The role of noradrenergic nerves in the development of the lymphoproliferative disease in Fas-deficient, lpr/lpr mice.
Lpr/lpr mice develop a lymphoproliferative, autoimmune, lupus-like disease. These mice lack functional Fas (CD95) expression and are resistant to Fas ligand (CD178)-mediated apoptosis, a critical mechanism for the maintenance of peripheral tolerance. In this study, we show that noradrenaline (NA), the main sympathetic neurotransmitter, can induce apoptosis of lymphoid cells independently of functional Fas. Based on this finding, we used lpr/lpr mice as model to study the role of noradrenergic nerves in the expression of a lymphoproliferative disease. Early in ontogeny, the concentration of NA was significantly increased in the spleen of lpr/lpr mice, compared with normal littermates. However, splenic sympathetic innervation gradually declined as the disease progressed, and IgM blood levels and splenic NA concentration inversely correlated when the disease was overtly manifested. When the loss of noradrenergic fibers that occurred naturally during adult life in lpr/lpr mice was experimentally advanced by neonatal sympathectomy, the concentration of IgM and IgG2a in blood was markedly higher than that of control lpr/lpr mice, and the appearance of lymphadenopathy was accelerated. Furthermore, although neonatal denervation did not affect the life span of normal animals, it shortened significantly the survival time of lpr/lpr mice. These data show that, in addition to defects in the Fas pathway, an altered sympathetic innervation in lpr/lpr mice also contributes to the pathogenesis of the autoimmune disease, and strongly support the hypothesis that the sympathetic nervous system can modulate the expression of lymphoproliferative diseases.
del Rey
Adriana
A
Department of Immunophysiology, Institute of Physiology, Medical Faculty, Marburg, Germany. delrey@mailer.uni-marburg.de
Roggero
Eduardo
E
Kabiersch
Alexa
A
Schäfer
Martin
M
Besedovsky
Hugo O
HO
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000276:immunology; D001327:Autoimmune Diseases / Q000276:immunology / Q000401:mortality / Q000503:physiopathology; D003714:Denervation; D005260:Female; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000097:blood; D007075:Immunoglobulin M / Q000096:biosynthesis / Q000097:blood; D008206:Lymphatic Diseases / Q000235:genetics / Q000503:physiopathology; D008232:Lymphoproliferative Disorders / Q000235:genetics* / Q000276:immunology* / Q000401:mortality / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D009638:Norepinephrine / Q000378:metabolism / Q000502:physiology*; D013154:Spleen / Q000276:immunology / Q000294:innervation / Q000378:metabolism; D013562:Sympathectomy; D015854:Up-Regulation / Q000276:immunology; D019014:fas Receptor / Q000235:genetics* / Q000502:physiology
D007074:Immunoglobulin G; D007075:Immunoglobulin M; D019014:fas Receptor; D009638:Norepinephrine