79 results on '"Hendriks JJ"'
Search Results
2. Changes in characteristics of rat skeletal muscle after experimental allergic encephalomyelitis.
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de Haan, A., van der Vliet, M.R., Hendriks, JJ, Heijnen, DA, Dijkstra, C.D., de Haan, A., van der Vliet, M.R., Hendriks, JJ, Heijnen, DA, and Dijkstra, C.D.
- Abstract
Experimental allergic encephalomyelitis (EAE) serves as an animal model for certain neuroinflammatory diseases of the central nervous system, in particular multiple sclerosis (MS). EAE is accompanied by transient weakness or paralysis of hind limbs. We have investigated the effect of partial and transient conduction failure in the central nervous system on skeletal muscle function. At ∼2.5 days after development of maximal clinical signs, body and medial gastrocnemius muscle mass were lower (by ∼21 and 33%, respectively; P < 0.05) in EAE rats compared with controls. Fiber cross-sectional area was lower by 40-50% in all fiber types. Maximal force and power were substantially lower (by 58% and 73%) in EAE rats, as was the force normalized for muscle mass (35%). However, no such weakness was found when lower stimulation frequencies were used. Generation of similar submaximal forces was attributable to a slower relaxation in EAE muscles. This advantage for the EAE muscles was lost during repeated exercise. While fatigability was similar, the difference in relaxation rate between EAE and control disappeared in fatigue. Our data suggest that, as a result of central neuroinflammatory diseases, maximal performance of skeletal muscle is impaired but submaximal performance is relatively well maintained.
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- 2004
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3. Analysis of the myelin-regulated inflammatory transcriptome in rat macrophages
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Bogie, JF, primary, Timmermans, S, additional, Huynh-Thu, VA, additional, Irrthum, A, additional, Smeets, HJ, additional, Gustafsson, JÅ, additional, Steffensen, KR, additional, Mulder, M, additional, Stinissen, P, additional, Hellings, N, additional, and Hendriks, JJ, additional
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4. Treatment failure of Helicobacter pylori in primary care: a retrospective cohort study.
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van den Brink G, Koggel LM, Hendriks JJ, de Boer MG, Siersema PD, and Numans ME
- Abstract
Background: Owing to increasing antibiotic resistance, the worldwide efficacy of Helicobacter pylori (HP) eradication treatment has decreased., Aim: To determine antimicrobial resistance of HP in primary care., Design & Setting: Retrospective cohort study using real-world routine healthcare data from 80 general practices in the Netherlands., Method: Patients with International Classification of Primary Care (ICPC) codes for gastric symptoms or Anatomical Therapeutic Chemical (ATC) codes for acid inhibition in the period 2010-2020 were selected. Main outcomes were antimicrobial resistance of HP, defined as the prescription of a second eradication treatment within 12 months, and clinical remission of gastric symptoms, defined as no usage of acid inhibition 1 year following eradication therapy., Results: We identified 138 455 patients with gastric symptoms and/or acid inhibition use (mean age 57 years [standard deviation 18.2 years], 43% male). A total of 5224 (4%) patients received an HP eradication treatment. A second treatment was prescribed to 416 (8%) of those patients. From these, 380 patients received amoxicillin-clarithromycin, 16 amoxicillin-metronidazole, and 11 clarithromycin-metronidazole as first regimen and were considered antimicrobial resistant. We observed a 0.8% increment per year of patients requiring a second eradication treatment ( P = 0.003, 95% confidence interval = 0.33 to 1.22). After successful eradication, 2329/4808 (48%) patients used acid inhibition compared with 355/416 (85%) patients following treatment failure ( P <0.001)., Conclusion: Antimicrobial treatment is not successful in almost one-tenth of HP infections in primary care after a first treatment containing clarithromycin and/or metronidazole. Although the treatment failure rate is not as high as reported in secondary care, the increasing trend is concerning and may require revision of the current guidelines., (Copyright © 2024, The Authors.)
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- 2024
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5. CNS delivery of anti-CD52 antibodies modestly reduces disease severity in an animal model for multiple sclerosis.
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Bogie JF, Grajchen E, Wouters E, Broux B, Stinissen P, Van Wijmeersch B, and Hendriks JJ
- Abstract
Background and Aims: Alemtuzumab is a humanized monoclonal antibody that depletes CD52-bearing B and T lymphocytes. Clinical trials defined that systemic administration of alemtuzumab reduces disease severity in the relapsing-remitting phase of multiple sclerosis (MS). However, its efficacy in progressive MS patients is limited, which may reflect the inability of alemtuzumab to cross the reconstituted BBB in these patients. Objective: to study whether central nervous system (CNS) delivery of anti-CD52 antibodies reduces disease severity and the neuroinflammatory burden in the experimental autoimmune encephalomyelitis (EAE) model., Methods: Anti-CD52 antibodies were administered intrathecally during the acute and chronic phases of EAE. Flow cytometry and immunohistochemistry were utilized to define immunological and pathological parameters., Results: We show that subcutaneously administrated anti-CD52 antibodies completely abolish EAE disease severity. CNS delivery of anti-CD52 antibodies during both the acute and chronic phases of EAE moderately reduces disease severity and the neuroinflammatory burden. Our findings further suggest that CNS delivery of anti-CD52 antibodies impacts both the peripheral and CNS immune cell compartments in the EAE model but not in healthy mice., Conclusion: Collectively, our findings highlight the therapeutic potential of CNS delivery of alemtuzumab for the treatment of progressive as well as early MS., Competing Interests: Conflict of interest statement: The authors declare that there is no conflict of interest., (© The Author(s), 2020.)
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- 2020
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6. CD169 is a marker for highly pathogenic phagocytes in multiple sclerosis.
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Bogie JF, Boelen E, Louagie E, Delputte P, Elewaut D, van Horssen J, Hendriks JJ, and Hellings N
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- Adult, Aged, Animals, Female, Humans, Male, Mice, Middle Aged, Biomarkers, Encephalomyelitis, Autoimmune, Experimental diagnosis, Inflammation diagnosis, Multiple Sclerosis diagnosis, Phagocytes, Sialic Acid Binding Ig-like Lectin 1
- Abstract
Background: Phagocytes, such as macrophages and microglia, are key effector cells in the pathophysiology of multiple sclerosis (MS). It is widely accepted that they instigate and promote neuroinflammatory and neurodegenerative events in MS. An increasing amount of studies indicate that Siglec-1, also known CD169, is a marker for activated phagocytes in inflammatory disorders., Objective: In this study, we set out to define how CD169
+ phagocytes contribute to neuroinflammation in MS., Methods: CD169-diphtheria toxin receptor (DTR) mice, which express human DTR under control of the CD169 promoter, were used to define the impact of CD169+ cells on neuroinflammation. Flow cytometry and immunohistochemistry were utilized to determine the expression and distribution of CD169., Results: We show that CD169 is highly expressed by lesional and circulating phagocytes in MS and experimental autoimmune encephalomyelitis (EAE). Our data further indicate that CD169 represents a selective marker for early activated microglia in MS and EAE lesions. Depletion of CD169+ cells markedly reduced neuroinflammation and ameliorated disease symptoms in EAE-affected mice., Conclusion: Our findings indicate that CD169+ cells promote neuroinflammation. Furthermore, they suggest that CD169+ phagocytes play a key role in the pathophysiology of MS. Hence, targeting CD169+ phagocytes may hold therapeutic value for MS.- Published
- 2018
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7. Active liver X receptor signaling in phagocytes in multiple sclerosis lesions.
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Mailleux J, Vanmierlo T, Bogie JF, Wouters E, Lütjohann D, Hendriks JJ, and van Horssen J
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- Cells, Cultured, Humans, Multiple Sclerosis, Brain immunology, Brain metabolism, Liver X Receptors metabolism, Macrophages immunology, Macrophages metabolism, Myelin Sheath metabolism, Signal Transduction, Tissue Banks
- Abstract
Objective: We sought to determine the liver X receptor (LXR) ligands present in human macrophages after myelin phagocytosis and whether LXRs are activated in multiple sclerosis (MS) lesions., Methods: We used real-time quantitative polymerase chain reaction (PCR) and immunohistochemistry to determine expression of LXRs and their response genes in human phagocytes after myelin phagocytosis and in active MS lesions. We used gas chromatographic/mass spectrometric analysis to determine LXR-activating oxysterols and cholesterol precursors present and formed in myelin and myelin-incubated cells, respectively., Results: Myelin induced LXR response genes ABCA1 and ABCG1 in human monocyte-derived macrophages. In active MS lesions, we found that both gene expression and protein levels of ABCA1 and apolipoprotein E ( APOE) are upregulated in foamy phagocytes. Moreover, we found that the LXR ligand 27-hydroxycholesterol (27OHC) is significantly increased in human monocyte-derived macrophages after myelin uptake., Conclusion: LXR response genes are upregulated in phagocytes present in active MS lesions, indicating that LXRs are activated in actively demyelinating phagocytes. In addition, we have shown that myelin contains LXR ligands and that 27OHC is generated in human monocyte-derived macrophages after myelin processing. This suggests that LXRs in phagocytes in active MS lesions are activated at least partially by (oxy)sterols present in myelin and the generation thereof during myelin processing.
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- 2018
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8. Scavenger receptor collectin placenta 1 is a novel receptor involved in the uptake of myelin by phagocytes.
