Calpain expression and infiltration of activated T cells in experimental allergic encephalomyelitis over time: increased calpain activity begins with onset of disease

Schaecher, Kurt E.; Rocchini, Anne; Dinkins, J; Matzelle, Denise; Banik, Naren L.

doi:10.1016/s0165-5728(02)00142-x

Cited by 35 publications

(40 citation statements)

References 34 publications

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“…Second, there are considerably less reagents available in guinea pigs than in either humans or mice. This is best exemplified by the relative lack of CD4 ϩ -and CD8 ϩ -specific guinea pig reagents and their inability for utility in immunohistochemistry (37,38). These deficiencies, notwithstanding, should not diminish the induction of biliary pathology in guinea pigs.…”

Section: Discussionmentioning

confidence: 99%

Induction of Primary Biliary Cirrhosis in Guinea Pigs following Chemical Xenobiotic Immunization

Leung

Park

Tsuneyama

et al. 2007

The Journal of Immunology

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Although significant advances have been made in dissecting the effector mechanisms in autoimmunity, the major stumbling block remains defining the etiological events that precede disease. Primary biliary cirrhosis (PBC) illustrates this paradigm because of its high degree of heritability, its female predominance, and its extraordinarily specific and defined immune response and target destruction. In PBC, the major autoantigens belong to E2 components of the 2-oxo-acid dehydrogenase family of mitochondrially located enzymes that share a lipoylated peptide sequence that is the immunodominant target. Our previous work has demonstrated that synthetic mimics of the lipoate molecule such as 6-bromohexoanate demonstrate a high degree of reactivity with PBC sera prompted us to immunize groups of guinea pigs with 6-bromohexoanate conjugated to BSA. In this study, we provide serologic and immunohistochemical evidence that such immunized guinea pigs not only develop antimitochondrial autoantibody responses similar to human PBC, but also develop autoimmune cholangitis after 18 mo. Xenobiotic-immunized guinea pigs are the first induced model of PBC and suggest an etiology that has implications for the causation of other human autoimmune diseases. The data also reflect the likelihood that, in PBC, the multilineage antimitochondrial response is a pathogenic mechanism and that loss of tolerance and subsequent development of biliary lesions depends on either modification of the host mitochondrial Ag or a similar breakdown due to molecular mimicry.

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Section: Discussionmentioning

confidence: 99%

Induction of Primary Biliary Cirrhosis in Guinea Pigs following Chemical Xenobiotic Immunization

Leung

Park

Tsuneyama

et al. 2007

The Journal of Immunology

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“…Using Western blot analysis, -calpain expression, a protease implicated in degradation of myelin Schaecher et al, 2002), is two times greater in females compared with males in 9-month-old spinal cord and brain. Using real-time PCR, transcription of -calpain is also ϳ160% higher in females compared with males at 9 months.…”

Section: Oligodendrocyte Proliferation and Cell Death Is Increased Inmentioning

confidence: 99%

“…If this is so, and assuming that these Olgs make myelin, myelin itself may also degenerate and, possibly, be regenerated at a greater rate in females than in males. The degradation of myelin has been indirectly monitored by examining levels of proteases abundant in myelin, especially -calpain, because its activity is upregulated in multiple sclerosis (MS) Schaecher et al, 2002) and in CNS injury (Ray et al, 1999). Most interestingly, the expression of total -calpain (zymogen and active form) in spinal cords of 9-month-old C57BL/6 mice is twofold greater in females compared with males (Fig.…”

Section: Glia Cell Deathmentioning

confidence: 99%

Proliferation and Death of Oligodendrocytes and Myelin Proteins Are Differentially Regulated in Male and Female Rodents

