Publications by authors named "Jon D Laman"

144 Publications

Multiple sclerosis is linked to MAPK overactivity in microglia.

J Mol Med (Berl) 2021 May 5. Epub 2021 May 5.

Department Biomedical Sciences of Cells & Systems, University Medical Center Groningen, Groningen, The Netherlands.

Reassessment of published observations in patients with multiple sclerosis (MS) suggests a microglial malfunction due to inappropriate (over)activity of the mitogen-activated protein kinase pathway ERK (MAPK). These observations regard biochemistry as well as epigenetics, and all indicate involvement of this pathway. Recent preclinical research on neurodegeneration already pointed towards a role of MAPK pathways, in particular MAPK. This is important as microglia with overactive MAPK have been identified to disturb local oligodendrocytes which can lead to locoregional demyelination, hallmark of MS. This constitutes a new concept on pathophysiology of MS, besides the prevailing view, i.e., autoimmunity. Acknowledged risk factors for MS, such as EBV infection, hypovitaminosis D, and smoking, all downregulate MAPK negative feedback phosphatases that normally regulate MAPK activity. Consequently, these factors may contribute to inappropriate MAPK overactivity, and thereby to neurodegeneration. Also, MAPK overactivity in microglia, as a factor in the pathophysiology of MS, could explain ongoing neurodegeneration in MS patients despite optimized immunosuppressive or immunomodulatory treatment. Currently, for these patients with progressive disease, no effective treatment exists. In such refractory MS, targeting the cause of overactive MAPK in microglia merits further investigation as this phenomenon may imply a novel treatment approach.
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http://dx.doi.org/10.1007/s00109-021-02080-4DOI Listing
May 2021

Between a hygiene rock and a hygienic hard place: Avoiding SARS-CoV-2 while needing environmental exposures for immunity.

Evol Med Public Health 2021 12;9(1):120-130. Epub 2021 Feb 12.

Department of Biomedical Sciences of Cells and Systems, University Medical Center Groningen, Groningen, The Netherlands.

Suboptimal understanding of concepts related to hygiene by the general public, clinicians and researchers is a persistent problem in health and medicine. Although hygiene is necessary to slow or prevent deadly pandemics of infectious disease such as coronavirus disease 2019 (COVID-19), hygiene can have unwanted effects. In particular, some aspects of hygiene cause a loss of biodiversity from the human body, characterized by the almost complete removal of intestinal worms (helminths) and protists. Research spanning more than half a century documents that this loss of biodiversity results in an increased propensity for autoimmune disease, allergic disorders, probably neuropsychiatric problems and adverse reactions to infectious agents. The differences in immune function between communities with and communities without helminths have become so pronounced that the reduced lethality of severe acute respiratory syndrome coronavirus 2 in low-income countries compared to high-income countries was predicted early in the COVID-19 pandemic. This prediction, based on the maladaptive immune responses observed in many cases of COVID-19 in high-income countries, is now supported by emerging data from low-income countries. Herein, hygiene is subdivided into components involving personal choice versus components instituted by community wide systems such as sewage treatment facilities and water treatment plants. The different effects of personal hygiene and systems hygiene are described, and appropriate measures to alleviate the adverse effects of hygiene without losing the benefits of hygiene are discussed. Finally, text boxes are provided to function as stand-alone, public-domain handouts with the goal of informing the public about hygiene and suggesting solutions for biomedical researchers and policy makers. Lay Summary: Hygiene related to sewer systems and other technology can have adverse effects on immune function, and is distinct from personal hygiene practices such as hand washing and social distancing. Dealing with the drawbacks of hygiene must be undertaken without compromising the protection from infectious disease imposed by hygiene.
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http://dx.doi.org/10.1093/emph/eoab006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7928958PMC
February 2021

Systemic administration of β-glucan induces immune training in microglia.

J Neuroinflammation 2021 Feb 22;18(1):57. Epub 2021 Feb 22.

Department of Biomedical Sciences of Cells & Systems, Section Molecular Neurobiology, University of Groningen, University Medical Center Groningen, Antonius Deusinglaan 1, 9713, AV, Groningen, The Netherlands.

Background: An innate immune memory response can manifest in two ways: immune training and immune tolerance, which refers to an enhanced or suppressed immune response to a second challenge, respectively. Exposing monocytes to moderate-to-high amounts of bacterial lipopolysaccharide (LPS) induces immune tolerance, whereas fungal β-glucan (BG) induces immune training. In microglia, it has been shown that different LPS inocula in vivo can induce either immune training or tolerance. Few studies focused on impact of BG on microglia and were only performed in vitro. The aim of the current study was to determine whether BG activates and induces immune memory in microglia upon peripheral administration in vivo.

Methods: Two experimental designs were used. In the acute design, mice received an intraperitoneal (i.p.) injection with PBS, 1 mg/kg LPS or 20 mg/kg BG and were terminated after 3 h, 1 or 2 days. In the preconditioning design, animals were first challenged i.p. with PBS, 1 mg/kg LPS or 20 mg/kg BG. After 2, 7 or 14 days, mice received a second injection with PBS or 1 mg/kg LPS and were sacrificed 3 h later. Microglia were isolated by fluorescence-activated cell sorting, and cytokine gene expression levels were determined. In addition, a self-developed program was used to analyze microglia morphological changes. Cytokine concentrations in serum were determined by a cytokine array.

Results: Microglia exhibited a classical inflammatory response to LPS, showing significant upregulation of Tnf, Il6, Il1β, Ccl2, Ccl3 and Csf1 expression, three h after injection, and obvious morphological changes 1 and 2 days after injection. With an interval of 2 days between two challenges, both BG and LPS induced immune training in microglia. The training effect of LPS changed into immune tolerance after a 7-day interval between 2 LPS challenges. Preconditioning with BG and LPS resulted in increased morphological changes in microglia in response to a systemic LPS challenge compared to naïve microglia.