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Bogie JF, Mailleux J, Wouters E, Jorissen W, Grajchen E, Vanmol J, Wouters K, Hellings N, van Horssen J, Vanmierlo T, and Hendriks JJ
- Subjects
- Animals, Cell Membrane metabolism, HEK293 Cells, Humans, Mice, Mice, Inbred C57BL, Multiple Sclerosis pathology, Myeloid Cells metabolism, RAW 264.7 Cells, Collectins metabolism, Myelin Sheath metabolism, Phagocytes metabolism, Receptors, Scavenger metabolism
- Abstract
Myelin-containing macrophages and microglia are the most abundant immune cells in active multiple sclerosis (MS) lesions. Our recent transcriptomic analysis demonstrated that collectin placenta 1 (CL-P1) is one of the most potently induced genes in macrophages after uptake of myelin. CL-P1 is a type II transmembrane protein with both a collagen-like and carbohydrate recognition domain, which plays a key role in host defense. In this study we sought to determine the dynamics of CL-P1 expression on myelin-containing phagocytes and define the role that it plays in MS lesion development. We show that myelin uptake increases the cell surface expression of CL-P1 by mouse and human macrophages, but not by primary mouse microglia in vitro. In active demyelinating MS lesions, CL-P1 immunoreactivity was localized to perivascular and parenchymal myelin-laden phagocytes. Finally, we demonstrate that CL-P1 is involved in myelin internalization as knockdown of CL-P1 markedly reduced myelin uptake. Collectively, our data indicate that CL-P1 is a novel receptor involved in myelin uptake by phagocytes and likely plays a role in MS lesion development.
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- 2017
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9. Relapsing-remitting multiple sclerosis patients display an altered lipoprotein profile with dysfunctional HDL.
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Jorissen W, Wouters E, Bogie JF, Vanmierlo T, Noben JP, Sviridov D, Hellings N, Somers V, Valcke R, Vanwijmeersch B, Stinissen P, Mulder MT, Remaley AT, and Hendriks JJ
- Subjects
- ATP Binding Cassette Transporter, Subfamily G, Member 1 genetics, Adaptive Immunity, Adult, Apolipoprotein A-I genetics, Body Mass Index, Case-Control Studies, Cholesterol, LDL blood, Cholesterol, VLDL blood, Disease Progression, Female, Gene Expression, Humans, Immunity, Innate, Insulin Resistance, Lipoproteins, HDL classification, Lipoproteins, HDL genetics, Magnetic Resonance Spectroscopy, Male, Middle Aged, Monocytes pathology, Multiple Sclerosis, Relapsing-Remitting genetics, Multiple Sclerosis, Relapsing-Remitting immunology, Multiple Sclerosis, Relapsing-Remitting pathology, Triglycerides blood, ATP Binding Cassette Transporter, Subfamily G, Member 1 blood, Apolipoprotein A-I blood, Lipoproteins, HDL blood, Monocytes immunology, Multiple Sclerosis, Relapsing-Remitting blood
- Abstract
Lipoproteins modulate innate and adaptive immune responses. In the chronic inflammatory disease multiple sclerosis (MS), reports on lipoprotein level alterations are inconsistent and it is unclear whether lipoprotein function is affected. Using nuclear magnetic resonance (NMR) spectroscopy, we analysed the lipoprotein profile of relapsing-remitting (RR) MS patients, progressive MS patients and healthy controls (HC). We observed smaller LDL in RRMS patients compared to healthy controls and to progressive MS patients. Furthermore, low-BMI (BMI ≤ 23 kg/m
2 ) RRMS patients show increased levels of small HDL (sHDL), accompanied by larger, triglyceride (TG)-rich VLDL, and a higher lipoprotein insulin resistance (LP-IR) index. These alterations coincide with a reduced serum capacity to accept cholesterol via ATP-binding cassette (ABC) transporter G1, an impaired ability of HDL3 to suppress inflammatory activity of human monocytes, and modifications of HDL3 's main protein component ApoA-I. In summary, lipoprotein levels and function are altered in RRMS patients, especially in low-BMI patients, which may contribute to disease progression in these patients.- Published
- 2017
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10. Methylglyoxal-Derived Advanced Glycation Endproducts in Multiple Sclerosis.
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Wetzels S, Wouters K, Schalkwijk CG, Vanmierlo T, and Hendriks JJ
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- Adaptive Immunity, Animals, Glycolysis, Humans, Immunity, Innate, Lipid Peroxidation, Multiple Sclerosis immunology, Oxidation-Reduction, Oxidative Stress, Receptor for Advanced Glycation End Products metabolism, Glycation End Products, Advanced metabolism, Multiple Sclerosis metabolism, Pyruvaldehyde metabolism
- Abstract
Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS). The activation of inflammatory cells is crucial for the development of MS and is shown to induce intracellular glycolytic metabolism in pro-inflammatory microglia and macrophages, as well as CNS-resident astrocytes. Advanced glycation endproducts (AGEs) are stable endproducts formed by a reaction of the dicarbonyl compounds methylglyoxal (MGO) and glyoxal (GO) with amino acids in proteins, during glycolysis. This suggests that, in MS, MGO-derived AGEs are formed in glycolysis-driven cells. MGO and MGO-derived AGEs can further activate inflammatory cells by binding to the receptor for advanced glycation endproducts (RAGE). Recent studies have revealed that AGEs are increased in the plasma and brain of MS patients. Therefore, AGEs might contribute to the inflammatory status in MS. Moreover, the main detoxification system of dicarbonyl compounds, the glyoxalase system, seems to be affected in MS patients, which may contribute to high MGO-derived AGE levels. Altogether, evidence is emerging for a contributing role of AGEs in the pathology of MS. In this review, we provide an overview of the current knowledge on the involvement of AGEs in MS.
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- 2017
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11. Urodynamic changes in mice with experimental autoimmune encephalomyelitis correlate with neurological impairment.
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Franken J, Gevaert T, Uvin P, Wauterickx K, Boeve AC, Rietjens R, Boudes M, Hendriks JJ, Hellings N, Voets T, and De Ridder D
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- Animals, Female, Mice, Urination, Encephalomyelitis, Autoimmune, Experimental physiopathology, Urinary Bladder physiopathology, Urinary Bladder, Neurogenic physiopathology, Urinary Bladder, Overactive physiopathology, Urodynamics physiology
- Abstract
Aims: Neurogenic bladder dysfunction is a major issue in Multiple Sclerosis (MS). High intravesical pressure should be treated early. Available therapies are insufficient and there is need for drug development and investigation of pathogenesis. Experimental Autoimmune Encephalomyelitis (EAE) in rodents is a well validated model to study MS. Previous research has shown that these animals develop urinary symptoms. However, from clinical studies, we know that symptoms do not necessarily reflect changes in bladder pressure. This paper aims to provide a complete overview of urodynamic changes in a model for detrusor overactivity in MS., Methods: Female C57Bl/6J mice, injected with MOG35-55 and control mice, injected with vehicle (Complete Freund's adjuvant), were monitored daily for neurologic symptoms. Within 1 month after symptom development, mice were used for cystometry or histology of the bladder., Results: Increasing disease score correlated with increased micturition frequency, basal pressure, and average pressure, and with a decrease in functional bladder capacity, voiding amplitude, and maximum pressure., Conclusions: This paper provides a detailed description of bladder function in C57Bl/6J mice with Myelin Oligodendrocyte Glycoprotein peptide (MOG35-55 ) induced EAE. This EAE model induces detrusor overactivity in close relationship to neurological impairment. EAE in mice is a suitable model to study detrusor overactivity in MS. Neurourol. Urodynam. 35:450-456, 2016. © 2015 Wiley Periodicals, Inc., (© 2015 Wiley Periodicals, Inc.)
- Published
- 2016
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12. Tolerogenic Dendritic Cells Generated by In Vitro Treatment With SAHA Are Not Stable In Vivo.
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Thewissen K, Broux B, Hendriks JJ, Vanhees M, Stinissen P, Slaets H, and Hellings N
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- Animals, Apoptosis drug effects, Apoptosis genetics, Bone Marrow Cells cytology, Bone Marrow Cells drug effects, CD11c Antigen metabolism, Cell Movement drug effects, Cell Movement genetics, Cells, Cultured, Cytokines metabolism, Dendritic Cells drug effects, Down-Regulation drug effects, Encephalomyelitis, Autoimmune, Experimental pathology, Encephalomyelitis, Autoimmune, Experimental therapy, Endocytosis drug effects, Female, Histocompatibility Antigens Class II metabolism, Inflammation Mediators metabolism, Lipopolysaccharides pharmacology, Mice, Inbred C57BL, Myelin Sheath metabolism, Myelin-Oligodendrocyte Glycoprotein, Phenotype, STAT Transcription Factors metabolism, Signal Transduction drug effects, Signal Transduction genetics, Toll-Like Receptors metabolism, Up-Regulation drug effects, Vorinostat, Dendritic Cells immunology, Hydroxamic Acids pharmacology, Immune Tolerance drug effects
- Abstract
The aim of this study is to examine whether the histone deacetylase inhibitor, suberoylanilide hydroxamic acid (SAHA), can generate dendritic cells (DCs) with a stable tolerogenic phenotype to counteract autoimmune responses in an animal model of multiple sclerosis. We investigated if the tolerogenic potency of DCs could be increased by continuous treatment during in vitro differentiation toward DCs compared to standard 24-h in vitro treatment of already terminally differentiated DCs. We show that in vitro treatment with SAHA reduces the generation of new CD11c(+) DCs out of mouse bone marrow. SAHA-generated DCs show reduced antigen-presenting function as evidenced by a reduction in myelin endocytosis, a decreased MHC II expression, and a failure to upregulate costimulatory molecules upon LPS challenge. In addition, SAHA-generated DCs display a reduction in proinflammatory cytokines and molecules involved in apoptosis induction, inflammatory migration, and TLR signaling, and they are less immunostimulatory compared to untreated DCs. We demonstrated that the underlying mechanism involves a diminished STAT1 phosphorylation and was independent of STAT6 activation. Although in vitro results were promising, SAHA-generated DCs were not able to alleviate the development of experimental autoimmune encephalomyelitis in mice. In vitro washout experiments demonstrated that the tolerogenic phenotype of SAHA-treated DCs is reversible. Taken together, while SAHA potently boosts tolerogenic properties in DCs during the differentiation process in vitro, SAHA-generated DCs were unable to reduce autoimmunity in vivo. Our results imply that caution needs to be taken when developing DC-based therapies to induce tolerance in the context of autoimmune disease.
