Immunopathology and Infectious Disease CD 4 T Cells Mediate Axonal Damage and Spinal Cord Motor Neuron Apoptosis in Murine P 0106 – 125-Induced Experimental Autoimmune Neuritis

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) autoimmunemediated 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 P0106–125-induced experimental autoimmune neuritis. Immunization of C57BL/6 mice with P0106–125 resulted in severe axonal damage and mild demyelination. Importantly, these mice developed a “dyingback” 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 antigenspecific interferonand 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, P0106–125-induced experimental autoimmune neuritis is a CD4 T cell-mediated autoimmune disease that affects both the peripheral and central nervous systems. (Am J Pathol 2008, 173:93–105; DOI: 10.2353/ajpath.2008.071101) Autoimmune-mediated diseases of the peripheral nervous system are a heterogeneous group of clinical entities, which are pathologically characterized by demyelination and/or axonal damage. The various immunopathological mechanisms, which underlie these diverse clinical manifestations, as well as the relative importance of axonal damage and demyelination, are still incompletely defined. In particular, the relative contribution of axonal degeneration and/or demyelination to the pathology is still controversially discussed. This also holds true for inflammatory demyelinating diseases of the central nervous system, ie, multiple sclerosis in humans and experimental autoimmune encephalomyelitis in rodents. In these disorders the extent and severity of inflammation has to some degree observed to be related to the amount of axonal damage. While some authors reported that demyelination precedes and triggers axonal damage (outside-in damage), the extent of which determines the final clinical outcome and degree of neurological disability in multiple sclerosis and experimental autoimmune encephalomyelitis, other groups provided evidence for primary axonal injury, followed by secondary demyelination (inside-out damage). Interestingly, a recent study indicated that axonal injury might herald or trigger demyelination in Theiler’s murine encephalomyelitis virus infection. So far, this issue has not been resolved for autoimmune inflammation of the peripheral nervous system. However, a sound understanding of the underlying immunological mechanisms and pathological responses is a prerequisite to improve or to establish rational therapeutic strategies. In this context, animal models of autoimmune neuritis are useful to prove basic pathogenetic concepts of the corresponding human diseases. The hallmark of rat experimental autoimmune neuritis (EAN) is the infiltration of the peripheral nervous system by lymphocytes and macrophages. However, it is still controversial whether CD4 T cells and macrophages are sufficient to induce EAN or whether the integrated attack