IFN-beta gene deletion leads to augmented and chronic demyelinating experimental autoimmune encephalomyelitis.
Since the basic mechanisms behind the beneficial effects of IFN-beta in multiple sclerosis (MS) patients are still obscure, here we have investigated the effects of IFN-beta gene disruption on the commonly used animal model for MS, experimental autoimmune encephalomyelitis (EAE). We show that IFN-beta 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-gamma in response to recall Ag. Consequently, we addressed the effect of IFN-beta 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-beta 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-beta 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-alpha production in IFN-beta KO mice; this was virtually absent in wt littermates. This coincided with an increase in effector functions of T cells in IFN-beta KO mice, as measured by IFN-gamma and IL-4 production. We suggest that lack of endogenous IFN-beta in CNS leads to augmented microglia activation, resulting in a sustained inflammation, cytokine production, and tissue damage with consequent chronic neurological deficits.
Teige
Ingrid
I
Section for Medical Inflammation Research, Department of Cell and Molecular Biology, University of Lund, Lund, Sweden.
Treschow
Alexandra
A
Teige
Anna
A
Mattsson
Ragnar
R
Navikas
Vaidrius
V
Leanderson
Tomas
T
Holmdahl
Rikard
R
Issazadeh-Navikas
Shohreh
S
D000276:Adjuvants, Immunologic / Q000235:genetics*; D019264:Adoptive Transfer; D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis; D001324:Autoantigens / Q000276:immunology; D002478:Cells, Cultured; D002908:Chronic Disease; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000453:epidemiology / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D017353:Gene Deletion; D020022:Genetic Predisposition to Disease; D016130:Immunophenotyping; D015994:Incidence; D007249:Inflammation / Q000235:genetics / Q000276:immunology; D016899:Interferon-beta / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics*; D008262:Macrophage Activation / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D004676:Myelin Basic Protein / Q000276:immunology; D009186:Myelin Sheath / Q000473:pathology; D010446:Peptide Fragments / Q000276:immunology; D012720:Severity of Illness Index; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000637:transplantation; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism
D000276:Adjuvants, Immunologic; D001323:Autoantibodies; D001324:Autoantigens; D004676:Myelin Basic Protein; D010446:Peptide Fragments; C446766:myelin basic protein 89-101; D016899:Interferon-beta