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- 2016
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13. Oncostatin M protects against demyelination by inducing a protective microglial phenotype.
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Janssens K, Maheshwari A, Van den Haute C, Baekelandt V, Stinissen P, Hendriks JJ, Slaets H, and Hellings N
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- Animals, Calcium-Binding Proteins metabolism, Central Nervous System drug effects, Central Nervous System metabolism, Central Nervous System pathology, Chelating Agents toxicity, Cuprizone toxicity, Cytokines genetics, Cytokines metabolism, Demyelinating Diseases chemically induced, Disease Models, Animal, Glial Fibrillary Acidic Protein metabolism, Growth Inhibitors pharmacology, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Microfilament Proteins metabolism, Microglia drug effects, Oncostatin M Receptor beta Subunit genetics, Oncostatin M Receptor beta Subunit metabolism, Phenotype, Time Factors, Transduction, Genetic, Up-Regulation drug effects, Up-Regulation genetics, Demyelinating Diseases pathology, Demyelinating Diseases prevention & control, Microglia metabolism, Oncostatin M pharmacology, Up-Regulation physiology
- Abstract
Multiple sclerosis (MS) is a chronic disabling disease of the central nervous system (CNS), in which destruction of myelin sheaths leads to disturbed axonal conduction. Available MS therapies modulate the immune response, but are unable to prevent neurological decline. Therefore, great efforts are made to develop therapies that limit demyelination and axonal degeneration. Oncostatin M (OSM), a member of the interleukin (IL)-6 cytokine family, is produced in demyelinating lesions of MS patients and stimulates neuronal survival. In this study, we reveal that the OSM receptor (OSMR) was robustly upregulated on microglia/macrophages and astrocytes in the cuprizone-induced demyelination model. While OSMR deficiency led to aggravated demyelination, CNS-targeted OSM treatment largely prevented demyelination. OSM treatment increased IL-4 expression and induced polarization of myeloid cells towards an anti-inflammatory M2 phenotype in vivo. This study reveals a previously uncharacterized and protective role for OSM during demyelination, and indicates that OSM is a promising therapeutic candidate to limit CNS damage in demyelinating diseases including MS., (© 2015 Wiley Periodicals, Inc.)
- Published
- 2015
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14. Plant sterols: Friend or foe in CNS disorders?
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Vanmierlo T, Bogie JF, Mailleux J, Vanmol J, Lütjohann D, Mulder M, and Hendriks JJ
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- Animals, Central Nervous System Diseases drug therapy, Central Nervous System Diseases pathology, Humans, Multiple Sclerosis drug therapy, Multiple Sclerosis metabolism, Phytosterols therapeutic use, Central Nervous System Diseases metabolism, Phytosterols metabolism
- Abstract
In mammals, the central nervous system (CNS) is the most cholesterol rich organ by weight. Cholesterol metabolism is tightly regulated in the CNS and all cholesterol available is synthesized in situ. Deficits in cholesterol homeostasis at the level of synthesis, transport, or catabolism result in severe disorders featured by neurological disability. Recent studies indicate that a disturbed cholesterol metabolism is involved in CNS disorders, such as Alzheimer's disease (AD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS). In contrast to circulating cholesterol, dietary plant sterols, can cross the blood-brain barrier and accumulate in the membranes of CNS cells. Plant sterols are well-known for their ability to lower circulating cholesterol levels. The finding that they gain access to the CNS has fueled research focusing on the physiological roles of plant sterols in the healthy and diseased CNS. To date, both beneficial and detrimental effects of plant sterols on CNS disorders are defined. In this review, we discuss recent findings regarding the impact of plant sterols on homeostatic and pathogenic processes in the CNS, and elaborate on the therapeutic potential of plant sterols in CNS disorders., (Copyright © 2015 Elsevier Ltd. All rights reserved.)
- Published
- 2015
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15. Leukemia inhibitory factor tips the immune balance towards regulatory T cells in multiple sclerosis.
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Janssens K, Van den Haute C, Baekelandt V, Lucas S, van Horssen J, Somers V, Van Wijmeersch B, Stinissen P, Hendriks JJ, Slaets H, and Hellings N
- Subjects
- Adult, Animals, CD4-Positive T-Lymphocytes drug effects, CD4-Positive T-Lymphocytes immunology, Case-Control Studies, Female, Humans, In Vitro Techniques, Interleukin-6 metabolism, Leukemia Inhibitory Factor pharmacology, Leukemia Inhibitory Factor Receptor alpha Subunit metabolism, Male, Mice, Middle Aged, T-Lymphocytes, Regulatory drug effects, Encephalomyelitis, Autoimmune, Experimental immunology, Interleukin-6 immunology, Leukemia Inhibitory Factor immunology, Leukemia Inhibitory Factor Receptor alpha Subunit immunology, Multiple Sclerosis immunology, T-Lymphocytes, Regulatory immunology
- Abstract
Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS), for which current treatments are unable to prevent disease progression. Based on its neuroprotective and neuroregenerating properties, leukemia inhibitory factor (LIF), a member of the interleukin-6 (IL-6) cytokine family, is proposed as a novel candidate for MS therapy. However, its effect on the autoimmune response remains unclear. In this study, we determined how LIF modulates T cell responses that play a crucial role in the pathogenesis of MS. We demonstrate that expression of the LIF receptor was strongly increased on immune cells of MS patients. LIF treatment potently boosted the number of regulatory T cells (Tregs) in CD4(+) T cells isolated from healthy controls and MS patients with low serum levels of IL-6. Moreover, IL-6 signaling was reduced in the donors that responded to LIF treatment in vitro. Our data together with previous findings revealing that IL-6 inhibits Treg development, suggest an opposing function of LIF and IL-6. In a preclinical animal model of MS we shifted the LIF/IL-6 balance in favor of LIF by CNS-targeted overexpression. This increased the number of Tregs in the CNS during active autoimmune responses and reduced disease symptoms. In conclusion, our data show that LIF downregulates the autoimmune response by enhancing Treg numbers, providing further impetus for the use of LIF as a novel treatment for MS and other autoimmune diseases., (Copyright © 2014 Elsevier Inc. All rights reserved.)
- Published
- 2015
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16. Human Wharton's Jelly-Derived Stem Cells Display Immunomodulatory Properties and Transiently Improve Rat Experimental Autoimmune Encephalomyelitis.
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Donders R, Vanheusden M, Bogie JF, Ravanidis S, Thewissen K, Stinissen P, Gyselaers W, Hendriks JJ, and Hellings N
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- Animals, Cell Differentiation immunology, Cell Proliferation physiology, Cytokines metabolism, Humans, Rats, T-Lymphocytes cytology, T-Lymphocytes immunology, Umbilical Cord cytology, Cell Differentiation physiology, Encephalomyelitis, Autoimmune, Experimental therapy, Lymphocyte Activation immunology, Mesenchymal Stem Cells cytology, Wharton Jelly cytology
- Abstract
Umbilical cord matrix or Wharton's jelly-derived stromal cells (WJ-MSCs) are an easily accessible source of mesenchymal-like stem cells. Recent studies describe a hypoimmunogenic phenotype, multipotent differentiation potential, and trophic support function for WJ-MSCs, with variable clinical benefit in degenerative disease models such as stroke, myocardial infarction, and Parkinson's disease. It remains unclear whether WJ-MSCs have therapeutic value for multiple sclerosis (MS), where autoimmune-mediated demyelination and neurodegeneration need to be halted. In this study, we investigated whether WJ-MSCs possess the required properties to effectively and durably reverse these pathological hallmarks and whether they survive in an inflammatory environment after transplantation. WJ-MSCs displayed a lowly immunogenic phenotype and showed intrinsic expression of neurotrophic factors and a variety of anti-inflammatory molecules. Furthermore, they dose-dependently suppressed proliferation of activated T cells using contact-dependent and paracrine mechanisms. Indoleamine 2,3-dioxygenase 1 was identified as one of the main effector molecules responsible for the observed T-cell suppression. The immune-modulatory phenotype of WJ-MSCs was further enhanced after proinflammatory cytokine treatment in vitro (licensing). In addition to their effect on adaptive immunity, WJ-MSCs interfered with dendritic cell differentiation and maturation, thus directly affecting antigen presentation and therefore T-cell priming. Systemically infused WJ-MSCs potently but transiently ameliorated experimental autoimmune encephalomyelitis (EAE), an animal model for MS, when injected at onset or during chronic disease. This protective effect was paralleled with a reduction in autoantigen-induced T-cell proliferation, confirming their immunomodulatory activity in vivo. Surprisingly, in vitro licensed WJ-MSCs did not ameliorate EAE, indicative of a fast rejection as a result of enhanced immunogenicity. Collectively, we show that WJ-MSCs have trophic support properties and effectively modulate immune cell functioning both in vitro and in the EAE model, suggesting WJ-MSC may hold promise for MS therapy. Future research is needed to optimize survival of stem cells and enhance clinical durability.
