Accelerated Course of Experimental Autoimmune Encephalomyelitis in PD-1-Deficient Central Nervous System Myelin Mutants

Antje Kroner^*, Nicholas Schwab^*, Chi Wang Ip^*, Sonja Ortler^*, Kerstin Göbel^*, Klaus-Armin Nave, Mathias Mäurer^*, Rudolf Martini^* and Heinz Wiendl^*

From the Department of Neurology,^* the Section of Developmental Neurobiology, and the Clinical Research Group for Multiple Sclerosis and Neuroimmunology, University of Wuerzburg, Wuerzburg; and the Department of Neurogenetics, Max-Planck-Institute of Experimental Medicine, Goettingen, Germany

It is assumed that the onset and course of autoimmune inflammatorycentral nervous system (CNS) disorders (eg, multiple sclerosis)are influenced by factors that afflict immune regulation aswell as CNS vulnerability. We challenged this concept experimentallyby investigating how genetic alterations that affect myelin(primary oligodendrocyte damage in PLPtg mice) and/or T-cellregulation (deficiency of PD-1) influence both the onset andcourse of an experimental autoimmune CNS inflammatory disease[MOG_35-55-induced experimental autoimmune encephalomyelitis(EAE)]. We observed that double pathology was associated witha significantly earlier onset of disease, a slight increasein the neurological score, an increase in the number of infiltratingcells, and enhanced axonal degeneration compared with wild-typemice and the respective, single mutant controls. Double-mutantPLPtg/PD-1^–/– mice showed an increased productionof interferon- ${gamma}$ by CNS immune cells at the peak of disease. NeitherPD-1 deficiency nor oligodendropathy led to detectable spreadof antigenic MHC class I- or class II-restricted epitopes duringEAE. However, absence of PD-1 clearly increased the propensityof T lymphocytes to expand, and the number of clonal expansionsreliably reflected the severity of the EAE disease course. Ourdata show that the interplay between immune dysregulation andmyelinopathy results in a stable exacerbation of actively inducedautoimmune CNS inflammation, suggesting that the combinationof several pathological issues contributes significantly todisease susceptibility or relapses in human disease.