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A pathogenic role for myelin-specific CD8(+) T cells in a model for multiple sclerosis.

Huseby ES, Liggitt D, Brabb T, Schnabel B, Ohlén C, Goverman J - J. Exp. Med. (2001)

Bottom Line: The role of CD8(+) myelin-specific T cells in mediating EAE or MS has not been described previously.The pathology and clinical symptoms in CD8(+) T cell-mediated CNS autoimmunity demonstrate similarities to MS not seen in myelin-specific CD4(+) T cell-mediated EAE.These data suggest that myelin-specific CD8(+) T cells could function as effector cells in the pathogenesis of MS.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology, University of Washington, Seattle, Washington 98195, USA.

ABSTRACT
Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS) characterized by plaques of infiltrating CD4(+) and CD8(+) T cells. Studies of MS and experimental autoimmune encephalomyelitis (EAE), an animal model of MS, focus on the contribution of CD4(+) myelin-specific T cells. The role of CD8(+) myelin-specific T cells in mediating EAE or MS has not been described previously. Here, we demonstrate that myelin-specific CD8(+) T cells induce severe CNS autoimmunity in mice. The pathology and clinical symptoms in CD8(+) T cell-mediated CNS autoimmunity demonstrate similarities to MS not seen in myelin-specific CD4(+) T cell-mediated EAE. These data suggest that myelin-specific CD8(+) T cells could function as effector cells in the pathogenesis of MS.

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MBP-specific CTLs isolated from C3H wild-type mice transfer CNS autoimmunity. (A) Mean clinical score of recipient mice after transfer of MBP–CTL or Vaccinia-specific CTLs (VAC–CTL) into C3H, C3H.scid, or C3H.shi recipient mice. (B) MBP–CTLs induced severe weight loss in recipient mice expressing endogenous MBP. The mean clinical score and weight loss is the average of three independent experiments using the same T cell clone. Of two independent T cell clones studied, both induced similar CNS disease. Incidence of disease after transfer of MBP–CTLs into recipient mice was 17/19 in C3H, 12/13 in C3H.scid, 0/15 in C3H.shi, and 0/14 after transfer of VAC–CTLs into C3H.
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Figure 2: MBP-specific CTLs isolated from C3H wild-type mice transfer CNS autoimmunity. (A) Mean clinical score of recipient mice after transfer of MBP–CTL or Vaccinia-specific CTLs (VAC–CTL) into C3H, C3H.scid, or C3H.shi recipient mice. (B) MBP–CTLs induced severe weight loss in recipient mice expressing endogenous MBP. The mean clinical score and weight loss is the average of three independent experiments using the same T cell clone. Of two independent T cell clones studied, both induced similar CNS disease. Incidence of disease after transfer of MBP–CTLs into recipient mice was 17/19 in C3H, 12/13 in C3H.scid, 0/15 in C3H.shi, and 0/14 after transfer of VAC–CTLs into C3H.

Mentions: To investigate whether CD8+ T cells could induce CNS autoimmunity, activated MBP-specific CD8+ T cell clones isolated from C3H wild-type mice (MBP-CTLs) were transferred intravenously into recipient mice. Both C3H wild-type and C3H.scid recipient mice exhibited pronounced neurological disease. The clinical symptoms were primarily associated with upper motor neuron impairment including ataxia, spastic reflexes, loss of coordinated movement, spinning, and head-tilt, with some mice developing hind limb paralysis. Mice often lost motor function in their hind legs yet retained sensory feelings. Because the clinical disease course is distinct from classic EAE in which the primary symptom is ascending flaccid paralysis, we developed a new scale for scoring the severity of clinical signs (see Materials and Methods). The disease course was rapid and severe in both wild-type and C3H.scid mice, with significant weight loss and a high incidence of mortality observed (Fig. 2). Wild-type mice receiving vaccinia-specific CTLs or C3H.shi−/− mice receiving MBP–CTLs were clinically normal and experienced no weight loss.