- Published
- 2015
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17. Sperm-associated antigen 16 is a novel target of the humoral autoimmune response in multiple sclerosis.
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de Bock L, Somers K, Fraussen J, Hendriks JJ, van Horssen J, Rouwette M, Hellings N, Villar LM, Alvarez-Cermeño JC, Espiño M, Hupperts R, Jongen P, Damoiseaux J, Verbeek MM, De Deyn PP, D'hooghe M, Van Wijmeersch B, Stinissen P, and Somers V
- Subjects
- Adult, Animals, Autoantibodies blood, Biomarkers blood, Brain immunology, Brain metabolism, Brain pathology, Encephalomyelitis, Autoimmune, Experimental blood, Encephalomyelitis, Autoimmune, Experimental immunology, Encephalomyelitis, Autoimmune, Experimental pathology, Enzyme-Linked Immunosorbent Assay, Female, Humans, Isoelectric Focusing, Male, Mice, Microtubule-Associated Proteins blood, Middle Aged, Multiple Sclerosis blood, Multiple Sclerosis diagnosis, Multiple Sclerosis pathology, Up-Regulation immunology, Antibody Specificity, Autoantibodies immunology, Microtubule-Associated Proteins immunology, Multiple Sclerosis immunology
- Abstract
We have previously identified eight novel autoantibody targets in the cerebrospinal fluid of multiple sclerosis (MS) patients, including sperm-associated Ag 16 (SPAG16). In the current study, we further investigated the autoantibody response against SPAG16-a protein with unknown function in the CNS-and its expression in MS pathology. Using isoelectric focusing, we detected SPAG16-specific oligoclonal bands in the cerebrospinal fluid of 5 of 23 MS patients (22%). Analysis of the anti-SPAG16 Ab reactivity in the plasma of a total of 531 donors using ELISA demonstrated significantly elevated anti-SPAG16 Ab levels (p = 0.002) in 32 of 153 MS patients (21%) compared with all other control groups with 95% specificity for the disease. To investigate the pathologic relevance of anti-SPAG16 Abs in vivo, anti-SPAG16 Abs were injected in mice with experimental autoimmune encephalomyelitis, resulting in a significant disease exacerbation. Finally, we demonstrated a consistent upregulation of SPAG16 in MS brain and experimental autoimmune encephalomyelitis spinal cord lesions, more specifically in reactive astrocytes. We conclude that SPAG16 is a novel autoantibody target in a subgroup of MS patients and in combination with other diagnostic criteria, elevated levels of anti-SPAG16 Abs could be used as a biomarker for diagnosis. Furthermore, the pathologic relevance of anti-SPAG16 Abs was shown in vivo., (Copyright © 2014 by The American Association of Immunologists, Inc.)
- Published
- 2014
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18. Macrophage subsets and microglia in multiple sclerosis.
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Bogie JF, Stinissen P, and Hendriks JJ
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- Animals, Humans, Macrophages drug effects, Macrophages pathology, Microglia drug effects, Microglia pathology, Multiple Sclerosis drug therapy, Multiple Sclerosis pathology, Macrophages physiology, Microglia physiology, Multiple Sclerosis immunology
- Abstract
Along with microglia and monocyte-derived macrophages, macrophages in the perivascular space, choroid plexus, and meninges are the principal effector cells in neuroinflammatory and neurodegenerative disorders. These phagocytes are highly heterogeneous cells displaying spatial- and temporal-dependent identities in the healthy, injured, and inflamed CNS. In the last decade, researchers have debated on whether phagocytes subtypes and phenotypes are pathogenic or protective in CNS pathologies. In the context of this dichotomy, we summarize and discuss the current knowledge on the spatiotemporal physiology of macrophage subsets and microglia in the healthy and diseased CNS, and elaborate on factors regulating their behavior. In addition, the impact of macrophages present in lymphoid organs on CNS pathologies is defined. The prime focus of this review is on multiple sclerosis (MS), which is characterized by inflammation, demyelination, neurodegeneration, and CNS repair, and in which microglia and macrophages have been extensively scrutinized. On one hand, microglia and macrophages promote neuroinflammatory and neurodegenerative events in MS by releasing inflammatory mediators and stimulating leukocyte activity and infiltration into the CNS. On the other hand, microglia and macrophages assist in CNS repair through the production of neurotrophic factors and clearance of inhibitory myelin debris. Finally, we define how microglia and macrophage physiology can be harnessed for new therapeutics aimed at suppressing neuroinflammatory and cytodegenerative events, as well as promoting CNS repair. We conclude that microglia and macrophages are highly dynamic cells displaying disease stage and location-specific fates in neurological disorders. Changing the physiology of divergent phagocyte subsets at particular disease stages holds promise for future therapeutics for CNS pathologies.
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- 2014
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19. Heat-transfer resistance measurement method (HTM)-based cell detection at trace levels using a progressive enrichment approach with highly selective cell-binding surface imprints.
- Author
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Bers K, Eersels K, van Grinsven B, Daemen M, Bogie JF, Hendriks JJ, Bouwmans EE, Püttmann C, Stein C, Barth S, Bos GM, Germeraad WT, De Ceuninck W, and Wagner P
- Subjects
- Animals, CHO Cells, Cells, Cultured, Cricetulus, Glycosylation, Microscopy, Fluorescence, Mucin-1 biosynthesis, Mucin-1 chemistry, Mucin-1 metabolism, Polyurethanes metabolism, Surface Properties, Hot Temperature, Molecular Imprinting, Polyurethanes chemistry
- Abstract
Surface-imprinted polymers allow for specific cell detection based on simultaneous recognition of the cell shape, cell size, and cell membrane functionalities by macromolecular cell imprints. In this study, the specificity of detection and the detection sensitivity for target cells within a pool of non-target cells were analyzed for a cell-specific surface-imprinted polymer combined with a heat-transfer-based read-out technique (HTM). A modified Chinese hamster ovarian cell line (CHO-ldlD) was used as a model system on which the transmembrane protein mucin-1 (MUC1) could be excessively expressed and for which the occurrence of MUC1 glycosylation could be controlled. In specific cancer cells, the overexpressed MUC1 protein typically shows an aberrant apical distribution and glycosylation. We show that surface-imprinted polymers discriminate between cell types that (1) only differ in the expression of a specific membrane protein (MUC1) or (2) only differ in the membrane protein being glycosylated or not. Moreover, surface-imprinted polymers of cells carrying different glycoforms of the same membrane protein do target both types of cells. These findings illustrate the high specificity of cell detection that can be reached by the structural imprinting of cells in polymer layers. Competitiveness between target and non-target cells was proven to negatively affect the detection sensitivity of target cells. Furthermore, we show that the detection sensitivity can be increased significantly by repetitively exposing the surface to the sample and eliminating non-specifically bound cells by flushing between consecutive cell exposures.
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- 2014
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20. High fat diet exacerbates neuroinflammation in an animal model of multiple sclerosis by activation of the Renin Angiotensin system.
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Timmermans S, Bogie JF, Vanmierlo T, Lütjohann D, Stinissen P, Hellings N, and Hendriks JJ
- Subjects
- Animals, Disease Models, Animal, Encephalomyelitis, Autoimmune, Experimental immunology, Encephalomyelitis, Autoimmune, Experimental metabolism, Female, Immunohistochemistry, Mice, Mice, Inbred C57BL, Multiple Sclerosis immunology, Multiple Sclerosis metabolism, Real-Time Polymerase Chain Reaction, Diet, High-Fat adverse effects, Encephalomyelitis, Autoimmune, Experimental pathology, Multiple Sclerosis pathology, Renin-Angiotensin System physiology
- Abstract
Epidemiological studies suggest a positive correlation between the incidence and severity of multiple sclerosis (MS) and the intake of fatty acids. It remains to be clarified whether high fat diet (HFD) indeed can exacerbate the disease pathology associated with MS and what the underlying mechanisms are. In this study, we determined the influence of HFD on the severity and pathology of experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Mice were fed either normal diet (ND) or HFD and subsequently induced with EAE. Immunohistochemical staining and real-time PCR were used to determine immune cell infiltration and inflammatory mediators in the central nervous system (CNS). Our data show that HFD increases immune cell infiltration and inflammatory mediator production in the CNS and thereby aggravates EAE. Moreover, our data demonstrate that activation of the renin angiotensin system (RAS) is associated with the HFD-mediated effects on EAE severity. These results show that HFD exacerbates an autoreactive immune response within the CNS. This indicates that diets containing excess fat have a significant influence on neuroinflammation in EAE, which may have important implications for the treatment and prevention of neuroinflammatory disorders.
- Published
- 2014
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21. Block of a subset of sodium channels exacerbates experimental autoimmune encephalomyelitis.
