IFN-beta gene deletion leads to augmented and chronic demyelinating experimental autoimmune encephalomyelitis.

Ingrid Teige; Alexandra Treschow; Anna Teige; Ragnar Mattsson; Vaidrius Navikas; Tomas Leanderson; Rikard Holmdahl; Shohreh Issazadeh-Navikas

IFN-beta gene deletion leads to augmented and chronic demyelinating experimental autoimmune encephalomyelitis.

Ingrid Teige, Alexandra Treschow, Anna Teige, Ragnar Mattsson, Vaidrius Navikas, Tomas Leanderson, Rikard Holmdahl, Shohreh Issazadeh-Navikas

170 Citations (Scopus)

Abstract

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.

Original language	English
Journal	Journal of Immunology
Volume	170
Issue number	9
Pages (from-to)	4776-84
Number of pages	8
ISSN	0022-1767
Publication status	Published - 2003

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title = "IFN-beta gene deletion leads to augmented and chronic demyelinating experimental autoimmune encephalomyelitis.",

abstract = "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.",

author = "Ingrid Teige and Alexandra Treschow and Anna Teige and Ragnar Mattsson and Vaidrius Navikas and Tomas Leanderson and Rikard Holmdahl and Shohreh Issazadeh-Navikas",

note = "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",

year = "2003",

language = "English",

volume = "170",

pages = "4776--84",

journal = "Journal of Immunology",

issn = "0022-1767",

publisher = "American Association of Immunologists",

number = "9",

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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 -

IFN-beta gene deletion leads to augmented and chronic demyelinating experimental autoimmune encephalomyelitis.

Abstract

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