T cell-mediated neuroprotection involves antithrombin activity.
Functional loss after injury to the mammalian central nervous system (CNS) has been attributed not only to the immediate loss of neurons but also to secondary neuronal degeneration caused by the toxicity of physiological compounds present in abnormally high amounts as a result of the injury. One such compound appears to be the protease thrombin. Here we show that the beneficial effect of T cells directed against myelin self-antigens can be attributed, at least in part, to the ability of these 'autoimmune' T cells to produce antithrombin III. Using transgenic mice lacking the thrombin receptor PAR-1, we also present molecular evidence indicating that down-regulation of PAR-1 by genetic manipulation leads to increased post-traumatic survival of CNS neurons. We further show that the ability of autoimmune T cells to produce thrombin inhibitors and to exert post-traumatic neuroprotection are both independent of their PAR-1 expression. These findings suggest that thrombin plays a key role in post-injury neuronal survival, and that its post-traumatic toxicity can be down-regulated by appropriate alteration of the amounts of PAR-1 receptors or of antithrombin III, the latter achieved by T cell-mediated autoimmunity.
Friedmann
I
I
Department of Neurobiology, The Weizmann Institute of Science, 76100, Rehovot, Israel
Hauben
E
E
Yoles
E
E
Kardash
L
L
Schwartz
M
M
D000818:Animals; D000990:Antithrombin III / Q000276:immunology*; D002455:Cell Division / Q000276:immunology; D002460:Cell Line; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009409:Nerve Crush; D009410:Nerve Degeneration / Q000276:immunology* / Q000473:pathology; D020221:Optic Nerve Injuries / Q000276:immunology / Q000473:pathology; D051381:Rats; D011917:Rats, Inbred Lew; D044463:Receptor, PAR-1; D018179:Receptors, Thrombin / Q000235:genetics* / Q000276:immunology; D012165:Retinal Ganglion Cells / Q000276:immunology / Q000473:pathology; D017386:Sequence Homology, Amino Acid; D013154:Spleen / Q000166:cytology; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*
D044463:Receptor, PAR-1; D018179:Receptors, Thrombin; D000990:Antithrombin III