- Author
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Stevens M, Timmermans S, Bottelbergs A, Hendriks JJ, Brône B, Baes M, and Tytgat J
- Subjects
- Animals, Cell Line, Transformed, Chemistry Techniques, Synthetic, Encephalomyelitis, Autoimmune, Experimental pathology, Female, Mice, Mice, Inbred C57BL, NAV1.2 Voltage-Gated Sodium Channel biosynthesis, NAV1.6 Voltage-Gated Sodium Channel biosynthesis, Peptide Fragments biosynthesis, Peptide Fragments toxicity, Encephalomyelitis, Autoimmune, Experimental chemically induced, Encephalomyelitis, Autoimmune, Experimental metabolism, NAV1.2 Voltage-Gated Sodium Channel metabolism, NAV1.6 Voltage-Gated Sodium Channel metabolism, Sodium Channel Blockers toxicity, Sodium Channels metabolism
- Abstract
Voltage-gated sodium channels (Navs) are involved in several aspects of the pathogenesis of multiple sclerosis (MS). Within acute MS plaques, they are expressed along demyelinated axons. Studies in experimental autoimmune encephalomyelitis (EAE) demonstrated a neuroprotective effect of non-specific Nav blockers. Further, block of specific Navs involved in MS is suggested to have an advantage over non-specific blockers. We investigated the effects of the synthetic Midi peptide in EAE, as it potently and specifically blocks Nav1.2, Nav1.4 and Nav1.6. Administration of this Midi peptide worsens the clinical disease pattern and Nav1.2 and Nav1.6 expression levels were elevated in brain but not in spinal cord of Midi-treated mice, implicating that Navs play a complex role in the pathogenesis of EAE., (Copyright © 2013 Elsevier B.V. All rights reserved.)
- Published
- 2013
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22. Selective identification of macrophages and cancer cells based on thermal transport through surface-imprinted polymer layers.
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Eersels K, van Grinsven B, Ethirajan A, Timmermans S, Jiménez Monroy KL, Bogie JF, Punniyakoti S, Vandenryt T, Hendriks JJ, Cleij TJ, Daemen MJ, Somers V, De Ceuninck W, and Wagner P
- Subjects
- Animals, Cell Line, Cell Line, Tumor, Equipment Design, Hot Temperature, Humans, Jurkat Cells, Leukocytes, Mononuclear cytology, MCF-7 Cells, Mice, Polymers chemistry, Polyurethanes chemistry, Rats, Surface Properties, Biomimetics, Macrophages metabolism, Macrophages pathology, Molecular Imprinting, Neoplasms metabolism, Neoplasms pathology
- Abstract
In this article, we describe a novel straightforward method for the specific identification of viable cells (macrophages and cancer cell lines MCF-7 and Jurkat) in a buffer solution. The detection of the various cell types is based on changes of the heat transfer resistance at the solid-liquid interface of a thermal sensor device induced by binding of the cells to a surface-imprinted polymer layer covering an aluminum chip. We observed that the binding of cells to the polymer layer results in a measurable increase of heat transfer resistance, meaning that the cells act as a thermally insulating layer. The detection limit was found to be on the order of 10(4) cells/mL, and mutual cross-selectivity effects between the cells and different types of imprints were carefully characterized. Finally, a rinsing method was applied, allowing for the specific detection of cancer cells with their respective imprints while the cross-selectivity toward peripheral blood mononuclear cells was negligible. The concept of the sensor platform is fast and low-cost while allowing also for repetitive measurements.
- Published
- 2013
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23. Myelin alters the inflammatory phenotype of macrophages by activating PPARs.
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Bogie JF, Jorissen W, Mailleux J, Nijland PG, Zelcer N, Vanmierlo T, Van Horssen J, Stinissen P, Hellings N, and Hendriks JJ
- Subjects
- Adult, Aged, Animals, Brain immunology, Brain pathology, Cell Proliferation physiology, Cells, Cultured, Encephalomyelitis, Autoimmune, Experimental immunology, Encephalomyelitis, Autoimmune, Experimental pathology, Female, Humans, Lysosomes metabolism, Male, Middle Aged, Multiple Sclerosis pathology, Nitric Oxide metabolism, Phosphatidylserines administration & dosage, Phosphatidylserines metabolism, Rats, Spleen immunology, T-Lymphocytes physiology, Macrophages immunology, Multiple Sclerosis immunology, Myelin Sheath physiology, PPAR delta metabolism, PPAR-beta metabolism
- Abstract
Background: Foamy macrophages, containing myelin degradation products, are abundantly found in active multiple sclerosis (MS) lesions. Recent studies have described an altered phenotype of macrophages after myelin internalization. However, mechanisms by which myelin affects the phenotype of macrophages and how this phenotype influences lesion progression remain unclear., Results: We demonstrate that myelin as well as phosphatidylserine (PS), a phospholipid found in myelin, reduce nitric oxide production by macrophages through activation of peroxisome proliferator-activated receptor β/δ (PPARβ/δ). Furthermore, uptake of PS by macrophages, after intravenous injection of PS-containing liposomes (PSLs), suppresses the production of inflammatory mediators and ameliorates experimental autoimmune encephalomyelitis (EAE), an animal model of MS. The protective effect of PSLs in EAE animals is associated with a reduced immune cell infiltration into the central nervous system and decreased splenic cognate antigen specific proliferation. Interestingly, PPARβ/δ is activated in foamy macrophages in active MS lesions, indicating that myelin also activates PPARβ/δ in macrophages in the human brain., Conclusion: Our data show that myelin modulates the phenotype of macrophages by PPAR activation, which may subsequently dampen MS lesion progression. Moreover, our results suggest that myelin-derived PS mediates PPARβ/δ activation in macrophages after myelin uptake. The immunoregulatory impact of naturally-occurring myelin lipids may hold promise for future MS therapeutics.
- Published
- 2013
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24. Systemic treatment with the inhibitory neurotransmitter γ-aminobutyric acid aggravates experimental autoimmune encephalomyelitis by affecting proinflammatory immune responses.
- Author
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Carmans S, Hendriks JJ, Slaets H, Thewissen K, Stinissen P, Rigo JM, and Hellings N
- Subjects
- Animals, Encephalomyelitis, Autoimmune, Experimental drug therapy, Female, GABA Agents administration & dosage, GABA Agents therapeutic use, Inflammation immunology, Inflammation metabolism, Inflammation pathology, Mice, Mice, Inbred C57BL, Multiple Sclerosis drug therapy, Multiple Sclerosis immunology, Multiple Sclerosis pathology, Neuroimmunomodulation drug effects, Neuroimmunomodulation immunology, Severity of Illness Index, gamma-Aminobutyric Acid physiology, gamma-Aminobutyric Acid therapeutic use, Encephalomyelitis, Autoimmune, Experimental immunology, Encephalomyelitis, Autoimmune, Experimental pathology, Neural Inhibition drug effects, Neural Inhibition immunology, gamma-Aminobutyric Acid administration & dosage
- Abstract
Transcriptomic and proteomic analyses of multiple sclerosis (MS) lesions indicate alterations in the gamma-aminobutyric acid (GABA) inhibitory system, suggesting its involvement in the disease process. To further elucidate the role of GABA in central nervous system (CNS) inflammation in vivo, the chronic myelin oligodendrocyte glycoprotein (MOG)(35-55) experimental autoimmune encephalomyelitis (EAE) model was used. Daily GABA injections (200mg/kg) from day 3 onwards significantly augmented disease severity, which was associated with increased CNS mRNA expression levels of tumor necrosis factor alpha (TNF-α) and interleukin (IL)-6. GABA-treated mice showed enhanced MOG-dependent proliferation and were skewed towards a T helper 1 phenotype. Moreover, in vitro, the lipopolysaccharide (LPS)-induced increase in interleukin (IL)-6 production by macrophages was enhanced at low GABA concentrations (0.03-0.3mM). In sharp contrast to exogenous GABA administration, endogenous GABA increment by systemic treatment with the GABA-transaminase inhibitor vigabatrin (250mg/kg) had prophylactic as well as therapeutic potential in EAE. Together, these results indicate an immune amplifying role of GABA in neuroinflammatory diseases like MS., (Copyright © 2012 Elsevier B.V. All rights reserved.)
- Published
- 2013
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25. Local overexpression of interleukin-11 in the central nervous system limits demyelination and enhances remyelination.
- Author
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Maheshwari A, Janssens K, Bogie J, Van Den Haute C, Struys T, Lambrichts I, Baekelandt V, Stinissen P, Hendriks JJ, Slaets H, and Hellings N
- Subjects
- Animals, Cell Proliferation drug effects, Central Nervous System ultrastructure, Cuprizone pharmacology, Demyelinating Diseases drug therapy, Humans, Immunohistochemistry, Interleukin-11 genetics, Male, Mice, Mice, Inbred C57BL, Microglia cytology, Microglia drug effects, Microglia ultrastructure, Microscopy, Electron, Transmission, Myelin Sheath metabolism, Central Nervous System metabolism, Demyelinating Diseases metabolism, Interleukin-11 metabolism
- Abstract
Demyelination is one of the pathological hallmarks of multiple sclerosis (MS). To date, no therapy is available which directly potentiates endogenous remyelination. Interleukin-11 (IL-11), a member of the gp130 family of cytokines, is upregulated in MS lesions. Systemic IL-11 treatment was shown to ameliorate clinical symptoms in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. IL-11 modulates immune cells and protects oligodendrocytes in vitro. In this study, the cuprizone-induced demyelination mouse model was used to elucidate effects of IL-11 on de- and remyelination, independent of the immune response. Prophylactic-lentiviral- (LV-) mediated overexpression of IL-11 in mouse brain significantly limited acute demyelination, which was accompanied with the preservation of CC1(+) mature oligodendrocytes (OLs) and a decrease in microglial activation (Mac-2(+)). We further demonstrated that IL-11 directly reduces myelin phagocytosis in vitro. When IL-11 expressing LV was therapeutically applied in animals with extensive demyelination, a significant enhancement of remyelination was observed as demonstrated by Luxol Fast Blue staining and electron microscopy imaging. Our results indicate that IL-11 promotes maturation of NG2(+) OPCs into myelinating CC1(+) OLs and may thus explain the enhanced remyelination. Overall, we demonstrate that IL-11 is of therapeutic interest for MS and other demyelinating diseases by limiting demyelination and promoting remyelination.
