TY - JOUR
T1 - IFN-beta gene deletion leads to augmented and chronic demyelinating experimental autoimmune encephalomyelitis.
AU - Teige, Ingrid
AU - Treschow, Alexandra
AU - Teige, Anna
AU - Mattsson, Ragnar
AU - Navikas, Vaidrius
AU - Leanderson, Tomas
AU - Holmdahl, Rikard
AU - Issazadeh-Navikas, Shohreh
N1 - Keywords: Adjuvants, Immunologic; Adoptive Transfer; Animals; Autoantibodies; Autoantigens; Cells, Cultured; Chronic Disease; Encephalomyelitis, Autoimmune, Experimental; Gene Deletion; Genetic Predisposition to Disease; Immunophenotyping; Incidence; Inflammation; Interferon-beta; Macrophage Activation; Mice; Mice, Inbred C57BL; Mice, Knockout; Myelin Basic Proteins; Myelin Sheath; Peptide Fragments; Severity of Illness Index; T-Lymphocyte Subsets; Th1 Cells; Th2 Cells
PY - 2003
Y1 - 2003
N2 - 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.
AB - 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.
M3 - Journal article
C2 - 12707359
SN - 0022-1767
VL - 170
SP - 4776
EP - 4784
JO - Journal of Immunology
JF - Journal of Immunology
IS - 9
ER -