Conclusions: Our results demonstrate that preconditioning with BG and LPS both induced immune training of microglia at two days after the first challenge. However, with an interval of 7 days between the first and second challenge, LPS-preconditioning resulted in immune tolerance in microglia.
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http://dx.doi.org/10.1186/s12974-021-02103-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7901224PMC
February 2021

Regionally diverse astrocyte subtypes and their heterogeneous response to EAE.

Glia 2021 May 17;69(5):1140-1154. Epub 2020 Dec 17.

Department of Biomedical Sciences of Cells & Systems, Section Molecular Neurobiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

Astrocytes fulfil many functions in the central nervous system (CNS), including contribution to the blood brain barrier, synapse formation, and trophic support. In addition, they can mount an inflammatory response and are heterogeneous in morphology and function. To extensively characterize astrocyte subtypes, we FACS-isolated and gene expression profiled distinct astrocyte subtypes from three central nervous system regions; forebrain, hindbrain and spinal cord. Astrocyte subpopulations were separated based on GLAST/SLC1A3 and ACSA-2/ATP1B2 cell surface expression. The local brain environment proved key in establishing different transcriptional programs in astrocyte subtypes. Transcriptional differences between subtypes were also apparent in experimental autoimmune encephalomyelitis (EAE) mice, where these astrocyte subtypes showed distinct responses. While gene expression signatures associated with blood-brain barrier maintenance were lost, signatures involved in neuroinflammation and neurotoxicity were increased in spinal cord astrocytes, especially during acute disease stages. In chronic stages of EAE, this reactive astrocyte signature was slightly decreased, while obtaining a more proliferative profile, which might be relevant for glia scar formation and tissue regeneration. Morphological heterogeneity of astrocytes previously indicated the presence of astrocyte subtypes, and here we show diversity based on transcriptome variation associated with brain regions and differential responsiveness to a neuroinflammatory insult (EAE).
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http://dx.doi.org/10.1002/glia.23954DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7985878PMC
May 2021

Exploring the VISTA of microglia: immune checkpoints in CNS inflammation.

J Mol Med (Berl) 2020 10 27;98(10):1415-1430. Epub 2020 Aug 27.

Department of Biomedical Sciences of Cells & Systems, Section Molecular Neurobiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

Negative checkpoint regulators (NCR) are intensely pursued as targets to modulate the immune response in cancer and autoimmunity. A large variety of NCR is expressed by central nervous system (CNS)-resident cell types and is associated with CNS homeostasis, interactions with peripheral immunity and CNS inflammation and disease. Immunotherapy blocking NCR affects the CNS as patients can develop neurological issues including encephalitis and multiple sclerosis (MS). How these treatments affect the CNS is incompletely understood, since expression and function of NCR in the CNS are only beginning to be unravelled. V-type immunoglobulin-like suppressor of T cell activation (VISTA) is an NCR that is expressed primarily in the haematopoietic system by myeloid and T cells. VISTA regulates T cell quiescence and activation and has a variety of functions in myeloid cells including efferocytosis, cytokine response and chemotaxis. In the CNS, VISTA is predominantly expressed by microglia and macrophages of the CNS. In this review, we summarize the role of NCR in the CNS during health and disease. We highlight expression of VISTA across cell types and CNS diseases and discuss the function of VISTA in microglia and during CNS ageing, inflammation and neurodegeneration. Understanding the role of VISTA and other NCR in the CNS is important considering the adverse effects of immunotherapy on the CNS, and in view of their therapeutic potential in CNS disease.
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http://dx.doi.org/10.1007/s00109-020-01968-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7525281PMC
October 2020

Bacterial Peptidoglycan as a Driver of Chronic Brain Inflammation.

Trends Mol Med 2020 07 21;26(7):670-682. Epub 2020 Feb 21.

Indiana University School of Medicine-Northwest, Gary, IN, USA.

Peptidoglycan (PGN) is a cell wall component of both Gram-positive and Gram-negative bacteria. Signature fragments of PGN are proinflammatory through engagement of pattern recognition receptors (PRR) on resident tissue cells and circulating leukocytes. Despite its abundance in the gut microbiota, there is limited recognition that PGN could contribute to chronic neuroinflammation. This review highlights current insights into the roles of PGN as a determinant of brain inflammation, notably in multiple sclerosis (MS) and its experimental autoimmune encephalomyelitis (EAE) models. Recent studies demonstrate PGN in blood of healthy adult humans. PGN amplifies autoimmune pathology via activation of innate immune cells. Novel uptake routes through (altered) gut mucosa by myeloid leukocyte subsets promote PGN transport to the brain.
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http://dx.doi.org/10.1016/j.molmed.2019.11.006DOI Listing
July 2020

Enhanced axonal response of mitochondria to demyelination offers neuroprotection: implications for multiple sclerosis.

Acta Neuropathol 2020 08 22;140(2):143-167. Epub 2020 Jun 22.

Wellcome Trust-MRC Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge Biomedical Campus, Cambridge, CB2 0AW, UK.