- Published
- 2013
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26. Identification of protein networks involved in the disease course of experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis.
- Author
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Vanheel A, Daniels R, Plaisance S, Baeten K, Hendriks JJ, Leprince P, Dumont D, Robben J, Brône B, Stinissen P, Noben JP, and Hellings N
- Subjects
- Animals, Brain metabolism, Brain pathology, Disease Models, Animal, Disks Large Homolog 4 Protein, Female, Intracellular Signaling Peptides and Proteins metabolism, Large-Conductance Calcium-Activated Potassium Channel alpha Subunits metabolism, Membrane Proteins metabolism, Principal Component Analysis, Protein Interaction Maps, Proteomics methods, Rats, Rats, Inbred Lew, Reproducibility of Results, Encephalomyelitis, Autoimmune, Experimental metabolism, Multiple Sclerosis metabolism, Protein Interaction Mapping, Proteome
- Abstract
A more detailed insight into disease mechanisms of multiple sclerosis (MS) is crucial for the development of new and more effective therapies. MS is a chronic inflammatory autoimmune disease of the central nervous system. The aim of this study is to identify novel disease associated proteins involved in the development of inflammatory brain lesions, to help unravel underlying disease processes. Brainstem proteins were obtained from rats with MBP induced acute experimental autoimmune encephalomyelitis (EAE), a well characterized disease model of MS. Samples were collected at different time points: just before onset of symptoms, at the top of the disease and following recovery. To analyze changes in the brainstem proteome during the disease course, a quantitative proteomics study was performed using two-dimensional difference in-gel electrophoresis (2D-DIGE) followed by mass spectrometry. We identified 75 unique proteins in 92 spots with a significant abundance difference between the experimental groups. To find disease-related networks, these regulated proteins were mapped to existing biological networks by Ingenuity Pathway Analysis (IPA). The analysis revealed that 70% of these proteins have been described to take part in neurological disease. Furthermore, some focus networks were created by IPA. These networks suggest an integrated regulation of the identified proteins with the addition of some putative regulators. Post-synaptic density protein 95 (DLG4), a key player in neuronal signalling and calcium-activated potassium channel alpha 1 (KCNMA1), involved in neurotransmitter release, are 2 putative regulators connecting 64% of the identified proteins. Functional blocking of the KCNMA1 in macrophages was able to alter myelin phagocytosis, a disease mechanism highly involved in EAE and MS pathology. Quantitative analysis of differentially expressed brainstem proteins in an animal model of MS is a first step to identify disease-associated proteins and networks that warrant further research to study their actual contribution to disease pathology.
- Published
- 2012
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27. Myelin-derived lipids modulate macrophage activity by liver X receptor activation.
- Author
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Bogie JF, Timmermans S, Huynh-Thu VA, Irrthum A, Smeets HJ, Gustafsson JÅ, Steffensen KR, Mulder M, Stinissen P, Hellings N, and Hendriks JJ
- Subjects
- Animals, Cell Movement genetics, Cell Movement immunology, Cell Movement physiology, Cells, Cultured, Cholesterol immunology, Cholesterol metabolism, Gene Expression Profiling, Humans, Hydrocarbons, Fluorinated pharmacology, Inflammation Mediators immunology, Inflammation Mediators metabolism, Interleukin-6 genetics, Interleukin-6 immunology, Interleukin-6 metabolism, Lipid Metabolism genetics, Lipid Metabolism immunology, Liver X Receptors, Macrophages, Peritoneal drug effects, Macrophages, Peritoneal immunology, Mice, Mice, Knockout, Multiple Sclerosis genetics, Multiple Sclerosis immunology, Multiple Sclerosis metabolism, Myelin Sheath immunology, Oligonucleotide Array Sequence Analysis, Orphan Nuclear Receptors genetics, Orphan Nuclear Receptors immunology, Phagocytosis genetics, Phagocytosis immunology, Phagocytosis physiology, Rats, Rats, Wistar, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction drug effects, Signal Transduction genetics, Sulfonamides pharmacology, Lipid Metabolism physiology, Macrophages, Peritoneal metabolism, Myelin Sheath metabolism, Orphan Nuclear Receptors metabolism
- Abstract
Multiple sclerosis is a chronic, inflammatory, demyelinating disease of the central nervous system in which macrophages and microglia play a central role. Foamy macrophages and microglia, containing degenerated myelin, are abundantly found in active multiple sclerosis lesions. Recent studies have described an altered macrophage phenotype after myelin internalization. However, it is unclear by which mechanisms myelin affects the phenotype of macrophages and how this phenotype can influence lesion progression. Here we demonstrate, by using genome wide gene expression analysis, that myelin-phagocytosing macrophages have an enhanced expression of genes involved in migration, phagocytosis and inflammation. Interestingly, myelin internalization also induced the expression of genes involved in liver-X-receptor signaling and cholesterol efflux. In vitro validation shows that myelin-phagocytosing macrophages indeed have an increased capacity to dispose intracellular cholesterol. In addition, myelin suppresses the secretion of the pro-inflammatory mediator IL-6 by macrophages, which was mediated by activation of liver-X-receptor β. Our data show that myelin modulates the phenotype of macrophages by nuclear receptor activation, which may subsequently affect lesion progression in demyelinating diseases such as multiple sclerosis.
- Published
- 2012
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28. Liver X receptors regulate cholesterol homeostasis in oligodendrocytes.
- Author
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Nelissen K, Mulder M, Smets I, Timmermans S, Smeets K, Ameloot M, and Hendriks JJ
- Subjects
- ATP Binding Cassette Transporter 1, ATP-Binding Cassette Transporters metabolism, Analysis of Variance, Animals, Animals, Newborn, Anticholesteremic Agents pharmacology, Antigens, Brain cytology, Cell Differentiation genetics, Cell Survival, Cells, Cultured, Flow Cytometry, Fluoresceins metabolism, Gene Expression Regulation genetics, Homeostasis drug effects, Hydrocarbons, Fluorinated pharmacology, Lipid Metabolism genetics, Lipoproteins, HDL metabolism, Liver X Receptors, Oligodendroglia drug effects, Orphan Nuclear Receptors genetics, Proteoglycans, RNA, Messenger metabolism, Rats, Rats, Wistar, Sulfonamides pharmacology, Time Factors, Tritium metabolism, Cholesterol metabolism, Homeostasis physiology, Oligodendroglia metabolism, Orphan Nuclear Receptors metabolism
- Abstract
Cholesterol synthesis and transport in oligodendrocytes are essential for optimal myelination and remyelination in pathological conditions such as multiple sclerosis. However, little is known about cholesterol homeostasis in the myelin-forming oligodendrocytes. Liver X receptors (LXRs) are nuclear oxysterol receptors that regulate genes involved in cholesterol homeostasis and may therefore play an important role in de- and remyelination. We investigated whether LXRs regulate cholesterol homeostasis in oligodendrocytes. mRNA expression of genes encoding LXR-α and LXR-β and their target genes (ABCA1, ABCG1, ABCG4, apoE, and LDLR) was detected in oligodendrocytes derived from both neonatal and adult rats using quantitative real-time PCR. The expression of LXR-β and several target genes was increased during oligodendrocyte differentiation. We further demonstrated that treatment of primary neonatal rat oligodendrocytes with the synthetic LXR agonist T0901317 induced the expression of several established LXR target genes, including ABCA1, ABCG1, apoE, and LDLR. Treatment of oligodendrocytes with T0901317 resulted in an enhanced cholesterol efflux in the presence of apolipoprotein A-I or high-density lipoprotein particles. These data show that LXRs are involved in regulating cholesterol homeostasis in oligodendrocytes., (Copyright © 2011 Wiley Periodicals, Inc.)
- Published
- 2012
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29. Atopic manifestations during childhood and fetal exposure to arachidonic acid.
- Author
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Dirix CE, Hogervorst JG, Rump P, Hendriks JJ, Bruins M, and Hornstra G
- Subjects
- Female, Humans, Male, Pregnancy, Diet adverse effects, Fatty Acids, Omega-3 blood, Fatty Acids, Omega-6 blood, Hypersensitivity, Immediate epidemiology
- Published
- 2011
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30. Myelin-phagocytosing macrophages modulate autoreactive T cell proliferation.