A pathogenic role for myelin-specific CD8(+) T cells in a model for multiple sclerosis.

Huseby ES, Liggitt D, Brabb T, Schnabel B, Ohlén C, Goverman J - J. Exp. Med. (2001)

MBP-specific CTLs isolated from C3H wild-type mice transfer CNS autoimmunity. (A) Mean clinical score of recipient mice after transfer of MBP–CTL or Vaccinia-specific CTLs (VAC–CTL) into C3H, C3H.scid, or C3H.shi recipient mice. (B) MBP–CTLs induced severe weight loss in recipient mice expressing endogenous MBP. The mean clinical score and weight loss is the average of three independent experiments using the same T cell clone. Of two independent T cell clones studied, both induced similar CNS disease. Incidence of disease after transfer of MBP–CTLs into recipient mice was 17/19 in C3H, 12/13 in C3H.scid, 0/15 in C3H.shi, and 0/14 after transfer of VAC–CTLs into C3H.
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2195947&req=5

Figure 2: MBP-specific CTLs isolated from C3H wild-type mice transfer CNS autoimmunity. (A) Mean clinical score of recipient mice after transfer of MBP–CTL or Vaccinia-specific CTLs (VAC–CTL) into C3H, C3H.scid, or C3H.shi recipient mice. (B) MBP–CTLs induced severe weight loss in recipient mice expressing endogenous MBP. The mean clinical score and weight loss is the average of three independent experiments using the same T cell clone. Of two independent T cell clones studied, both induced similar CNS disease. Incidence of disease after transfer of MBP–CTLs into recipient mice was 17/19 in C3H, 12/13 in C3H.scid, 0/15 in C3H.shi, and 0/14 after transfer of VAC–CTLs into C3H.
Mentions: To investigate whether CD8+ T cells could induce CNS autoimmunity, activated MBP-specific CD8+ T cell clones isolated from C3H wild-type mice (MBP-CTLs) were transferred intravenously into recipient mice. Both C3H wild-type and C3H.scid recipient mice exhibited pronounced neurological disease. The clinical symptoms were primarily associated with upper motor neuron impairment including ataxia, spastic reflexes, loss of coordinated movement, spinning, and head-tilt, with some mice developing hind limb paralysis. Mice often lost motor function in their hind legs yet retained sensory feelings. Because the clinical disease course is distinct from classic EAE in which the primary symptom is ascending flaccid paralysis, we developed a new scale for scoring the severity of clinical signs (see Materials and Methods). The disease course was rapid and severe in both wild-type and C3H.scid mice, with significant weight loss and a high incidence of mortality observed (Fig. 2). Wild-type mice receiving vaccinia-specific CTLs or C3H.shi−/− mice receiving MBP–CTLs were clinically normal and experienced no weight loss.

Bottom Line: The role of CD8(+) myelin-specific T cells in mediating EAE or MS has not been described previously.The pathology and clinical symptoms in CD8(+) T cell-mediated CNS autoimmunity demonstrate similarities to MS not seen in myelin-specific CD4(+) T cell-mediated EAE.These data suggest that myelin-specific CD8(+) T cells could function as effector cells in the pathogenesis of MS.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology, University of Washington, Seattle, Washington 98195, USA.

ABSTRACT
Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS) characterized by plaques of infiltrating CD4(+) and CD8(+) T cells. Studies of MS and experimental autoimmune encephalomyelitis (EAE), an animal model of MS, focus on the contribution of CD4(+) myelin-specific T cells. The role of CD8(+) myelin-specific T cells in mediating EAE or MS has not been described previously. Here, we demonstrate that myelin-specific CD8(+) T cells induce severe CNS autoimmunity in mice. The pathology and clinical symptoms in CD8(+) T cell-mediated CNS autoimmunity demonstrate similarities to MS not seen in myelin-specific CD4(+) T cell-mediated EAE. These data suggest that myelin-specific CD8(+) T cells could function as effector cells in the pathogenesis of MS.

Show MeSH
Related in: MedlinePlus