Axonal loss is the key pathological substrate of neurological disability in demyelinating disorders, including multiple sclerosis (MS). However, the consequences of demyelination on neuronal and axonal biology are poorly understood. The abundance of mitochondria in demyelinated axons in MS raises the possibility that increased mitochondrial content serves as a compensatory response to demyelination. Here, we show that upon demyelination mitochondria move from the neuronal cell body to the demyelinated axon, increasing axonal mitochondrial content, which we term the axonal response of mitochondria to demyelination (ARMD). However, following demyelination axons degenerate before the homeostatic ARMD reaches its peak. Enhancement of ARMD, by targeting mitochondrial biogenesis and mitochondrial transport from the cell body to axon, protects acutely demyelinated axons from degeneration. To determine the relevance of ARMD to disease state, we examined MS autopsy tissue and found a positive correlation between mitochondrial content in demyelinated dorsal column axons and cytochrome c oxidase (complex IV) deficiency in dorsal root ganglia (DRG) neuronal cell bodies. We experimentally demyelinated DRG neuron-specific complex IV deficient mice, as established disease models do not recapitulate complex IV deficiency in neurons, and found that these mice are able to demonstrate ARMD, despite the mitochondrial perturbation. Enhancement of mitochondrial dynamics in complex IV deficient neurons protects the axon upon demyelination. Consequently, increased mobilisation of mitochondria from the neuronal cell body to the axon is a novel neuroprotective strategy for the vulnerable, acutely demyelinated axon. We propose that promoting ARMD is likely to be a crucial preceding step for implementing potential regenerative strategies for demyelinating disorders.
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http://dx.doi.org/10.1007/s00401-020-02179-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7360646PMC
August 2020

Fecal Microbiota Transplantation in Neurological Disorders.

Front Cell Infect Microbiol 2020 24;10:98. Epub 2020 Mar 24.

Department of Neurology, Leiden University Medical Center, Leiden, Netherlands.

Several studies suggested an important role of the gut microbiota in the pathophysiology of neurological disorders, implying that alteration of the gut microbiota might serve as a treatment strategy. Fecal microbiota transplantation (FMT) is currently the most effective gut microbiota intervention and an accepted treatment for recurrent infections. To evaluate indications of FMT for patients with neurological disorders, we summarized the available literature on FMT. In addition, we provide suggestions for future directions. In July 2019, five main databases were searched for studies and case descriptions on FMT in neurological disorders in humans or animal models. In addition, the ClinicalTrials.gov website was consulted for registered planned and ongoing trials. Of 541 identified studies, 34 were included in the analysis. Clinical trials with FMT have been performed in patients with autism spectrum disorder and showed beneficial effects on neurological symptoms. For multiple sclerosis and Parkinson's disease, several animal studies suggested a positive effect of FMT, supported by some human case reports. For epilepsy, Tourette syndrome, and diabetic neuropathy some studies suggested a beneficial effect of FMT, but evidence was restricted to case reports and limited numbers of animal studies. For stroke, Alzheimer's disease and Guillain-Barré syndrome only studies with animal models were identified. These studies suggested a potential beneficial effect of healthy donor FMT. In contrast, one study with an animal model for stroke showed increased mortality after FMT. For Guillain-Barré only one study was identified. Whether positive findings from animal studies can be confirmed in the treatment of human diseases awaits to be seen. Several trials with FMT as treatment for the above mentioned neurological disorders are planned or ongoing, as well as for amyotrophic lateral sclerosis. Preliminary literature suggests that FMT may be a promising treatment option for several neurological disorders. However, available evidence is still scanty and some contrasting results were observed. A limited number of studies in humans have been performed or are ongoing, while for some disorders only animal experiments have been conducted. Large double-blinded randomized controlled trials are needed to further elucidate the effect of FMT in neurological disorders.
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http://dx.doi.org/10.3389/fcimb.2020.00098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7105733PMC
March 2020

Potential of mesenchymal- and cardiac progenitor cells for therapeutic targeting of B-cells and antibody responses in end-stage heart failure.

PLoS One 2019 31;14(12):e0227283. Epub 2019 Dec 31.

Laboratory of Experimental Cardiology, UMC Utrecht Regenerative Medicine Center, University Medical Center Utrecht, Utrecht, the Netherlands.

Upon myocardial damage, the release of cardiac proteins induces a strong antibody-mediated immune response, which can lead to adverse cardiac remodeling and eventually heart failure (HF). Stem cell therapy using mesenchymal stromal cells (MSCs) or cardiomyocyte progenitor cells (CPCs) previously showed beneficial effects on cardiac function despite low engraftment in the heart. Paracrine mediators are likely of great importance, where, for example, MSC-derived extracellular vesicles (EVs) also show immunosuppressive properties in vitro. However, the limited capacity of MSCs to differentiate into cardiac cells and the sufficient scaling of MSC-derived EVs remain a challenge to clinical translation. Therefore, we investigated the immunosuppressive actions of endogenous CPCs and CPC-derived EVs on antibody production in vitro, using both healthy controls and end-stage HF patients. Both MSCs and CPCs strongly inhibit lymphocyte proliferation and antibody production in vitro. Furthermore, CPC-derived EVs significantly lowered the levels of IgG1, IgG4, and IgM, especially when administered for longer duration. In line with previous findings, plasma cells of end-stage HF patients showed high production of IgG3, which can be inhibited by MSCs in vitro. MSCs and CPCs inhibit in vitro antibody production of both healthy and end-stage HF-derived immune cells. CPC-derived paracrine factors, such as EVs, show similar effects, but do not provide the complete immunosuppressive capacity of CPCs. The strongest immunosuppressive effects were observed using MSCs, suggesting that MSCs might be the best candidates for therapeutic targeting of B-cell responses in HF.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0227283PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6938331PMC
April 2020

Increased circulating IgG levels, myocardial immune cells and IgG deposits support a role for an immune response in pre- and end-stage heart failure.

J Cell Mol Med 2019 11 26;23(11):7505-7516. Epub 2019 Sep 26.

Laboratory of Experimental Cardiology, UMC Utrecht Regenerative Medicine Center, University Medical Center Utrecht, Utrecht, The Netherlands.

