Polyreactive myelin oligodendrocyte glycoprotein antibodies: Implications for systemic autoimmunity in progressive experimental autoimmune encephalomyelitis

Peterson, Lisa K.; Tsunoda, Ikuo; Masaki, Takahisa; Fujinami, Robert S.

doi:10.1016/j.jneuroim.2006.11.024

Cited by 13 publications

(27 citation statements)

References 69 publications

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“…Previously, we reported that two MOG 92–106 anti-bodies produced by two hybridoma cell lines were NAA of the IgM isotype, which reacted not only with the initiating antigen, but also protein isolated from organs outside the CNS and antigens associated with systemic autoimmune disease [33], such as dsDNA and histone H1a [41]. If these NAA contribute significantly to the amount of IgM antibodies reactive with MOG 92–106 and dsDNA, depletion of the major producer of these antibodies, B-1 cells, should drastically reduce serum titer of MOG 92–106 and dsDNA antibodies of the IgM isotype.…”

Section: Resultsmentioning

confidence: 99%

“…I.c. injection of the MOG 92–106 antibody producing hybridomas into naïve mice resulted in antibody deposition and demyelination in the CNS [33]. This led us to hypothesize that NAA were involved in the disease progression and demyelination in A.SW mice with MOG 92–106 induced P-EAE.…”

Section: Discussionmentioning

confidence: 99%

“…To investigate the contribution of MOG 92–106 antibodies to disease, we generated hybridoma cell lines from an A.SW mouse with progressive EAE (P-EAE) [33]. Two hybridoma cell lines producing MOG 92–106 antibodies were found to be of the IgM isotype, encoded by Ig genes in their germline configuration [34] and polyreactive.…”

Section: Introductionmentioning

confidence: 99%

“…In addition, intraperitoneal (i.p.) injection of the MOG 92–106 antibody producing hybridoma cells into naïve mice resulted in antibody deposition in the kidney [33]. Thus, the MOG 92–106 reactive NAA recognize a variety of antigens including several ubiquitously expressed antigens and transfer of the antibodies recapitulates disease manifestations observed in P-EAE.…”

Section: Introductionmentioning

confidence: 99%

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Role of CD5⁺B-1 cells in EAE pathogenesis

2008

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Hybridoma cell lines producing natural autoantibodies (NAA), generated from A.SW mice with progressive experimental autoimmune encephalomyelitis (P-EAE), have been shown to cause demyelination and renal pathology when injected into naïve mice. To investigate the relative contribution of these antibodies to disease pathogenesis, B-1 cells, the major producers of NAA, were depleted by hypotonic shock. Depletion of B-1 cells during the effector phase of EAE significantly decreased the severity of demyelination and overall pathology in the brain. There was also a decreased incidence of P-EAE and a decrease in clinical score. Depletion during the induction phase of the disease resulted in an increase in the incidence of P-EAE and in the clinical score. Overall, B-1 cells were found to modulate EAE pathogenesis.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Role of CD5⁺B-1 cells in EAE pathogenesis

2008

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“…A.SW mice sensitized with amino acids 92-106 from myelin oligodendrocyte glycoprotein (MOG) developed a PP form of experimental autoimmune encephalomyelitis (EAE), an autoimmune animal model of MS, which is traditionally considered to be organ-specific [13,14]. Surprisingly, mice with PP-EAE had antibody deposition in the glomeruli of their kidneys [13,14].…”

Section: Introductionmentioning

confidence: 99%

Cross-reactive myelin antibody induces renal pathology

et al. 2008

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Experimental autoimmune encephalomyelitis (EAE) is an autoimmune model for multiple sclerosis (MS). Previously, we reported renal immunoglobulin (Ig) deposition in mice with myelin oligodendrocyte glycoprotein ) induced progressive-EAE and naïve mice injected with MOG 92-106 hybridoma cells producing antibody that cross-reacts with various autoantigens including double-stranded DNA. To assess whether MOG 92-106 antibodies actually induce kidney changes, the extent of renal Ig deposition and changes in glomerular histology and filtration were investigated. Mice with progressive-EAE exhibited Ig deposition, glomerular hypercellularity and proteinuria indicating kidney dysfunction. MOG 92-106 hybridoma cell injected mice also had Ig in the kidneys and proteinuria. Therefore, sensitization with MOG 92-106 and transfer of MOG [92][93][94][95][96][97][98][99][100][101][102][103][104][105][106] antibodies can induce both central nervous system and renal pathology. The renal involvement reported in MS is believed to occur as a side effect of nephrotoxic drugs or neurogenic bladder. Our results demonstrate that an autoimmune response against myelin could induce pathologic changes in the kidney and may help explain renal changes reported in patients with progressive MS.

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Lovastatin induces the formation of abnormal myelin‐like membrane sheets in primary oligodendrocytes

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et al. 2008

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Statins, well-known inhibitors of cholesterol synthesis and protein isoprenylation, have been proposed as therapeutic drugs for multiple sclerosis (MS). As lovastatin and simvastatin, which are currently tested for their use in MS, can cross the blood-brain barrier, they may affect cellular processes in the central nervous system. This is especially relevant with respect to remyelination as a proposed additional treatment for MS, because cholesterol is a major component of myelin. Here, we show that primary oligodendrocytes, treated with lovastatin, form extensive membrane sheets, which contain galactosphingolipids. However, these membrane sheets are devoid of the major myelin proteins, myelin basic protein (MBP) and proteolipid protein (PLP). Reduced MBP protein expression was confirmed by SDS-PAGE and Western blotting, and in situ hybridization experiments revealed that lovastatin blocks MBP mRNA transport into oligodendrocyte processes. In contrast, PLP expression was only mildly affected by lovastatin. However, lovastatin treatment resulted in intracellular accumulation of PLP and prevented its translocation to the cell surface. Interestingly, another inhibitor of cholesterol synthesis (ro48-8071), which does not interfere with isoprenylation, had a similar effect on the localization of PLP, but it did not affect MBP expression and localization. These results suggest that lovastatin affects PLP transport predominantly by the inhibition of cholesterol synthesis, whereas reduced MBP expression is caused by impaired isoprenylation. Based on these results we recommend to carefully monitor the effect of statins on myelination prior to their use in demyelinating diseases.

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Polyreactive myelin oligodendrocyte glycoprotein antibodies: Implications for systemic autoimmunity in progressive experimental autoimmune encephalomyelitis

Cited by 13 publications

References 69 publications

Role of CD5⁺B-1 cells in EAE pathogenesis

Role of CD5⁺B-1 cells in EAE pathogenesis

Cross-reactive myelin antibody induces renal pathology

Lovastatin induces the formation of abnormal myelin‐like membrane sheets in primary oligodendrocytes

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Polyreactive myelin oligodendrocyte glycoprotein antibodies: Implications for systemic autoimmunity in progressive experimental autoimmune encephalomyelitis

Cited by 13 publications

References 69 publications

Role of CD5+B-1 cells in EAE pathogenesis

Role of CD5+B-1 cells in EAE pathogenesis

Cross-reactive myelin antibody induces renal pathology

Lovastatin induces the formation of abnormal myelin‐like membrane sheets in primary oligodendrocytes

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Product

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Role of CD5⁺B-1 cells in EAE pathogenesis

Role of CD5⁺B-1 cells in EAE pathogenesis