Calpain secreted by activated human lymphoid cells degrades myelin

Deshpande, Rajendra V.; Goust, Jean‐Michel; Hogan, Edward L.; Banik, Naren L.

doi:10.1002/jnr.490420214

Cited by 55 publications

(44 citation statements)

References 44 publications

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“…In fact, the calpain and IFN-␥ labeling appeared to obscure the cell borders. These observations suggest that activated T cells may secrete calpain in vivo, confirming previous studies demonstrating cellular release of calpain in the presence of stimulatory factors (10,36,37). Activated T cells therefore may secrete calpain in EAE.…”

Section: Discussionsupporting

confidence: 89%

“…In vitro studies have demonstrated vesicular disruption of the myelin sheath, as seen in demyelinating diseases, when rat sciatic nerves are exposed to calcium ionophores at physiological pH (31). Activated calpain also participates in programmed cell death in certain cell types, but reports of (10). Using fluorescent double-labeling techniques with both anti-CD2 and IFN-␥ antibodies, we found little calpain expression in CD2-positive cells, but markedly increased calpain immunoreactivity in cells expressing IFN-␥, which is produced by activated T cells.…”

Section: Discussionmentioning

confidence: 99%

“…In vitro studies have shown secretion of neutral proteinases by microglia, up-regulation and secretion of calpain in activated T cells, and increased expression of calpain and other proteases in reactive astrocytes (8)(9)(10)(11)(12).…”

mentioning

confidence: 99%

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Increased calpain expression in activated glial and inflammatory cells in experimental allergic encephalomyelitis

Shields

Tyor

Deibler

et al. 1998

Proc. Natl. Acad. Sci. U.S.A.

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In demyelinating diseases such as multiple sclerosis (MS), myelin membrane structure is destabilized as myelin proteins are lost. Calcium-activated neutral proteinase (calpain) is believed to participate in myelin protein degradation because known calpain substrates [myelin basic protein (MBP); myelin-associated glycoprotein] are degraded in this disease. In exploring the role of calpain in demyelinating diseases, we examined calpain expression in Lewis rats with acute experimental allergic encephalomyelitis (EAE), an animal model for MS. Using double-immunof luorescence labeling to identify cells expressing calpain, we labeled rat spinal cord sections for calpain with a polyclonal millicalpain antibody and with mAbs for glial (GFAP, OX42, GalC) and inf lammatory (CD2, ED2, interferon ␥) cell-specific markers. Calpain expression was increased in activated microglia (OX42) and infiltrating macrophages (ED2) compared with controls. Oligodendrocytes (galactocerebroside) and astrocytes (GFAP) had constitutive calpain expression in normal spinal cords whereas reactive astrocytes in spinal cords from animals with EAE exhibited markedly increased calpain levels compared with astrocytes in adjuvant controls. Oligodendrocytes in spinal cords from rats with EAE expressed increased calpain levels in some areas, but overall the increases in calpain expression were small. Most T cells in grade 4 EAE expressed low levels of calpain, but interferon ␥-positive cells demonstrated markedly increased calpain expression. These findings suggest that increased levels of calpain in activated glial and inf lammatory cells in EAE may contribute to myelin destruction in demyelinating diseases such as MS.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Increased calpain expression in activated glial and inflammatory cells in experimental allergic encephalomyelitis

Shields

Tyor

Deibler

et al. 1998

Proc. Natl. Acad. Sci. U.S.A.

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“…Myelin proteins also may be degraded by calpain secreted from activated glial͞inflammatory cells because calpain is activated at extracellular calcium levels. Previous in vitro and in vivo studies have observed calpain secretion from various cell types, including activated macrophages and T cells, with subsequent degradation of myelin proteins (26,(43)(44)(45).…”

Section: Discussionmentioning

confidence: 99%

A putative mechanism of demyelination in multiple sclerosis by a proteolytic enzyme, calpain

Shields

Schaecher²,

Saido³

et al. 1999

Proc. Natl. Acad. Sci. U.S.A.

151

111

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In autoimmune demyelinating diseases such as multiple sclerosis (MS), the degradation of myelin proteins results in destabilization of the myelin sheath. Thus, proteases have been implicated in myelin protein degradation, and recent studies have demonstrated increased expression and activity of a calcium-activated neutral proteinase (calpain) in experimental allergic encephalomyelitis, the corresponding animal model of MS. In the present study, calpain activity and expression (at translational and transcriptional levels) were evaluated in white matter from human patients with MS and Parkinson's and Alzheimer's diseases and compared with that of white matter from normal controls. Western blot analysis revealed that levels of the active form of calpain and calpainspecific degradation products (fodrin) were increased by 90.1% and 52.7%, respectively, in MS plaques compared with normal white matter. Calpain translational expression was up-regulated by 462.5% in MS plaques compared with controls, although levels of the specific endogenous inhibitor, calpastatin, were not altered significantly. At the transcriptional level, no significant changes in calpain or calpastatin expression were detected by reverse transcription-PCR. Using double immunof luorescent labeling, increased calpain expression was observed in reactive astrocytes, activated T cells, and activated mononuclear phagocytes in and adjacent to demyelinating lesions. Calpain activity and translational expression were not increased significantly in white matter from patients with Parkinson's or Alzheimer's diseases compared with that of normal controls. Because calpain degrades all major myelin proteins, the increased activity and expression of this proteinase may play a critical role in myelinolysis in autoimmune demyelinating diseases such as MS.

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“…Activated calpain may be released from these cells (e.g. microglia, macrophages, T cells), thereby producing immunogenic peptides from digested myelin proteins for presentation to and sensitization of other T lymphocytes (Deshpande et al, 1995b;Smith et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

Increased calpain correlates with Th1 cytokine profile in PBMCs from MS patients

Imam

Guyton

Haque

et al. 2007

Journal of Neuroimmunology

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Multiple sclerosis (MS) is a devastating autoimmune demyelinating disease of the CNS. This study investigated whether expression and activity of the calcium-activated protease calpain correlated with Th1/Th2 dysregulation in MS patients during states of relapse and remission. Calpain expression and activity were significantly increased in peripheral blood mononuclear cells (PBMCs) from MS patients, compared to controls, with the highest expression and activity noted during relapse. Th1 cytokines were highest and Th2 cytokines were lowest in MS patients during relapse. Treatment with calpain inhibitor, calpeptin, decreased Th1 cytokines in PBMCs from MS patients. Calpain inhibitor also reduced degradation of myelin basic protein (MBP) by inhibiting the calpain secreted from MBPspecific T cells. Taken together, these results suggested calpain involvement in Th1/Th2 dysregulation in MS patients.

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Calpain secreted by activated human lymphoid cells degrades myelin

Cited by 55 publications

References 44 publications

Increased calpain expression in activated glial and inflammatory cells in experimental allergic encephalomyelitis

Increased calpain expression in activated glial and inflammatory cells in experimental allergic encephalomyelitis

A putative mechanism of demyelination in multiple sclerosis by a proteolytic enzyme, calpain

Increased calpain correlates with Th1 cytokine profile in PBMCs from MS patients

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