The chronic inflammatory response plays an important role in adverse cardiac remodelling and the development of heart failure (HF). There is also evidence that in the pathogenesis of several cardiovascular diseases, chronic inflammation is accompanied by antibody and complement deposits in the heart, suggestive of a true autoimmune response. However, the role of antibody-mediated immune responses in HF progression is less clear. We assessed whether immune cell infiltration and immunoglobulin levels are associated with HF type and disease stage, taking sex differences into account. We found IgG deposits and increased infiltration of immune cells in the affected myocardium of patients with end-stage HF with reduced ejection fraction (HFrEF, n = 20). Circulating levels of IgG1 and IgG3 were elevated in these patients. Furthermore, the percentage of transitional/regulatory B cells was decreased (from 6.9% to 2.4%) compared with healthy controls (n = 5). Similarly, increased levels of circulating IgG1 and IgG3 were observed in men with left ventricular diastolic dysfunction (LVDD, n = 5), possibly an early stage of HF with preserved EF (HFpEF). In conclusion, IgG deposits and infiltrates of immune cells are present in end-stage HFrEF. In addition, both LVDD patients and end-stage HFrEF patients show elevated levels of circulating IgG1 and IgG3, suggesting an antibody-mediated immune response upon cardiac remodelling, which in the early phase of remodelling appear to differ between men and women. These immunoglobulin subclasses might be used as marker for pre-stage HF and its progression. Future identification of auto-antigens might open possibilities for new therapeutic interventions.
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http://dx.doi.org/10.1111/jcmm.14619DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6815814PMC
November 2019

Bone marrow chimeras-a vital tool in basic and translational research.

J Mol Med (Berl) 2019 07 26;97(7):889-896. Epub 2019 Apr 26.

Institute of Laboratory Animal Science, University of Zurich, Zurich, Switzerland.

Bone marrow chimeras are used routinely in immunology research as well as in other fields of biology. Here, we provide a concise state-of-the-art review about the types of chimerisms that can be achieved and the type of information that each model generates. We include separate sections for caveats and future developments. We provide examples from the literature in which different types of chimerism were employed to answer specific questions. While simple bone marrow chimeras allow to dissect the role of genes in distinct cell populations such as the hematopoietic cells versus non-hematopoietic cells, mixed bone marrow chimeras can provide detailed information about hematopoietic cell types and the intrinsic and extrinsic roles of individual genes. The advantages and caveats of bone marrow chimerism for the study of microglia are addressed, as well as alternatives to irradiation that minimize blood-brain-barrier disruption. Elementary principles are introduced and their potential is exemplified through summarizing recent studies.
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http://dx.doi.org/10.1007/s00109-019-01783-zDOI Listing
July 2019

Misinterpretation of Study Data.

JAMA Neurol 2019 01;76(1):113

Department of Medicine (Neurology), University of Alberta, Edmonton, Alberta, Canada.

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http://dx.doi.org/10.1001/jamaneurol.2018.3668DOI Listing
January 2019

Targeted Diet Modification Reduces Multiple Sclerosis-like Disease in Adult Marmoset Monkeys from an Outbred Colony.

J Immunol 2018 12 19;201(11):3229-3243. Epub 2018 Oct 19.

Department of Immunobiology, Biomedical Primate Research Centre, 2280 GH Rijswijk, the Netherlands.

Experimental autoimmune encephalomyelitis (EAE) in common marmosets is a translationally relevant model of the chronic neurologic disease multiple sclerosis. Following the introduction of a new dietary supplement in our purpose-bred marmoset colony, the percentage of marmosets in which clinically evident EAE could be induced by sensitization against recombinant human myelin oligodendrocyte glycoprotein in IFA decreased from 100 to 65%. The reduced EAE susceptibility after the dietary change coincided with reduced expression in the colony, an EBV-related γ1-herpesvirus associated with EAE. We then investigated, in a controlled study in marmoset twins, which disease-relevant parameters were affected by the dietary change. The selected twins had been raised on the new diet for at least 12 mo prior to the study. In twin siblings reverted to the original diet 8 wk prior to EAE induction, 100% disease prevalence (eight out of eight) was restored, whereas in siblings remaining on the new diet the EAE prevalence was 75% (six out of eight). Spinal cord demyelination, a classical hallmark of the disease, was significantly lower in new-diet monkeys than in monkeys reverted to the original diet. In new-diet monkeys, the proinflammatory T cell response to recombinant human myelin oligodendrocyte glycoprotein was significantly reduced, and RNA-sequencing revealed reduced apoptosis and enhanced myelination in the brain. Systematic typing of the marmoset gut microbiota using 16S rRNA sequencing demonstrated a unique, Bifidobacteria-dominated composition, which changed after disease induction. In conclusion, targeted dietary intervention exerts positive effects on EAE-related parameters in multiple compartments of the marmoset's gut-immune-CNS axis.
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http://dx.doi.org/10.4049/jimmunol.1800822DOI Listing
December 2018

VISTA expression by microglia decreases during inflammation and is differentially regulated in CNS diseases.

Glia 2018 12 11;66(12):2645-2658. Epub 2018 Oct 11.

Department of Neuroscience, Section Medical Physiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

V-type immunoglobulin domain-containing suppressor of T-cell activation (VISTA) is a negative checkpoint regulator (NCR) involved in inhibition of T cell-mediated immunity. Expression changes of other NCRs (PD-1, PD-L1/L2, CTLA-4) during inflammation of the central nervous system (CNS) were previously demonstrated, but VISTA expression in the CNS has not yet been explored. Here, we report that in the human and mouse CNS, VISTA is most abundantly expressed by microglia, and to lower levels by endothelial cells. Upon TLR stimulation, VISTA expression was reduced in primary neonatal mouse and adult rhesus macaque microglia in vitro. In mice, microglial VISTA expression was reduced after lipopolysaccharide (LPS) injection, during experimental autoimmune encephalomyelitis (EAE), and in the accelerated aging Ercc1 mouse model. After LPS injection, decreased VISTA expression in mouse microglia was accompanied by decreased acetylation of lysine residue 27 in histone 3 in both its promoter and enhancer region. ATAC-sequencing indicated a potential regulation of VISTA expression by Pu.1 and Mafb, two transcription factors crucial for microglia function. Finally, our data suggested that VISTA expression was decreased in microglia in multiple sclerosis lesion tissue, whereas it was increased in Alzheimer's disease patients. This study is the first to demonstrate that in the CNS, VISTA is expressed by microglia, and that VISTA is differentially expressed in CNS pathologies.
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http://dx.doi.org/10.1002/glia.23517DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6585704PMC
December 2018

Targeting senescence to delay progression of multiple sclerosis.

