Accelerated course of experimental autoimmune encephalomyelitis in PD-1-deficient central nervous system myelin mutants. Am J Pathol 2009 Jun;174(6):2290-9
Date
05/16/2009Pubmed ID
19443704Pubmed Central ID
PMC2684193DOI
10.2353/ajpath.2009.081012Scopus ID
2-s2.0-67049142939 (requires institutional sign-in at Scopus site) 34 CitationsAbstract
It is assumed that the onset and course of autoimmune inflammatory central nervous system (CNS) disorders (eg, multiple sclerosis) are influenced by factors that afflict immune regulation as well as CNS vulnerability. We challenged this concept experimentally by investigating how genetic alterations that affect myelin (primary oligodendrocyte damage in PLPtg mice) and/or T-cell regulation (deficiency of PD-1) influence both the onset and course of an experimental autoimmune CNS inflammatory disease [MOG(35-55)-induced experimental autoimmune encephalomyelitis (EAE)]. We observed that double pathology was associated with a significantly earlier onset of disease, a slight increase in the neurological score, an increase in the number of infiltrating cells, and enhanced axonal degeneration compared with wild-type mice and the respective, single mutant controls. Double-mutant PLPtg/PD-1(-/-) mice showed an increased production of interferon-gamma by CNS immune cells at the peak of disease. Neither PD-1 deficiency nor oligodendropathy led to detectable spread of antigenic MHC class I- or class II-restricted epitopes during EAE. However, absence of PD-1 clearly increased the propensity of T lymphocytes to expand, and the number of clonal expansions reliably reflected the severity of the EAE disease course. Our data show that the interplay between immune dysregulation and myelinopathy results in a stable exacerbation of actively induced autoimmune CNS inflammation, suggesting that the combination of several pathological issues contributes significantly to disease susceptibility or relapses in human disease.
Author List
Kroner A, Schwab N, Ip CW, Ortler S, Göbel K, Nave KA, Mäurer M, Martini R, Wiendl HAuthor
Antje Kroner-Milsch MD, PhD Associate Professor in the Neurosurgery department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsAntigens, Differentiation
Central Nervous System
Encephalomyelitis, Autoimmune, Experimental
Enzyme-Linked Immunosorbent Assay
Immunohistochemistry
Mice
Mice, Knockout
Mice, Transgenic
Myelin Sheath
Oligodendroglia
Programmed Cell Death 1 Receptor
T-Lymphocytes
