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Is multiple sclerosis an autoimmune disease?

Wootla B, Eriguchi M, Rodriguez M - Autoimmune Dis (2012)

Bottom Line: There is strong evidence that MS is, at least in part, an immune-mediated disease.There is less evidence that MS is a classical autoimmune disease, even though many authors state this in the description of the disease.In addition, we present an alternate hypothesis based on virus infection to explain the pathogenesis of MS.

View Article: PubMed Central - PubMed

Affiliation: Departments of Neurology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.

ABSTRACT
Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) with varied clinical presentations and heterogeneous histopathological features. The underlying immunological abnormalities in MS lead to various neurological and autoimmune manifestations. There is strong evidence that MS is, at least in part, an immune-mediated disease. There is less evidence that MS is a classical autoimmune disease, even though many authors state this in the description of the disease. We show the evidence that both supports and refutes the autoimmune hypothesis. In addition, we present an alternate hypothesis based on virus infection to explain the pathogenesis of MS.

No MeSH data available.


Related in: MedlinePlus

Perforin is the primary mediator of  injury by CD8+ T cells. Perforin is the primary molecule known to mediate injury by CD8+ T cells. Perforin mediates axonal transection in multiple sclerosis (MS) and correlates with neurological disability. Cytotoxic T cells secrete perforin in the form of granules along with granzymes. This release activates calcium, which results in “poly-perforin” channels on the target cells. This results in holes in the membrane of the target cells, causing leakage of intracellular material, which results in cell death.
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fig2: Perforin is the primary mediator of  injury by CD8+ T cells. Perforin is the primary molecule known to mediate injury by CD8+ T cells. Perforin mediates axonal transection in multiple sclerosis (MS) and correlates with neurological disability. Cytotoxic T cells secrete perforin in the form of granules along with granzymes. This release activates calcium, which results in “poly-perforin” channels on the target cells. This results in holes in the membrane of the target cells, causing leakage of intracellular material, which results in cell death.

Mentions: Finally, CD8+ T cells show oligoclonal expansion in MS brains, blood, and CSF that have not been reported with CD4+ T cells [69–71]. Some of the cytotoxic T cells react against autoantigens such as myelin-basic protein [72]. If these cells traveled randomly in the CNS, then presumably their CD3 junction region length would show a normal Gaussian distribution. In contrast, there is skewing of the CDR3 junction regions in MS, suggesting a selective infiltration or expansion of CD8+ T cell clones into the CNS [71]. Moreover, the T-cell receptors of the CD8+ T cells demonstrate distinct CD8+ T-cell clones with conserved specificity implying recognition of a similar antigen that results in their proliferation in the CNS. Much effort has focused on the potential role of IL17 in the MS plaque, and because of the bias of experiments in EAE, it has been proposed that this comes from the CD4+ T cells. However, there is evidence that IL17 is also made by CD8+ T cells [73]. Defining IL17+ CD8+ T cells opens up new avenues for future research and new targets from the standpoint of immunotherapy. CD8+ T cells secrete a number of molecules including granzymes and perforin. Strong evidence suggests that perforin contributes to axonal injury in the MS plaque (Figure 2). The presence of perforin correlates with neurologic disability and with the presence of “black holes” on MRI. Therefore, CD8+ T cells play a critical role during the acute inflammatory phase of the disease as well as during the neurodegenerative phase. CD8+ T cells account for axonal damage in MS as well as long-term neurological deficits. There is evidence that CD8+ T cells play a major role in the secondary progressive phase of the disease by the secretion of lymphotoxin [74]. In studies of cytokine secretion in patients with secondary progressive MS and normal controls, investigators found clear evidence of anti-CD3-stimulated CD8+ T cells in the patients with secondary progressive MS. These cells secreted lymphotoxin and other cytokines, which play a critical role in the evolution of the progressive phase of the disease. This provides strong evidence that the CD8+ T cell plays a role in the neurodegenerative aspect of the progressive phase of the disease as well as in the early acute phase.