J Mol Med (Berl) 2018 11 18;96(11):1153-1166. Epub 2018 Sep 18.

Department of Neuroscience, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

Multiple sclerosis (MS) is a chronic and often progressive, demyelinating disease of the central nervous system (CNS) white and gray matter and the single most common cause of disability in young adults. Age is one of the factors most strongly influencing the course of progression in MS. One of the hallmarks of aging is cellular senescence. The elimination of senescent cells with senolytics has very recently been shown to delay age-related dysfunction in animal models for other neurological diseases. In this review, the possible link between cellular senescence and the progression of MS is discussed, and the potential use of senolytics as a treatment for progressive MS is explored. Currently, there is no cure for MS and there are limited treatment options to slow the progression of MS. Current treatment is based on immunomodulatory approaches. Various cell types present in the CNS can become senescent and thus potentially contribute to MS disease progression. We propose that, after cellular senescence has indeed been shown to be directly implicated in disease progression, administration of senolytics should be tested as a potential therapeutic approach for the treatment of progressive MS.
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http://dx.doi.org/10.1007/s00109-018-1686-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6208951PMC
November 2018

Selective Modulation of TNF-TNFRs Signaling: Insights for Multiple Sclerosis Treatment.

Front Immunol 2018 30;9:925. Epub 2018 Apr 30.

Department of Molecular Neurobiology (GELIFES), University of Groningen, Groningen, Netherlands.

Autoimmunity develops when self-tolerance mechanisms are failing to protect healthy tissue. A sustained reaction to self is generated, which includes the generation of effector cells and molecules that destroy tissues. A way to restore this intrinsic tolerance is through immune modulation that aims at refurbishing this immunologically naïve or unresponsive state, thereby decreasing the aberrant immune reaction taking place. One major cytokine has been shown to play a pivotal role in several autoimmune diseases such as rheumatoid arthritis (RA) and multiple sclerosis (MS): tumor necrosis factor alpha (TNFα) modulates the induction and maintenance of an inflammatory process and it comes in two variants, soluble TNF (solTNF) and transmembrane bound TNF (tmTNF). tmTNF signals TNFR1 and TNFR2, whereas solTNF signals mainly TNFR1. TNFR1 is widely expressed and promotes mainly inflammation and apoptosis. Conversely, TNFR2 is restricted mainly to immune and endothelial cells and it is known to activate the pro-survival PI3K-Akt/PKB signaling pathway and to sustain regulatory T cells function. Anti-TNFα therapies are successfully used to treat diseases such as RA, colitis, and psoriasis. However, clinical studies with a non-selective inhibitor of TNFα in MS patients had to be halted due to exacerbation of clinical symptoms. One possible explanation for this failure is the non-selectivity of the treatment, which avoids TNFR2 stimulation and its immune and tissue protective properties. Thus, a receptor-selective modulation of TNFα signal pathways provides a novel therapeutic concept that might lead to new insights in MS pathology with major implications for its effective treatment.
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http://dx.doi.org/10.3389/fimmu.2018.00925DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5936749PMC
July 2019

Low-Fat Diet With Caloric Restriction Reduces White Matter Microglia Activation During Aging.

Front Mol Neurosci 2018 12;11:65. Epub 2018 Mar 12.

Department of Neuroscience, Medical Physiology Section, University Medical Center Groningen, University of Groningen, Groningen, Netherlands.

Rodent models of both aging and obesity are characterized by inflammation in specific brain regions, notably the corpus callosum, fornix, and hypothalamus. Microglia, the resident macrophages of the central nervous system, are important for brain development, neural support, and homeostasis. However, the effects of diet and lifestyle on microglia during aging are only partly understood. Here, we report alterations in microglia phenotype and functions in different brain regions of mice on a high-fat diet (HFD) or low-fat diet (LFD) during aging and in response to voluntary running wheel exercise. We compared the expression levels of genes involved in immune response, phagocytosis, and metabolism in the hypothalamus of 6-month-old HFD and LFD mice. We also compared the immune response of microglia from HFD or LFD mice to peripheral inflammation induced by intraperitoneal injection of lipopolysaccharide (LPS). Finally, we investigated the effect of diet, physical exercise, and caloric restriction (40% reduction compared to intake) on microglia in 24-month-old HFD and LFD mice. Changes in diet caused morphological changes in microglia, but did not change the microglia response to LPS-induced systemic inflammation. Expression of phagocytic markers (i.e., Mac-2/Lgals3, Dectin-1/Clec7a, and CD16/CD32) in the white matter microglia of 24-month-old brain was markedly decreased in calorically restricted LFD mice. In conclusion, LFD resulted in reduced activation of microglia, which might be an underlying mechanism for the protective role of caloric restriction during aging-associated decline.
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http://dx.doi.org/10.3389/fnmol.2018.00065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5857900PMC
March 2018

Merits and complexities of modeling multiple sclerosis in non-human primates: implications for drug discovery.

Expert Opin Drug Discov 2018 05 25;13(5):387-397. Epub 2018 Feb 25.

a Department of Immunobiology , Biomedical Primate Research Centre , Rijswijk , The Netherlands.

