The small heat-shock protein αB-crystallin as candidate autoantigen in multiple sclerosis

Noort, Johannes M. van; Sechel, Arianne C. van; Bajramović, Jeffrey J.; Ouagmiri, Mustapha Ei; Polman, Chris H.; Lassmann, Hans; Ravid, Rivka

doi:10.1038/375798a0

Cited by 382 publications

(221 citation statements)

References 20 publications

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“…S-100b Kojima et al, 1993 , the heat-shock protein Ž . alpha-B crystallin Van Noort et al, 1995 , and functional molecular mimicry between infectious agents and myelin Ž constituents may be involved Wucherpfennig and Stro-. minger, 1995 . In MS and EAE, antigen-specific and non-specific interactions between CNS-infiltrating mononuclear cells and interactions of these cells with brain glia cells are mediated by accessory molecules and cytokines.…”

Section: žmentioning

confidence: 99%

Expression of accessory molecules and cytokines in acute EAE in marmoset monkeys (Callithrix jacchus)

Laman

Meurs²,

Schellekens³

et al. 1998

Journal of Neuroimmunology

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Ž .Accessory molecules and cytokines are involved in the immunopathogenesis of multiple sclerosis MS and experimental autoimmune Ž . encephalomyelitis EAE in rodent models, and are potential targets for immunotherapy. Evaluation of such experimental therapies requires appropriate animal models. Therefore, we analysed the expression of selected accessory molecules and cytokines in the brain of Ž . marmoset monkeys Callithrix jacchus with acute EAE, a newly described non-human primate model for MS. All animals experienced active disease clinically and histopathologically with strong resemblance to MS. Perivascular infiltrates of mononuclear cells showed abundant expression of CD40. CD40 was expressed on macrophages, indicating that T cell priming and macrophage effector functions Ž . Ž . may result from local CD40-CD40L interactions. CD40 ligand CD40L and B7-2 CD86 were also expressed, but to a lower extent, Ž . while B7-1 CD80 expression was limited. Both pro-inflammatory and anti-inflammatory cytokines were produced within individual Ž . lesions during active disease IFN-a, IFN-g , TNF-a, IL-1a , IL-1b, IL-2, IL-4, IL-10 and IL-12 . This suggests that relative levels rather than sequential expression of Th1-and Th2-type cytokines determine disease activity. These findings demonstrate the value of EAE in marmoset monkeys as a model to assess the role of accessory molecules and cytokines in multiple sclerosis, and to evaluate targeted intervention. q

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Section: žmentioning

confidence: 99%

Expression of accessory molecules and cytokines in acute EAE in marmoset monkeys (Callithrix jacchus)

Laman

Meurs²,

Schellekens³

et al. 1998

Journal of Neuroimmunology

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“…The autoantigen(s) probably reside in CNS myelin, the target of the immune response. In addition to the wellcharacterized autoreactivity to the quantitatively major proteins of CNS myelin, myelin basic protein and proteolipid protein [3][4][5][6], autoreactivity to other myelin proteins such as myelin oligodendrocyte glycoprotein (MOG) [7,8], myelin-associated glycoprotein (MAG) [9,10] and oligodendrocyte-specific protein (OSP) [11,12], as well as myelin-associated proteins like aB-crystallin [13,14] have more recently been detected in MS patients.…”

Section: Introductionmentioning

confidence: 99%

Oligodendrocyte‐specific protein is encephalitogenic in rhesus macaques and induces specific demyelination of the optic nerve

et al. 2008

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Oligodendrocyte-specific protein (OSP) is a candidate autoantigen in the development of multiple sclerosis (MS). We evaluated the potential of OSP to induce EAE in rhesus monkeys, an out bred animal model for MS that is immunologically close to humans. Since OSP is a four-membrane spanning protein with highly hydrophobic regions, we synthesized recombinant proteins encompassing only the hydrophilic regions of human OSP (soluble (s)hOSP). Immunization with shOSP proteins induced clinical signs and histological features of optic neuritis in four out of ten rhesus monkeys. The development of clinical disease was associated with the presence of a strong cellular proliferative response to the immunizing shOSP protein. Analysis of the cellular responses in combination with neuropathological observations also indicates an important role for neutrophils in the disease process. Interestingly, all immunized monkeys developed antibody responses to OSP peptide 103-123, a B cell epitope previously identified in MS patients. These responses did not correlate with the development of clinical disease, but may have relevance as a biomarker for immunoreactivity towards OSP in myelin disorders. Our data demonstrate that in rhesus monkeys immune responses directed at OSP are encephalitogenic, leading to inflammatory responses throughout the central nervous system and to selective demyelination of the optic nerve.

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“…Using a combination of large-scale expressed-sequencetags sequencing and microarray technology, we reported differentially expressed genes in active lesions and control brains from MS patients and EAE animals. 107 In that study, alpha B-crystallin, an inducible heat shock protein localized in the myelin sheath and a putative target for T cells in MS, 108 was identified as the most abundant transcript unique to MS plaques. The next five most abundant transcripts included those for prostaglandin D synthase, prostatic binding protein, ribosomal protein L17, and osteopontin.…”

Section: Functional Genomicsmentioning

confidence: 98%

Multiple sclerosis genetics: leaving no stone unturned

2005

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Compelling epidemiologic and molecular data indicate that genes play a primary role in determining who is at risk for developing multiple sclerosis (MS), how the disease progresses, and how someone responds to therapy. The genetic component of MS etiology is believed to result from the action of allelic variants in several genes. Their incomplete penetrance and moderate individual effect probably reflects epistatic interactions, post-transcriptional regulatory mechanisms, and significant environmental influences. Equally significant, it is also likely that locus heterogeneity exists, whereby specific genes influence susceptibility and pathogenesis in some individuals but not in others. With the aid of novel analytical algorithms, the combined study of genomic, transcriptional, proteomic, and phenotypic information in well-controlled study groups will define a useful conceptual model of pathogenesis and a framework for understanding the mechanisms of action of existing therapies for this disorder, as well as the rationale for novel curative strategies.

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The small heat-shock protein αB-crystallin as candidate autoantigen in multiple sclerosis

Cited by 382 publications

References 20 publications

Expression of accessory molecules and cytokines in acute EAE in marmoset monkeys (Callithrix jacchus)

Expression of accessory molecules and cytokines in acute EAE in marmoset monkeys (Callithrix jacchus)

Oligodendrocyte‐specific protein is encephalitogenic in rhesus macaques and induces specific demyelination of the optic nerve

Multiple sclerosis genetics: leaving no stone unturned

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