- Author
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Bogie JF, Stinissen P, Hellings N, and Hendriks JJ
- Subjects
- Animals, Brain immunology, Brain pathology, Cells, Cultured, Coculture Techniques, Female, Lymphocyte Activation immunology, Macrophages, Peritoneal cytology, Macrophages, Peritoneal drug effects, Myelin Basic Protein immunology, Nitric Oxide metabolism, Ovalbumin immunology, Ovalbumin pharmacology, Rats, Rats, Inbred Lew, Receptors, Antigen, T-Cell immunology, Spinal Cord immunology, Spinal Cord pathology, T-Lymphocytes cytology, Cell Proliferation, Macrophages, Peritoneal immunology, Myelin Sheath metabolism, Phagocytosis immunology, T-Lymphocytes immunology
- Abstract
Introduction: Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating disease of the central nervous system (CNS) in which macrophages play a central role. Initially, macrophages where thought to be merely detrimental in MS, however, recent evidence suggests that their functional phenotype is altered following myelin phagocytosis. Macrophages that have phagocytosed myelin may be less inflammatory and may exert beneficial effects. The presence of myelin-containing macrophages in CNS-draining lymph nodes and perivascular spaces of MS patients suggests that these cells are ideally positioned to exert an immune regulatory role. Therefore we evaluated in this study the effect of myelin-phagocytosing macrophages on lymphocyte reactivity., Methods: Thioglycolate-elicited rat peritoneal macrophages were loaded with myelin and cocultured with myelin-basic protein (MBP) or ovalbumin (OVA) reactive lymphocytes. Lymphocyte proliferation was determined by CFSE-labeling. The role of nitric oxide in regulating lymphocyte proliferation was assessed by addition of an inhibitor of inducible nitric oxide synthase to the coculture. In vivo immune regulation was investigated by treating MBP- and OVA-immunized animals subcutaneously with myelin. Cognate antigen specific lymphocyte proliferation and nitric oxide production were determined 9 d post-immunization., Results: In this study we demonstrate that myelin-phagocytosing macrophages inhibit TCR-triggered lymphocyte proliferation in an antigen-independent manner. The observed immune suppression is mediated by an increase in NO production by myelin-phagocytosing macrophages upon contact with lymphocytes. Additionally, myelin delivery to primarily CD169+ macrophages in popliteal lymph nodes of OVA-immunized animals results in a reduced cognate antigen specific proliferation. In contrast to OVA-immunized animals, lymphocytes from MBP-immunized animals displayed an increased proliferation after stimulation with their cognate antigen, indicating that myelin-phagocytosing macrophages have dual effects depending on the specificity of surrounding lymphocytes., Conclusions: Collectively our data show that myelin phagocytosis leads to an altered macrophage function that inhibits lymphocyte proliferation. Additionally, results from this study indicate that myelin-phagocytosing macrophages fulfill a dual role in vivo. On one hand they aggravate autoimmunity by activating myelin-reactive lymphocytes and on the other hand they suppress lymphocyte reactivity by producing NO.
- Published
- 2011
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31. Therapeutic potential of LIF in multiple sclerosis.
- Author
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Slaets H, Hendriks JJ, Stinissen P, Kilpatrick TJ, and Hellings N
- Subjects
- Animals, Cell Proliferation, Demyelinating Diseases genetics, Demyelinating Diseases metabolism, Demyelinating Diseases therapy, Encephalomyelitis, Autoimmune, Experimental genetics, Encephalomyelitis, Autoimmune, Experimental metabolism, Encephalomyelitis, Autoimmune, Experimental therapy, Genetic Therapy methods, Humans, Leukemia Inhibitory Factor genetics, Multiple Sclerosis genetics, Multiple Sclerosis therapy, Neurons cytology, Neurons metabolism, Stem Cells metabolism, Leukemia Inhibitory Factor metabolism, Multiple Sclerosis metabolism
- Abstract
Therapies for multiple sclerosis (MS) reduce the relapse rate but are unable to stop neurological decline. Here, we evaluate the potential of leukemia inhibitory factor (LIF) as a novel therapeutic in diseases with a neurodegenerative and inflammatory component, such as MS. LIF, which can be a proinflammatory cytokine, can also modulate the immune response in a beneficial way. Recent evidence demonstrates a crucial role of LIF in neuroprotection and axonal regeneration as well as the prevention of demyelination. Finally, LIF is an important survival factor for stem cells and neuronal precursors. Therefore, we propose that LIF is a potential therapeutic candidate for MS., (Copyright © 2010 Elsevier Ltd. All rights reserved.)
- Published
- 2010
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32. The inhibitory neurotransmitter glycine modulates macrophage activity by activation of neutral amino acid transporters.
- Author
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Carmans S, Hendriks JJ, Thewissen K, Van den Eynden J, Stinissen P, Rigo JM, and Hellings N
- Subjects
- Animals, Biotransformation drug effects, Cell Proliferation drug effects, Cell Survival, Dose-Response Relationship, Drug, Fluorescent Antibody Technique, Glycine Agents pharmacology, Inflammation pathology, Male, Multiple Sclerosis metabolism, Myelin Sheath physiology, Nitric Oxide biosynthesis, Phagocytosis drug effects, Rats, Rats, Wistar, Reactive Oxygen Species metabolism, Receptors, Glycine biosynthesis, Receptors, Glycine genetics, Reverse Transcriptase Polymerase Chain Reaction, Strychnine pharmacology, Tumor Necrosis Factor-alpha biosynthesis, Amino Acid Transport Systems, Neutral metabolism, Glycine pharmacology, Macrophages, Peritoneal drug effects, Neurotransmitter Agents pharmacology
- Abstract
Glycine, an important inhibitory neurotransmitter in the mammalian central nervous system (CNS), has been shown to modulate peripheral immune cell responses. In that respect, glycine levels are increased in several neuroinflammatory disorders, such as amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS). In this study, we show that glycine modulates macrophage effector functions implicated in CNS inflammation and in other, related inflammatory conditions. We demonstrate that glycine does not affect the production of reactive oxygen species but stimulates myelin phagocytosis and the production of the proinflammatory mediators nitric oxide (NO) and tumor necrosis factor (TNF)-alpha by rat macrophages. These effects of glycine are not mediated by the glycine receptor (GlyR) or by glycine transporters (GlyTs), as neither the GlyR antagonist strychnine nor the antagonist of GlyT1 (ALX5407) reverses the observed effects. In contrast, 2-aminoisobutyric acid, a substrate of neutral amino acid transporters (NAATs), inhibits the glycine-mediated enhancement of myelin phagocytosis as well as of NO and TNF-alpha production. In conclusion, our findings demonstrate that glycine modulates macrophage function through activation of NAATs. Glycine may thereby influence immunological processes in inflammatory diseases involving macrophage activation and demyelination, including MS and related conditions associated with altered glycine levels., ((c) 2010 Wiley-Liss, Inc.)
- Published
- 2010
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33. CNS-targeted LIF expression improves therapeutic efficacy and limits autoimmune-mediated demyelination in a model of multiple sclerosis.
- Author
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Slaets H, Hendriks JJ, Van den Haute C, Coun F, Baekelandt V, Stinissen P, and Hellings N
- Subjects
- Animals, Blood-Brain Barrier metabolism, Demyelinating Autoimmune Diseases, CNS therapy, Disease Models, Animal, Genetic Vectors, Lentivirus, Macrophages immunology, Mice, Mice, Inbred C57BL, Oligodendroglia pathology, T-Lymphocytes transplantation, Encephalomyelitis, Autoimmune, Experimental therapy, Genetic Therapy methods, Leukemia Inhibitory Factor genetics, Multiple Sclerosis therapy
- Abstract
Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS) with an inflammatory and a neurodegenerative component. The neuropoietic cytokine leukemia inhibitory factor (LIF) is expressed in MS lesions, but its effect on lesion development is far from understood. LIF is an interesting candidate for MS therapy, as it has neuroprotective properties and may also promote the survival of myelinating oligodendrocytes (OLGs). However, therapeutic administration of LIF is complicated by its limited ability to cross the blood-brain barrier and its pleiotropic actions outside the CNS. In this study, lentiviral vectors (LVs) were used to achieve stable expression and secretion of LIF in the CNS of adult mice. CNS-targeted expression of LIF significantly reduced demyelination in a murine model of MS. In addition, local expression of LIF ameliorated clinical symptoms with enhanced efficacy compared to systemic treatment with recombinant protein. These findings demonstrate that gene therapeutic administration of LIF is a promising approach to limit lesion burden and clinical symptoms in neuroinflammatory disease.
- Published
- 2010
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34. Selection of reference genes for gene expression studies in rat oligodendrocytes using quantitative real time PCR.
- Author
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Nelissen K, Smeets K, Mulder M, Hendriks JJ, and Ameloot M
- Subjects
- Aging, Animals, Animals, Newborn, Brain metabolism, Cells, Cultured, Liver X Receptors, Orphan Nuclear Receptors agonists, Orphan Nuclear Receptors metabolism, Rats, Rats, Wistar, Gene Expression, Genes, Oligodendroglia metabolism, Polymerase Chain Reaction methods
- Abstract
Quantitative real time polymerase chain reaction (qPCR) has become a widely used tool to examine gene expression levels. Reliable quantification, however, depends on a proper normalization strategy. Normalization with multiple reference genes is becoming the standard, although the most suitable reference genes depend on the applied treatment as well as the tissue or cell type studied. In this study the stability of various reference genes was investigated in cultures of oligodendrocytes derived from either mature or neonatal rats, the latter also in the presence of the liver X receptor (LXR) agonist. The expression stability of ten commonly used reference genes (HPRT, GAPDH, 18S, ActB, CycA, Tbp, Rpl13A, YWHAZ, HMBS, Pgk1) was analyzed using geNorm and NormFinder. When comparing the different types of cell cultures, Rpl13A, CycA, Pgk1 and YWHAZ were identified as most stable genes. After LXR agonist treatment, CycA, Pgk1 and Rpl13A were found to be the most stable by both geNorm and NormFinder. HMBS and the commonly used housekeeping genes GAPDH and 18S turned out to be the most variable according to geNorm and NormFinder. In conclusion, the use of multiple reference genes, instead of only one, in qPCR experiments with rat oligodendrocytes is strongly advised and standard housekeeping genes such as GAPDH and 18S are not recommended as they appear to be relatively unstable under the experimental conditions used. Reference gene selection should always be performed for each individual experiment, since useful reference genes are very specific for every situation., (Copyright (c) 2010 Elsevier B.V. All rights reserved.)