et al. 2006

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Sexual dimorphism of neurons and astrocytes has been demonstrated in different centers of the brain, but sexual dimorphism of oligodendrocytes and myelin has not been examined. We show, using immunocytochemistry and in situ hybridization, that the density of oligodendrocytes in corpus callosum, fornix, and spinal cord is 20 -40% greater in males compared with females. These differences are present in young and aged rodents and are independent of strain and species. Proteolipid protein and carbonic anhydrase-II transcripts, measured by real-time PCR, are approximately two to three times greater in males. Myelin basic protein and 2Ј,3Ј-cyclic nucleotide 3Ј-phosphodiesterase, measured by Western blots, are 20 -160% greater in males compared with females. Surprisingly, both generation of new glia and apoptosis of glia, including oligodendrocytes, are approximately two times greater in female corpus callosum. These results indicate that the lifespan of oligodendrocytes is shorter in females than in males. Castration of males produces a female phenotype characterized by fewer oligodendrocytes and increased generation of new glia. These findings indicate that exogenous androgens differentially affect the lifespan of male and female oligodendrocytes, and they can override the endogenous production of neurosteroids. The data imply that turnover of myelin is greater in females than in males. -Calpain, a protease upregulated in degeneration of myelin, is dramatically increased at both transcriptional and translational levels in females compared with males. These morphological, molecular, and biochemical data show surprisingly large differences in turnover of oligodendrocytes and myelin between sexes. We discuss the potential significance of these differences to multiple sclerosis, a sexually dimorphic disease, whose progression is altered by exogenous hormones.

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“…Whether, lack of an active immune response at the level of proinflammatory cytokine production in GMFKO animals or the resistance of myelin itself to immune attack is critical in understanding the biochemistry behind demyelination. Though the biochemical mechanism leading to myelinolysis is poorly understood, previous studies, both in vitro (de Rosbo and Bernard 1989;Johns et al 1995;Menon et al 1997) and in EAE animals implicated an important role for the calcium activated neutral proteases (CANP) in MBP degradation (Schaecher et al 2001;Schaecher et al 2002). Injection of anti-GalC antiserum into the normal rabbit vitreous body resulted in demyelination of epiretinal myelinated fibers (Ozawa et al, 1989) and that intrathecal injection of anti-GalC (galactocerebroside) along with complement induced focal demyelination (Keirstead et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

Diminished degradation of myelin basic protein by anti-sulfatide antibody and interferon-γ in myelin from glia maturation factor-deficient mice

Menon

Haas

et al. 2007

Neuroscience Research

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In this study we show the effect of anti-sulfatide (RmAb) antibodies and inflammatory cytokines, TNF-α and IFN-γ in inducing myelin basic protein (MBP) degradation in myelin isolated from control wild type (WT) and glia maturation factor (GMF)-deficient (GMF-KO) mice. GMF was not detected in isolated myelin from WT and GMF-KO mice although it is present in brains of WT mice. Our results show that calcium dependent neutral protease activity caused significantly elevated degradation of 18.5 and/or 17.5 kDa isoforms of MBP in WT-myelin treated with RmAb or IFN-γ. In contrast, MBP degradation in isolated myelin from GMF-KO mice remained unaffected following treatment with RmAb, IFN-γ, or GM-CSF. Neither the 14 kDa isoform of MBP or proteolipid protein (PLP) showed an elevated degradation compared to controls. A virtual absence of GM-CSF, TNF-α and IFN-γ in GMF-KO brain compared to WT was also evident when the animals were challenged with MOG 35-55. Additionally, the myelin from GMF-KO mice showed difference in distribution of myelin oligodendrocyte glycoprotein (MOG) and β-tubulin in a sucrose density gradient myelinaxolemmal fractions compared to WT. Taken together, our data suggests a role for GMF in the biochemical organization of myelin and thereby its effect on MBP degradation induced by RmAb and IFN-γ.

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Calpain expression and infiltration of activated T cells in experimental allergic encephalomyelitis over time: increased calpain activity begins with onset of disease

Cited by 35 publications

References 34 publications

Induction of Primary Biliary Cirrhosis in Guinea Pigs following Chemical Xenobiotic Immunization

Induction of Primary Biliary Cirrhosis in Guinea Pigs following Chemical Xenobiotic Immunization

Proliferation and Death of Oligodendrocytes and Myelin Proteins Are Differentially Regulated in Male and Female Rodents

Diminished degradation of myelin basic protein by anti-sulfatide antibody and interferon-γ in myelin from glia maturation factor-deficient mice

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