Introduction: The translation of scientific discoveries made in animal models into effective treatments for patients often fails, indicating that currently used disease models in preclinical research are insufficiently predictive for clinical success. An often-used model in the preclinical research of autoimmune neurological diseases, multiple sclerosis in particular, is experimental autoimmune encephalomyelitis (EAE). Most EAE models are based on genetically susceptible inbred/SPF mouse strains used at adolescent age (10-12 weeks), which lack exposure to genetic and microbial factors which shape the human immune system. Areas covered: Herein, the authors ask whether an EAE model in adult non-human primates from an outbred conventionally-housed colony could help bridge the translational gap between rodent EAE models and MS patients. Particularly, the authors discuss a novel and translationally relevant EAE model in common marmosets (Callithrix jacchus) that shares remarkable pathological similarity with MS. Expert opinion: The MS-like pathology in this model is caused by the interaction of effector memory T cells with B cells infected with the γ1-herpesvirus (CalHV3), both present in the pathogen-educated marmoset immune repertoire. The authors postulate that depletion of only the small subset (<0.05%) of CalHV3-infected B cells may be sufficient to limit chronic inflammatory demyelination.
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http://dx.doi.org/10.1080/17460441.2018.1443075DOI Listing
May 2018

Severe oxidative stress in an acute inflammatory demyelinating model in the rhesus monkey.

PLoS One 2017 14;12(11):e0188013. Epub 2017 Nov 14.

Department of Immunobiology, Biomedical Primate Research Centre, Rijswijk, The Netherlands.

Oxidative stress is increasingly implicated as a co-factor of tissue injury in inflammatory/demyelinating disorders of the central nervous system (CNS), such as multiple sclerosis (MS). While rodent experimental autoimmune encephalomyelitis (EAE) models diverge from human demyelinating disorders with respect to limited oxidative injury, we observed that in a non-human primate (NHP) model for MS, namely EAE in the common marmoset, key pathological features of the disease were recapitulated, including oxidative tissue injury. Here, we investigated the presence of oxidative injury in another NHP EAE model, i.e. in rhesus macaques, which yields an acute demyelinating disease, which may more closely resemble acute disseminated encephalomyelitis (ADEM) than MS. Rhesus monkey EAE diverges from marmoset EAE by abundant neutrophil recruitment into the CNS and destructive injury to white matter. This difference prompted us to investigate to which extent the oxidative pathway features elicited in MS and marmoset EAE are reflected in the acute rhesus monkey EAE model. The rhesus EAE brain was characterized by widespread demyelination and active lesions containing numerous phagocytic cells and to a lesser extent T cells. We observed induction of the oxidative stress pathway, including injury, with a predilection of p22phox expression in neutrophils and macrophages/microglia. In addition, changes in iron were observed. These results indicate that pathogenic mechanisms in the rhesus EAE model may differ from the marmoset EAE and MS brain due to the neutrophil involvement, but may in the end lead to similar induction of oxidative stress and injury.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0188013PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5685592PMC
December 2017

Modulation of Multiple Sclerosis and Its Animal Model Experimental Autoimmune Encephalomyelitis by Food and Gut Microbiota.

Front Immunol 2017 5;8:1081. Epub 2017 Sep 5.

Department of Neuroscience, University Medical Center Groningen, University of Groningen, Groningen, Netherlands.

Multiple sclerosis (MS) is an autoimmune neurological disease characterized by chronic inflammation of the central nervous system (CNS), leading to demyelination, axonal damage, and symptoms such as fatigue and disability. Although the cause of MS is not known, the infiltration of peripherally activated immune cells into the CNS has a key pathogenic role. Accumulating evidence supports an important role of diet and gut microbiota in immune-mediated diseases. Preclinical as well as clinical studies suggest a role for gut microbiota and dietary components in MS. Here, we review these recent studies on gut microbiota and dietary interventions in MS and its animal model experimental autoimmune encephalomyelitis. We also propose directions for future research.
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http://dx.doi.org/10.3389/fimmu.2017.01081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5591889PMC
September 2017

Reverse Translation for Assessment of Confidence in Animal Models of Multiple Sclerosis for Drug Discovery.

Clin Pharmacol Ther 2018 02 29;103(2):262-270. Epub 2017 Aug 29.

Department Immunobiology, Biomedical Primate Research Centre, Rijswijk, The Netherlands.

The poor predictive quality of currently used animal models in preclinical research is an important cause of the high attrition of promising drug candidates for human autoimmune disease in clinical trials. Examples from own work in a primate multiple sclerosis (MS) model illustrate that important lessons can be learned from a critical reassessment of failed drugs in the animal model, which can help improve the animal model and better understand the targeted disease.
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http://dx.doi.org/10.1002/cpt.801DOI Listing
February 2018

A B Cell-Driven Autoimmune Pathway Leading to Pathological Hallmarks of Progressive Multiple Sclerosis in the Marmoset Experimental Autoimmune Encephalomyelitis Model.

Front Immunol 2017 11;8:804. Epub 2017 Jul 11.

Department of Immunobiology, Biomedical Primate Research Center, Rijswijk, Netherlands.

The absence of pathological hallmarks of progressive multiple sclerosis (MS) in commonly used rodent models of experimental autoimmune encephalomyelitis (EAE) hinders the development of adequate treatments for progressive disease. Work reviewed here shows that such hallmarks are present in the EAE model in marmoset monkeys (). The minimal requirement for induction of progressive MS pathology is immunization with a synthetic peptide representing residues 34-56 from human myelin oligodendrocyte glycoprotein (MOG) formulated with a mineral oil [incomplete Freund's adjuvant (IFA)]. Pathological aspects include demyelination of cortical gray matter with microglia activation, oxidative stress, and redistribution of iron. When the peptide is formulated in complete Freund's adjuvant, which contains mycobacteria that relay strong activation signals to myeloid cells, oxidative damage pathways are strongly boosted leading to more intensive pathology. The proven absence of immune potentiating danger signals in the MOG34-56/IFA formulation implies that a narrow population of antigen-experienced T cells present in the monkey's immune repertoire is activated. This novel pathway involves the interplay of lymphocryptovirus-infected B cells with MHC class Ib/Caja-E restricted CD8+ CD56+ cytotoxic T lymphocytes.
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http://dx.doi.org/10.3389/fimmu.2017.00804DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5504154PMC
July 2017

Transcriptomic analysis of purified human cortical microglia reveals age-associated changes.

