by Nur77 after T cell stimulation through the CD3 molecule. Mice with defective Nur77 signaling undergo AICD using the Fas-Fas ligand pathway to eliminate autoreactive T cells. A third defect of AICD is observed in HCP-mutant me/me (motheaten) mice which develop autoimmune disease related to defective Fas apoptosis signaling. Therefore, multiple interactive pathways play a role in limiting development of autoimmunity.
Mountz
J D
JD
University of Alabama at Birmingham 35294-0007, USA.
Zhou
T
T
Su
X
X
Cheng
J
J
Pierson
M
M
Bluethmann
H
H
Edwards
C K
CK
D000818:Animals; D017209:Apoptosis; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology*; D053222:Fas Ligand Protein; D006801:Humans; D007249:Inflammation; D008232:Lymphoproliferative Disorders / Q000276:immunology / Q000473:pathology; D008562:Membrane Glycoproteins / Q000502:physiology*; D051379:Mice; D008817:Mice, Mutant Strains; D018448:Models, Immunological; D017260:Receptor-CD3 Complex, Antigen, T-Cell / Q000502:physiology; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D019014:fas Receptor / Q000502:physiology
C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D017260:Receptor-CD3 Complex, Antigen, T-Cell; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor