Delta Crystallon BV

Leiden, Netherlands

Delta Crystallon BV

Leiden, Netherlands
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Bsibsi M.,Delta Crystallon BV | Nomden A.,University of Groningen | van Noort J.M.,Delta Crystallon BV | Baron W.,University of Groningen
Journal of Neuroscience Research | Year: 2012

Toll-like receptors (TLRs) play a key role in controlling innate immune responses to a wide variety of pathogen-associated molecules as well as endogenous signals. In addition, TLR expression within nonimmune cells has been recognized as as modulator of cell behavior. In this study we have addressed the question of whether functional TLRs are expressed on oligodendrocytes, the myelinating cells of the central nervous system. Primary cultures of rat oligodendrocytes at different maturation stages were found to express TLR2 and, to lesser extent, TLR3. Immunocytochemical analysis revealed that both TLRs were localized at the cell body and primary processes and were excluded from myelin-like membranes. Interestingly, innate immune receptor ligands were able to modulate oligodendrocyte survival, differentiation, and myelin-like membrane formation, indicating that TLRs on oligodendrocytes are functional. In highly purified oligodendrocytes cultures, the TLR2 agonist zymosan promoted survival, differentiation, and myelin-like membrane formation, whereas poly-I:C, a TLR3 ligand, was a potent inducer of apoptosis. Together, these data indicate that, in addition to other neural cell types, also oligodendrocytes express functional TLRs, which play a role in regulating various aspects of oligodendrocyte behavior. © 2011 Wiley Periodicals, Inc.

Bsibsi M.,Delta Crystallon BV | Holtman I.R.,University of Groningen | Gerritsen W.H.,VU University Amsterdam | Eggen B.J.L.,University of Groningen | And 6 more authors.
Journal of Neuropathology and Experimental Neurology | Year: 2013

Microglial nodules are frequently observed in the normal-appearing white matter of multiple sclerosis (MS) patients. Previously, we have shown that these clusters, which we call "preactive MS lesions," are closely associated with stressed oligodendrocytes and myelin sheaths that contain markedly elevated levels of the small stress protein alpha-B-crystallin (HspB5). Here, we show that microglia in these lesions express the recently identified receptors for HspB5, that is, CD14, Toll-like receptor family 1 and 2 (TLR1 and TLR2), and several molecular markers of the microglial response to HspB5. These markers were identified by genome-wide transcript profiling of 12 primary human microglial cultures at 2 time points after exposure to HspB5. These data indicate that HspB5 activates production by microglia of an array of chemokines, immune-regulatory mediators, and a striking number of antiviral genes that are generally inducible by type I interferons. Together, our data suggest that preactive MS lesions are at least in part driven by HspB5 derived from stressed oligodendrocytes and may reflect a local attempt to restore tissue homeostasis. © 2013 by the American Association of Neuropathologists, Inc.

PubMed | Ludwig Maximilians University of Munich, University of Groningen, VU University Amsterdam and Delta Crystallon BV
Type: | Journal: Glia | Year: 2017

The glial stress protein alpha B-crystallin (HSPB5) is an endogenous agonist for Toll-like receptor 2 in CD14

van Noort J.M.,Delta Crystallon BV | Baker D.,Queen Mary, University of London | Amor S.,Queen Mary, University of London | Amor S.,VU University Amsterdam
CNS and Neurological Disorders - Drug Targets | Year: 2012

Both immune-mediated and neurodegenerative processes play a role in the pathogenesis of multiple sclerosis (MS). There is still considerable debate, however, on how to link these two seemingly unrelated elements in disease. It has also remained unclear how the immune system can be involved without harboring any obvious myelin-directed abnormality in MS patients. Here, we propose that the unique properties of a small heat shock protein, HSPB5, can help reconcile the role of the immune system with the neurodegenerative element in MS, and explain the absence of any peripheral immune abnormality in patients. By being selectively induced as a protective stress protein in oligodendrocytes, and subsequently triggering activation of nearby microglia, HSPB5 accumulation translates neurodegenerative signals into a local innate immune response. The immune-regulatory profile of HSPB5-activated microglia, as well as animal model data, indicate that the HSPB5-induced innate response is neuroprotective. However, the presence of pro-inflammatory HSPB5-reactive memory T cells in the human immune repertoire, a unique feature among mammals, can subvert this response. Recruited by the innate response, such T cells respond to the accumulation of HSPB5 by an adaptive immune response, dominated by IFN-γ production, that ultimately overwhelms the originally protective microglial response, and culminates in tissue damage. Thus, HSPB5 accumulation caused by neurodegeneration can provoke a destructive local adaptive response of an otherwise normal immune system. This scenario is fully consistent with known causative factors and the pathology of MS, and with the effects of various therapies. It also helps explain why MS develops only in humans. © 2012 Bentham Science Publishers.

Van Noort J.M.,TNO | Van Noort J.M.,Delta Crystallon BV | Bsibsi M.,TNO | Bsibsi M.,Delta Crystallon BV | And 6 more authors.
Journal of Neuropathology and Experimental Neurology | Year: 2010

We present the first comparative analysis of serum immunoglobulinG reactivity profiles against the full spectrum of human myelin-associated proteins in multiple sclerosis patients and healthy control subjects. In both groups, serum antibodies display a consistent and prominent reaction to αB-crystallin (CRYAB) versus other myelin proteins. As an apparently major target for the adaptive immune system in humans, CRYAB selectively accumulates in oligodendrocytes, but not in astrocytes, or axons in so-called preactive multiple sclerosis lesions. These are clusters of activated HLA-DR-expressing microglia in myelinated normal-appearing white matter with no obvious leukocyte infiltration. They are found in most multiple sclerosis patients at all stages of disease. In these lesion areas, CRYAB in oligodendrocytes may come directly in contact with activated HLA-DR microglia. We demonstrate that CRYAB activates innate responses bymicroglia by stimulating the secretion of leukocyte-recruiting factors, including tumor necrosis factor, interleukin 17, CCL5, and CCL1, and immune-regulatory cytokines such as interleukin 10, transforming growth factor-β, and interleukin 13. Together, these data suggest that CRYAB accumulation in preactive lesions may be part of a reversible reparative local response that involves both oligodendrocytes and microglia. At the same time, however, accumulated CRYAB may represent a major target for adaptive immune responses that could contribute to progression of preactive lesions to a stage of demyelination. © 2010 by the American Association of Neuropathologists, Inc.

van Noort J.M.,Delta Crystallon BV | van den Elsen P.J.,VU University Amsterdam | van den Elsen P.J.,Leiden University | van Horssen J.,VU University Amsterdam | And 4 more authors.
CNS and Neurological Disorders - Drug Targets | Year: 2011

For the development of novel central nervous system (CNS) drugs to promote neuroprotection, it is helpful to gain a better understanding of natural neuroprotective phenomena. Microglia play key roles in endogenous neuroprotective pathways and their activation is a common theme in several neurodegenerative disorders. Yet, while it is widely appreciated that activated microglia can have neuroprotective qualities, their contribution to tissue destruction and neurodegeneration within the CNS is equally obvious. This apparent duality in microglial functions renders it difficult to determine whether microglial activation under certain conditions is something to counteract, or to support. Also, it is far from clear which microglial functions support neuroprotection, and which support destruction. Here, we review evidence that a special phenomenon in multiple sclerosis (MS) patients offers a unique possibility to study polarized protective functions of microglia. During MS, small clusters of activated microglia frequently emerge throughout normalappearing white matter. Several lines of evidence suggest that these clusters, which are referred to as preactive MS lesions, represent a reversible first stage in the development of inflammatory, demyelinating MS lesions. Progression onto this final destructive stage may occur but, importantly, does not seem to be inevitable. Instead, resolution of preactive lesions is probably the rule rather than the exception. For as long as preactive lesions remain non-infiltrated by peripheral lymphocytes, they reflect a local neuroprotective and reparative response. A critical factor in the emergence of preactive lesions is oligodendrocyte stress, which leads to accumulation of factors such as small heat shock proteins. At least some of these can induce an immune-regulatory response in neighboring microglia. A closer understanding of the molecular make-up of preactive MS lesions, of the signals which cause microglial activation, and of the protective mediators produced by microglia in this context, will help uncover novel clues for neuroprotective therapeutic strategies with relevance for clinical applications well beyond the field of MS alone. © 2011 Bentham Science Publishers.

Van Noort J.M.,Delta Crystallon BV | Bsibsi M.,Delta Crystallon BV | Nacken P.,Delta Crystallon BV | Gerritsen W.H.,VU University Amsterdam | And 2 more authors.
International Journal of Biochemistry and Cell Biology | Year: 2012

There is now compelling evidence that members of the family of small heat shock proteins (HSP) can be secreted by a variety of different types of cells. Secretion of small HSP may at times represent altruistic delivery of supporting and stabilizing factors from one cell to another. A probably more general effect of extracellular small HSP, however, is exerted by their ability to activate macrophages and macrophage-like cells. When doing so, small HSP induce an immune-regulatory state of activation, stimulating macrophages to suppress inflammation. For this reason, small HSP deserve consideration as broadly applicable therapeutic agents for inflammatory disorders. In one particular case, however, adaptive immune responses to the small HSP itself may subvert the protective quality of the innate immune response it triggers. This situation only applies to alpha B-crystallin, and is unique for humans as well. In this special case, local concentrations of alpha B-crystallin determine the balance between protective innate responses and destructive adaptive responses, the latter of which are held responsible for the development of multiple sclerosis lesions. This article is part of a Directed Issue entitled: Small HSPs in physiology and pathology. © 2012 Elsevier Ltd. All rights reserved.

Peferoen L.,VU University Amsterdam | Kipp M.,RWTH Aachen | van der Valk P.,VU University Amsterdam | van Noort J.M.,Delta Crystallon BV | And 2 more authors.
Immunology | Year: 2014

Communication between the immune system and the central nervous system (CNS) is exemplified by cross-talk between glia and neurons shown to be essential for maintaining homeostasis. While microglia are actively modulated by neurons in the healthy brain, little is known about the cross-talk between oligodendrocytes and microglia. Oligodendrocytes, the myelin-forming cells in the CNS, are essential for the propagation of action potentials along axons, and additionally serve to support neurons by producing neurotrophic factors. In demyelinating diseases such as multiple sclerosis, oligodendrocytes are thought to be the victims. Here, we review evidence that oligodendrocytes also have strong immune functions, express a wide variety of innate immune receptors, and produce and respond to chemokines and cytokines that modulate immune responses in the CNS. We also review evidence that during stress events in the brain, oligodendrocytes can trigger a cascade of protective and regenerative responses, in addition to responses that elicit progressive neurodegeneration. Knowledge of the cross-talk between microglia and oligodendrocytes may continue to uncover novel pathways of immune regulation in the brain that could be further exploited to control neuroinflammation and degeneration. © 2013 John Wiley & Sons Ltd.

Amor S.,VU University Amsterdam | Amor S.,Blizard Institute of Cell and Molecular Science | Peferoen L.A.N.,VU University Amsterdam | Vogel D.Y.S.,VU University Amsterdam | And 4 more authors.
Immunology | Year: 2014

Neurodegeneration, the progressive dysfunction and loss of neurons in the central nervous system (CNS), is the major cause of cognitive and motor dysfunction. While neuronal degeneration is well-known in Alzheimer's and Parkinson's diseases, it is also observed in neurotrophic infections, traumatic brain and spinal cord injury, stroke, neoplastic disorders, prion diseases, multiple sclerosis and amyotrophic lateral sclerosis, as well as neuropsychiatric disorders and genetic disorders. A common link between these diseases is chronic activation of innate immune responses including those mediated by microglia, the resident CNS macrophages. Such activation can trigger neurotoxic pathways leading to progressive degeneration. Yet, microglia are also crucial for controlling inflammatory processes, and repair and regeneration. The adaptive immune response is implicated in neurodegenerative diseases contributing to tissue damage, but also plays important roles in resolving inflammation and mediating neuroprotection and repair. The growing awareness that the immune system is inextricably involved in mediating damage as well as regeneration and repair in neurodegenerative disorders, has prompted novel approaches to modulate the immune system, although it remains whether these approaches can be used in humans. Additional factors in humans include ageing and exposure to environmental factors such as systemic infections that provide additional clues that may be human specific and therefore difficult to translate from animal models. Nevertheless, a better understanding of how immune responses are involved in neuronal damage and regeneration, as reviewed here, will be essential to develop effective therapies to improve quality of life, and mitigate the personal, economic and social impact of these diseases. © 2013 John Wiley & Sons Ltd.

Delta Crystallon B.V. | Date: 2011-07-14

The invention relates to a biodegradable microparticle having a diameter between 0.2 and 3.5 micrometer and comprising a pharmaceutically effective amount of at least one small heat-shock protein that induces IL-10 production in macrophages, said small heat-shock protein comprising an amino acid sequence identity of at least 50% to any of the sequences listed as SEQ ID NOs: 1 and 12-26.

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