Nat Neurosci 2017 Aug 3;20(8):1162-1171. Epub 2017 Jul 3.

Department of Neuroscience, Section Medical Physiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

Microglia are essential for CNS homeostasis and innate neuroimmune function, and play important roles in neurodegeneration and brain aging. Here we present gene expression profiles of purified microglia isolated at autopsy from the parietal cortex of 39 human subjects with intact cognition. Overall, genes expressed by human microglia were similar to those in mouse, including established microglial genes CX3CR1, P2RY12 and ITGAM (CD11B). However, a number of immune genes, not identified as part of the mouse microglial signature, were abundantly expressed in human microglia, including TLR, Fcγ and SIGLEC receptors, as well as TAL1 and IFI16, regulators of proliferation and cell cycle. Age-associated changes in human microglia were enriched for genes involved in cell adhesion, axonal guidance, cell surface receptor expression and actin (dis)assembly. Limited overlap was observed in microglial genes regulated during aging between mice and humans, indicating that human and mouse microglia age differently.
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http://dx.doi.org/10.1038/nn.4597DOI Listing
August 2017

Oxidative Injury and Iron Redistribution Are Pathological Hallmarks of Marmoset Experimental Autoimmune Encephalomyelitis.

J Neuropathol Exp Neurol 2017 Jun;76(6):467-478

From the Department of Immunobiology, Biomedical Primate Research Centre, Rijswijk, The Netherlands (JD, NvD, BAH, YSK); Department of Neuroscience, University Medical Center, University of Groningen, Groningen, The Netherlands (JD, BAH, JDL); Medical University of Vienna, Center for Brain Research, Vienna, Austria (JB, HL); Centre for Neuroregeneration, University of Edinburgh, Edinburgh, United Kingdom (GRC, DJM); and Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands (SMAvdP, JvH).

Oxidative damage and iron redistribution are associated with the pathogenesis and progression of multiple sclerosis (MS), but these aspects are not entirely replicated in rodent experimental autoimmune encephalomyelitis (EAE) models. Here, we report that oxidative burst and injury as well as redistribution of iron are hallmarks of the MS-like pathology in the EAE model in the common marmoset. Active lesions in the marmoset EAE brain display increased expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (p22phox, p47phox, and gp91phox) and inducible nitric oxide synthase immunoreactivity within lesions with active inflammation and demyelination, coinciding with enhanced expression of mitochondrial heat-shock protein 70 and superoxide dismutase 1 and 2. The EAE lesion-associated liberation of iron (due to loss of iron-containing myelin) was associated with altered expression of the iron metabolic markers FtH1, lactoferrin, hephaestin, and ceruloplasmin. The enhanced expression of oxidative damage markers in inflammatory lesions indicates that the enhanced antioxidant enzyme expression could not counteract reactive oxygen and nitrogen species-induced cellular damage, as is also observed in MS brains. This study demonstrates that oxidative injury and aberrant iron distribution are prominent pathological hallmarks of marmoset EAE thus making this model suitable for therapeutic intervention studies aimed at reducing oxidative stress and associated iron dysmetabolism.
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http://dx.doi.org/10.1093/jnen/nlx034DOI Listing
June 2017

Analysis of the cross-talk of Epstein-Barr virus-infected B cells with T cells in the marmoset.

Clin Transl Immunology 2017 Feb 10;6(2):e127. Epub 2017 Feb 10.

Department of Immunobiology, Biomedical Primate Research Centre , Rijswijk, The Netherlands.

Despite the well-known association of Epstein-Barr virus (EBV), a lymphocryptovirus (LCV), with multiple sclerosis, a clear pathogenic role for disease progression has not been established. The translationally relevant experimental autoimmune encephalomyelitis (EAE) model in marmoset monkeys revealed that LCV-infected B cells have a central pathogenic role in the activation of T cells that drive EAE progression. We hypothesized that LCV-infected B cells induce T-cell functions relevant for EAE progression. In the current study, we examined the cross-talk between lymph node mononuclear cells (MNCs) from EAE marmosets and (semi-) autologous EBV-infected B-lymphoblastoid cell lines (B-LCLs). Results presented here demonstrate that infection with EBV B95-8 has a strong impact on gene expression profile of marmoset B cells, particularly those involved with antigen processing and presentation or co-stimulation to T cells. At the cellular level, we observed that MNC co-culture with B-LCLs induced decrease of CCR7 expression on T cells from EAE responder marmosets, but not in EAE monkeys without clinically evident disease. B-LCL interaction with T cells also resulted in significant loss of CD27 expression and reduced expression of IL-23R and CCR6, which coincided with enhanced IL-17A production. These results highlight the profound impact that EBV-infected B-LCL cells can have on second and third co-stimulatory signals involved in (autoreactive) T-cell activation.
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http://dx.doi.org/10.1038/cti.2017.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5311918PMC
February 2017

Pathophysiological and behavioral effects of systemic inflammation in aged and diseased rodents with relevance to delirium: A systematic review.

Brain Behav Immun 2017 May 11;62:362-381. Epub 2017 Jan 11.

University of Groningen, University Medical Center Groningen, University Center for Geriatric Medicine, Groningen, The Netherlands. Electronic address:

Delirium is a frequent outcome for aged and demented patients that suffer a systemic inflammatory insult. Animal models that reconstruct these etiological processes have potential to provide a better understanding of the pathophysiology of delirium. Therefore, we systematically reviewed animal studies in which systemic inflammation was superimposed on aged or diseased animal models. In total, 77 studies were identified. Aged animals were challenged with a bacterial endotoxin in 29 studies, 25 studies superimposed surgery on aged animals, and in 6 studies a bacterial infection, Escherichia coli (E. coli), was used. Diseased animals were challenged with a bacterial endotoxin in 15 studies, two studies examined effects of the cytokine IL-1β, and one study used polyinosinic:polycytidilic acid (poly I:C). This systematic review analyzed the impact of systemic inflammation on the production of inflammatory and neurotoxic mediators in peripheral blood, cerebrospinal fluid (CSF), and on the central nervous system (CNS). Moreover, concomitant behavioral and cognitive symptoms were also evaluated. Finally, outcomes of behavioral and cognitive tests from animal studies were compared to features and symptoms present in delirious patients.
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http://dx.doi.org/10.1016/j.bbi.2017.01.010DOI Listing
May 2017

Reproducibility Issues: Avoiding Pitfalls in Animal Inflammation Models.

Methods Mol Biol 2017 ;1559:1-17

Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, Obere Zahlbacher Straße 67, Mainz, D-55131, Germany.

In light of an enhanced awareness of ethical questions and ever increasing costs when working with animals in biomedical research, there is a dedicated and sometimes fierce debate concerning the (lack of) reproducibility of animal models and their relevance for human inflammatory diseases. Despite evident advancements in searching for alternatives, that is, replacing, reducing, and refining animal experiments-the three R's of Russel and Burch (1959)-understanding the complex interactions of the cells of the immune system, the nervous system and the affected tissue/organ during inflammation critically relies on in vivo models. Consequently, scientific advancement and ultimately novel therapeutic interventions depend on improving the reproducibility of animal inflammation models. As a prelude to the remaining hands-on protocols described in this volume, here, we summarize potential pitfalls of preclinical animal research and provide resources and background reading on how to avoid them.
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http://dx.doi.org/10.1007/978-1-4939-6786-5_1DOI Listing
January 2018

Functions of CD40 and Its Ligand, gp39 (CD40L).

Crit Rev Immunol 2017 ;37(2-6):371-420

Department of Microbiology, Dartmouth Medical School, One Medical Center Drive, Lebanon, NH 03756.

Initially, a role for the interaction between CD40, expressed on B cells, and gp39 (CD40L), expressed on activated T cells, has been defined in humoral immunity. CD40-CD40L interaction is an essential signal for B cell proliferation, expression of activation markers, immunoglobulin production, and isotype switching. CD40-CD40L interaction is also required for formation of B memory cells and germinal centers, and signaling through CD40 prevents apoptosis of germinal center B cells. Defective expression of CD40L in humans leads to an inability to produce isotypes other than IgM (hyper IgM syndrome), and to an absence of germinal centers. More recent evidence indicates an expansion of the role of the CD40-CD40L axis in cellular interactions beyond antibody formation. Induced expression of CD40 on monocytes can lead to CD40L-activated monocyte effector mechanisms. In addition, CD40-CD40L interactions are crucially involved in development of autoimmune disease in a number of animal models. CD40-CD40L interactions also impact on growth regulation of certain carcinomas. Manipulation of CD40L has also been used to develop novel strategies for long-term antigen-specific tolerization of peripheral T cells. Finally, the CD40-CD40L axis is involved in thymic selection. Following is a comprehensive overview of CD40L-CD40 interactions in physiological and pathogenic cellular responses and a discussion of the therapeutic ramifications of these interactions.
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http://dx.doi.org/10.1615/CritRevImmunol.v37.i2-6.100DOI Listing
April 2019

EBV Infection and Multiple Sclerosis: Lessons from a Marmoset Model.

Trends Mol Med 2016 12 8;22(12):1012-1024. Epub 2016 Nov 8.

Division of Clinical Neuroscience, University of Nottingham School of Medicine, Nottingham, UK; Department of Neurology, Nottingham University Hospitals National Health Service (NHS) Trust, Nottingham, UK.

Multiple sclerosis (MS) is thought to be initiated by the interaction of genetic and environmental factors, eliciting an autoimmune attack on the central nervous system. Epstein-Barr virus (EBV) is the strongest infectious risk factor, but an explanation for the paradox between high infection prevalence and low MS incidence remains elusive. We discuss new data using marmosets with experimental autoimmune encephalomyelitis (EAE) - a valid primate model of MS. The findings may help to explain how a common infection can contribute to the pathogenesis of MS. We propose that EBV infection induces citrullination of peptides in conjunction with autophagy during antigen processing, endowing B cells with the capacity to cross-present autoantigen to CD8CD56 T cells, thereby leading to MS progression.
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http://dx.doi.org/10.1016/j.molmed.2016.10.007DOI Listing
December 2016

Elevation of glycoprotein nonmetastatic melanoma protein B in type 1 Gaucher disease patients and mouse models.

FEBS Open Bio 2016 09 30;6(9):902-13. Epub 2016 Jul 30.

Department of Medical Biochemistry Academic Medical Center Amsterdam The Netherlands; Department of Medical Biochemistry Leiden Institute of Chemistry Leiden University The Netherlands.

Gaucher disease is caused by inherited deficiency of lysosomal glucocerebrosidase. Proteome analysis of laser-dissected splenic Gaucher cells revealed increased amounts of glycoprotein nonmetastatic melanoma protein B (gpNMB). Plasma gpNMB was also elevated, correlating with chitotriosidase and CCL18, which are established markers for human Gaucher cells. In Gaucher mice, gpNMB is also produced by Gaucher cells. Correction of glucocerebrosidase deficiency in mice by gene transfer or pharmacological substrate reduction reverses gpNMB abnormalities. In conclusion, gpNMB acts as a marker for glucosylceramide-laden macrophages in man and mouse and gpNMB should be considered as candidate biomarker for Gaucher disease in treatment monitoring.
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http://dx.doi.org/10.1002/2211-5463.12078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5011488PMC
September 2016