Is multiple sclerosis an autoimmune disease?

Wootla B, Eriguchi M, Rodriguez M - Autoimmune Dis (2012)

Perforin is the primary mediator of  injury by CD8+ T cells. Perforin is the primary molecule known to mediate injury by CD8+ T cells. Perforin mediates axonal transection in multiple sclerosis (MS) and correlates with neurological disability. Cytotoxic T cells secrete perforin in the form of granules along with granzymes. This release activates calcium, which results in “poly-perforin” channels on the target cells. This results in holes in the membrane of the target cells, causing leakage of intracellular material, which results in cell death.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3361990&req=5

fig2: Perforin is the primary mediator of  injury by CD8+ T cells. Perforin is the primary molecule known to mediate injury by CD8+ T cells. Perforin mediates axonal transection in multiple sclerosis (MS) and correlates with neurological disability. Cytotoxic T cells secrete perforin in the form of granules along with granzymes. This release activates calcium, which results in “poly-perforin” channels on the target cells. This results in holes in the membrane of the target cells, causing leakage of intracellular material, which results in cell death.
Mentions: Finally, CD8+ T cells show oligoclonal expansion in MS brains, blood, and CSF that have not been reported with CD4+ T cells [69–71]. Some of the cytotoxic T cells react against autoantigens such as myelin-basic protein [72]. If these cells traveled randomly in the CNS, then presumably their CD3 junction region length would show a normal Gaussian distribution. In contrast, there is skewing of the CDR3 junction regions in MS, suggesting a selective infiltration or expansion of CD8+ T cell clones into the CNS [71]. Moreover, the T-cell receptors of the CD8+ T cells demonstrate distinct CD8+ T-cell clones with conserved specificity implying recognition of a similar antigen that results in their proliferation in the CNS. Much effort has focused on the potential role of IL17 in the MS plaque, and because of the bias of experiments in EAE, it has been proposed that this comes from the CD4+ T cells. However, there is evidence that IL17 is also made by CD8+ T cells [73]. Defining IL17+ CD8+ T cells opens up new avenues for future research and new targets from the standpoint of immunotherapy. CD8+ T cells secrete a number of molecules including granzymes and perforin. Strong evidence suggests that perforin contributes to axonal injury in the MS plaque (Figure 2). The presence of perforin correlates with neurologic disability and with the presence of “black holes” on MRI. Therefore, CD8+ T cells play a critical role during the acute inflammatory phase of the disease as well as during the neurodegenerative phase. CD8+ T cells account for axonal damage in MS as well as long-term neurological deficits. There is evidence that CD8+ T cells play a major role in the secondary progressive phase of the disease by the secretion of lymphotoxin [74]. In studies of cytokine secretion in patients with secondary progressive MS and normal controls, investigators found clear evidence of anti-CD3-stimulated CD8+ T cells in the patients with secondary progressive MS. These cells secreted lymphotoxin and other cytokines, which play a critical role in the evolution of the progressive phase of the disease. This provides strong evidence that the CD8+ T cell plays a role in the neurodegenerative aspect of the progressive phase of the disease as well as in the early acute phase.

Bottom Line: There is strong evidence that MS is, at least in part, an immune-mediated disease.There is less evidence that MS is a classical autoimmune disease, even though many authors state this in the description of the disease.In addition, we present an alternate hypothesis based on virus infection to explain the pathogenesis of MS.

View Article: PubMed Central - PubMed

Affiliation: Departments of Neurology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.

ABSTRACT
Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) with varied clinical presentations and heterogeneous histopathological features. The underlying immunological abnormalities in MS lead to various neurological and autoimmune manifestations. There is strong evidence that MS is, at least in part, an immune-mediated disease. There is less evidence that MS is a classical autoimmune disease, even though many authors state this in the description of the disease. We show the evidence that both supports and refutes the autoimmune hypothesis. In addition, we present an alternate hypothesis based on virus infection to explain the pathogenesis of MS.

No MeSH data available.


Related in: MedlinePlus