Published online before print June 5, 2008

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Copyright © 2008 American Society for Investigative Pathology
American Journal of Pathology, doi:10.2353/ajpath.2008.071101

Accepted for publication April 3, 2008.

Article

CD4 T Cells Mediate Axonal Damage and Spinal Cord Motor Neuron Apoptosis in Murine P0_106–125-Induced Experimental Autoimmune Neuritis

Anna Brunn^*@, Olaf Utermöhlen, Mariana Carstov^*, Monica Sánchez Ruiz^*, Hrvoje Miletic^*, Dirk Schlüter, and Martina Deckert^*

From the Abteilung für Neuropathologie,* and the Institut für Medizinische Mikrobiologie, Immunologie und Hygiene, Universität zu Köln, Köln, Germany; and the Institut für Medizinische Mikrobiologie, Otto-von-Guericke Universität Magdeburg, Magdeburg, Germany

^@ To whom correspondence should be addressed. E-mail: anna.brunn{at}uni-koeln.de.

	Abstract

The pathogenesis of inflammatory autoimmune diseases of the peripheral nervous system, leading to demyelination and/or axonal damage, remains incompletely understood. In particular, it is controversial regarding the extent to which (i) autoimmune-mediated destruction of peripheral nerves results in secondary damage of the central nervous system, and (ii) CD4 and CD8 T cells contribute to disease. To address these issues, we applied the murine model of P0_106–125-induced experimental autoimmune neuritis. Immunization of C57BL/6 mice with P0_106–125 resulted in severe axonal damage and mild demyelination. Importantly, these mice developed a "dying-back" axonopathy with apoptosis of a large fraction of neurons in the anterior horn of the lumbar and thoracic spinal cord and a progressive neurogenic muscular atrophy. T cell-depletion experiments identified CD4, but not CD8, T cells as important mediators of experimental autoimmune neuritis. CD4 T cells represented the major cellular source of antigen-specific interferon- and interleukin-17 production, regulated the number of tumor necrosis factor-positive and inducible nitric oxide synthase-positive macrophages in the diseased sciatic nerve, and mediated axonal damage and subsequent neuronal apoptosis and neurogenic muscular atrophy. In contrast, the demyelination of peripheral nerves was only slightly ameliorated in CD4 T cell-depleted mice. In conclusion, P0_106–125-induced experimental autoimmune neuritis is a CD4 T cell-mediated autoimmune disease that affects both the peripheral and central nervous systems.