| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Gene Deletion Leads to Augmented and Chronic Demyelinating Experimental Autoimmune Encephalomyelitis1
* Sections for Medical Inflammation Research and
Immunology, Department of Cell and Molecular Biology, University of Lund, Lund, Sweden
Since the basic mechanisms behind the beneficial effects of IFN-
in multiple sclerosis (MS) patients are still obscure, here we have investigated the effects of IFN- gene disruption on the commonly used animal model for MS, experimental autoimmune encephalomyelitis (EAE). We show that IFN- knockout (KO) mice are more susceptible to EAE than their wild-type (wt) littermates; they develop more severe and chronic neurological symptoms with more extensive CNS inflammation and demyelination. However, there was no discrepancy observed between wt and KO mice regarding the capacity of T cells to proliferate or produce IFN-
in response to recall Ag. Consequently, we addressed the effect of IFN- on encephalitogenic T cell development and the disease initiation phase by passive transfer of autoreactive T cells from KO or wt littermates to both groups of mice. Interestingly, IFN- KO mice acquired a higher incidence and augmented EAE regardless of the source of T cells. This shows that the anti-inflammatory effect of endogenous IFN- is predominantly exerted on the effector phase of the disease. Histopathological investigations of CNS in the effector phase revealed an extensive microglia activation and TNF-
production in IFN- KO mice; this was virtually absent in wt littermates. This coincided with an increase in effector functions of T cells in IFN- KO mice, as measured by IFN- and IL-4 production. We suggest that lack of endogenous IFN- in CNS leads to augmented microglia activation, resulting in a sustained inflammation, cytokine production, and tissue damage with consequent chronic neurological deficits.
This article has been cited by other articles:
|
|
 |
|
  H. Qin, S. A. Niyongere, S. J. Lee, B. J. Baker, and E. N. Benveniste Expression and Functional Significance of SOCS-1 and SOCS-3 in Astrocytes J. Immunol., September 1, 2008; 181(5): 3167 - 3176. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G Kristjansdottir, J K Sandling, A Bonetti, I M Roos, L Milani, C Wang, S M Gustafsdottir, S Sigurdsson, A Lundmark, P J Tienari, et al. Interferon regulatory factor 5 (IRF5) gene variants are associated with multiple sclerosis in three distinct populations J. Med. Genet., June 1, 2008; 45(6): 362 - 369. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. A. Eskan, B. G. Rose, M. R. Benakanakere, M.-J. Lee, and D. F. Kinane Sphingosine 1-Phosphate 1 and TLR4 Mediate IFN-{beta} Expression in Human Gingival Epithelial Cells J. Immunol., February 1, 2008; 180(3): 1818 - 1825. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. N. Benveniste and H. Qin Type I Interferons as Anti-Inflammatory Mediators Sci. Signal., December 11, 2007; 2007(416): pe70 - pe70. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Molle, M. Nguyen, V. Flamand, J. Renneson, F. Trottein, D. De Wit, F. Willems, M. Goldman, and S. Goriely IL-27 Synthesis Induced by TLR Ligation Critically Depends on IFN Regulatory Factor 3 J. Immunol., June 15, 2007; 178(12): 7607 - 7615. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Mastronardi, H. Tsui, S. Winer, D. Wood, T. Selvanantham, C. Galligan, E. Fish, H-M. Dosch, and M. Moscarello Synergy between paclitaxel plus an exogenous methyl donor in the suppression of murine demyelinating diseases Multiple Sclerosis, June 1, 2007; 13(5): 596 - 609. [Abstract] [PDF]
|
|
|
|
 |
|
 R. Burdeinick-Kerr, J. Wind, and D. E. Griffin Synergistic Roles of Antibody and Interferon in Noncytolytic Clearance of Sindbis Virus from Different Regions of the Central Nervous System J. Virol., June 1, 2007; 81(11): 5628 - 5636. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. J. Fabis, G. S. Scott, R. B. Kean, H. Koprowski, and D. C. Hooper Loss of blood-brain barrier integrity in the spinal cord is common to experimental allergic encephalomyelitis in knockout mouse models PNAS, March 27, 2007; 104(13): 5656 - 5661. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Wahl, P. Bochtler, R. Schirmbeck, and J. Reimann Type I IFN-Producing CD4 V{alpha}14i NKT Cells Facilitate Priming of IL-10-Producing CD8 T Cells by Hepatocytes J. Immunol., February 15, 2007; 178(4): 2083 - 2093. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Yarilina, E. DiCarlo, and L. B. Ivashkiv Suppression of the Effector Phase of Inflammatory Arthritis by Double-Stranded RNA Is Mediated by Type I IFNs J. Immunol., February 15, 2007; 178(4): 2204 - 2211. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Teige, Y. Liu, and S. Issazadeh-Navikas IFN-beta Inhibits T Cell Activation Capacity of Central Nervous System APCs J. Immunol., September 15, 2006; 177(6): 3542 - 3553. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. M. Shapiro, C. S. Jack, Y. Lapierre, N. Arbour, A. Bar-Or, and J. P. Antel Potential for interferon Beta-induced serum antibodies in multiple sclerosis to inhibit endogenous interferon-regulated chemokine/cytokine responses within the central nervous system. Arch Neurol, September 1, 2006; 63(9): 1296 - 1299. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. N. Sharif, D. Sosic, C. V. Rothlin, E. Kelly, G. Lemke, E. N. Olson, and L. B. Ivashkiv Twist mediates suppression of inflammation by type I IFNs and Axl J. Exp. Med., August 7, 2006; 203(8): 1891 - 1901. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. H Polman, J. Killestein, and H. Schellekens Neutralizing antibodies to interferon-beta may persist after cessation of therapy: what impact could they have? Multiple Sclerosis, June 1, 2006; 12(3): 245 - 246. [PDF]
|
|
|
|
 |
|
 H. Qin, C. A. Wilson, S. J. Lee, and E. N. Benveniste IFN-{beta}-induced SOCS-1 negatively regulates CD40 gene expression in macrophages and microglia FASEB J, May 1, 2006; 20(7): 985 - 987. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Schwarting, K. Paul, S. Tschirner, J. Menke, T. Hansen, W. Brenner, V. R. Kelley, M. Relle, and P. R. Galle Interferon-{beta}: A Therapeutic for Autoimmune Lupus in MRL-Faslpr Mice J. Am. Soc. Nephrol., November 1, 2005; 16(11): 3264 - 3272. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. K. Palucka, J.-P. Blanck, L. Bennett, V. Pascual, and J. Banchereau Cross-regulation of TNF and IFN-{alpha} in autoimmune diseases PNAS, March 1, 2005; 102(9): 3372 - 3377. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Hadjilambreva, E. Mix, A. Rolfs, J. Muller, and U. Strauss Neuromodulation by a Cytokine: Interferon-{beta} Differentially Augments Neocortical Neuronal Activity and Excitability J Neurophysiol, February 1, 2005; 93(2): 843 - 852. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Dikopoulos, A. Bertoletti, A. Kroger, H. Hauser, R. Schirmbeck, and J. Reimann Type I IFN Negatively Regulates CD8+ T Cell Responses through IL-10-Producing CD4+ T Regulatory 1 Cells J. Immunol., January 1, 2005; 174(1): 99 - 109. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