- Published
- 2010
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35. Prenatal arachidonic acid exposure and selected immune-related variables in childhood.
- Author
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Dirix CE, Hogervorst JG, Rump P, Hendriks JJ, Bruins M, and Hornstra G
- Subjects
- Arachidonic Acid blood, Asthma diagnosis, Biomarkers blood, C-Reactive Protein analysis, Child, Female, Fetal Blood chemistry, Fibrinogen analysis, Follow-Up Studies, Humans, Hypersensitivity diagnosis, Infant, Newborn, Leptin blood, Linear Models, Peak Expiratory Flow Rate, Pregnancy, Pregnancy Trimester, Second, Pregnancy Trimester, Third, Prospective Studies, Respiratory Function Tests, von Willebrand Factor analysis, Arachidonic Acid physiology, Child Development physiology, Prenatal Exposure Delayed Effects
- Abstract
Arachidonic acid (AA) is considered essential in fetal development and some of its metabolites are thought to be important mediators of the immune responses. Therefore, we studied whether prenatal exposure to AA is associated with some immune-related clinical conditions and plasma markers in childhood. In 280 children aged 7 years, atopy, lung function and plasma inflammation markers were measured and their relationships with early AA exposure were studied by linear and logistic regression analyses. AA exposure was deduced from AA concentrations in plasma phospholipids of the mothers collected at several time points during pregnancy and at delivery, and in umbilical cord plasma and arterial and venous wall phospholipids. In unadjusted regression analyses, significant positive associations were observed between maternal AA concentrations at 16 and 32 weeks of pregnancy (proxies for fetal AA exposure) and peak expiratory flow decline after maximal physical exercise and plasma fibrinogen concentrations of their children, respectively. However, after correction for relevant covariables, only trends remained. A significant negative relationship was observed between AA concentrations in cord plasma (reflecting prenatal AA exposure) and the average daily amplitude of peak expiratory flow at rest, which lost significance after appropriate adjustment. Because of these few, weak and inconsistent relationships, a major impact of early-life exposure to AA on atopy, lung function and selected plasma inflammation markers of children at 7 years of age seems unlikely.
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- 2009
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36. Using EQ-5D in children with asthma, rheumatic disorders, diabetes, and speech/language and/or hearing disorders.
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Willems DC, Joore MA, Nieman FH, Severens JL, Wouters EF, and Hendriks JJ
- Subjects
- Adolescent, Child, Humans, Surveys and Questionnaires, Asthma, Diabetes Mellitus, Hearing Disorders, Quality of Life, Rheumatic Diseases, Speech Disorders
- Abstract
Objectives: This study explores several variables of the EQ-5D child version, a multi-attribute utility instrument, in children with chronic conditions., Methods: A convenience sample was selected from hospital outpatient records and school records. The sample included children aged 7-18 years with the following chronic conditions: asthma, rheumatic disorders, diabetes, and speech/language and/or hearing disorders. The practicality, convergent validity, and discriminant power were compared with a generic quality of life questionnaire for children (TACQOL) and the 2-week test-retest reliability was assessed., Results: A total of 182 children or their parents completed the first questionnaire and 161 children/parents completed both questionnaires. The practicality of the EQ-5D was good. Low to moderate correlations were found between the utilities and VAS scores and the TACQOL scales. The discriminant power of the EQ-5D items was low overall and was greater for children with a rheumatic disorder than for children with the other conditions. In the subset of children who experienced no health change between the test and the retest, the reliability of the EQ-5D was moderate to high., Conclusions: The EQ-5D seems suitable for children, although the use of an additional disease-specific questionnaire is still recommended. The EQ-5D seems the most suitable for children with a chronic physical condition and appears to be reliable for children with a stable health status.
- Published
- 2009
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37. Growth monitoring to detect children with cystic fibrosis.
- Author
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van Dommelen P, Grote FK, Oostdijk W, de Muinck Keizer-Schrama SM, Bouquet J, Hendriks JJ, Kouwenberg J, Verkerk PH, van Buuren S, and Wit JM
- Subjects
- Aging, Body Height, Body Mass Index, Body Weight, Child, Preschool, Confidence Intervals, Cystic Fibrosis complications, Cystic Fibrosis epidemiology, Failure to Thrive diagnosis, False Positive Reactions, Female, Humans, Infant, Infant, Newborn, Longitudinal Studies, Male, Netherlands epidemiology, Referral and Consultation standards, Sensitivity and Specificity, Sex Factors, Cystic Fibrosis diagnosis, Failure to Thrive etiology, Mass Screening methods
- Abstract
Background/aims: Cystic fibrosis (CF) in infancy and childhood is often associated with failure to thrive (FTT). This would suggest that in countries without a newborn screening program for CF, FTT could be used as a clinical screening tool. The aim of this study is to assess the diagnostic performance of FTT for identifying children with CF., Methods: Longitudinal length and weight measurements up to 2.5 years of age were used from CF patients (n = 123) and a reference group (n = 2,151) in The Netherlands. Growth measurements after diagnosis were excluded. We developed five potential screening rules based upon length, weight and body mass index (BMI) standardized by age and gender (SDS). Outcome measures were sensitivity, specificity and positive predictive value (PPV)., Results: BMI SDS had the highest sensitivity at low false-positive rates. An efficient scenario is a BMI SDS below -2.5 SD in combination with a decrease in BMI SDS of at least 0.5 SD. This scenario had a sensitivity of 32%, a specificity of 98.3% and a PPV of 0.75%., Conclusion: In the absence of a newborn screening program, young children with FTT for BMI are candidates to consider testing for CF.
- Published
- 2009
- Full Text
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38. Leukemia inhibitory factor modulates production of inflammatory mediators and myelin phagocytosis by macrophages.
- Author
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Hendriks JJ, Slaets H, Carmans S, de Vries HE, Dijkstra CD, Stinissen P, and Hellings N
- Subjects
- Animals, Cytokine Receptor gp130 metabolism, Dose-Response Relationship, Drug, Leukemia Inhibitory Factor Receptor alpha Subunit metabolism, Mice, Mice, Inbred C57BL, Mitogen-Activated Protein Kinase 3 metabolism, Oncogene Protein v-akt metabolism, STAT3 Transcription Factor metabolism, Time Factors, Leukemia Inhibitory Factor pharmacology, Macrophages, Peritoneal drug effects, Myelin Sheath metabolism, Phagocytosis drug effects, Reactive Oxygen Species metabolism, Tumor Necrosis Factor-alpha metabolism
- Abstract
Leukemia inhibitory factor (LIF) promotes survival of glial cells and neurons during autoimmune and injury responses in the central nervous system (CNS). While various studies indicate that LIF also modulates ongoing inflammatory responses, data on underlying events are lacking. In this study we demonstrate that LIF modulates macrophage function. LIF inhibits the production of oxygen radicals and TNFalpha and stimulates myelin uptake by macrophages. These effects of LIF are accompanied by activation of the JAK/STAT3 signalling pathway. Our findings demonstrate that LIF has anti-inflammatory properties and enhances myelin clearance, implicating that LIF may be an important factor in CNS inflammatory disease.
- Published
- 2008
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- View/download PDF
39. The effectiveness of nurse-led telemonitoring of asthma: results of a randomized controlled trial.
- Author
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Willems DC, Joore MA, Hendriks JJ, Nieman FH, Severens JL, and Wouters EF
- Subjects
- Adolescent, Adult, Child, Female, Humans, Male, Middle Aged, Respiratory Function Tests, Time Factors, Treatment Outcome, Young Adult, Asthma nursing, Asthma therapy, Health Services statistics & numerical data, Quality of Life, Telemedicine organization & administration
- Abstract
Rationale, Aims and Objectives: The aim of the study was to evaluate the effects on, and the relationship between, asthma symptoms, asthma-specific quality of life and medical consumption of a nurse-led telemonitoring intervention compared with regular care in asthma in the Netherlands., Methods: One hundred and nine asthmatic outpatients (56 children; 53 adults) were randomly assigned to the treatment arms (12-month follow-up). The control group received regular outpatient care, while the intervention group used an asthma monitor with modem at home with an asthma nurse as the main caregiver. Clinical asthma symptoms and medical consumption were measured by using diaries. Asthma-specific quality of life was measured by the (Paediatric) Asthma Quality of Life Questionnaire., Results: The study population generally represented mild to moderate asthmatics. The results show improvement in follow-up, but no statistically significant difference between the groups was observed. Moderate to high correlations were found within the outcome parameters, but the most remarkable was the low and statistically significant correlation between asthma-specific quality of life (daily functioning) and the self-reported beta-2 agonists., Conclusion: Overall, the telemonitoring programme evaluated in this study did not significantly decrease asthma symptoms or medical consumption, or improve asthma-specific quality of life. The results showed that a telemonitoring programme on its own is not a guarantee of success. The patients' perception of asthma-specific quality of life (daily functioning) should be a key element in asthma telemonitoring programmes.
- Published
- 2008
- Full Text
- View/download PDF
40. Visualisation of the kinetics of macrophage infiltration during experimental autoimmune encephalomyelitis by magnetic resonance imaging.
- Author
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Baeten K, Hendriks JJ, Hellings N, Theunissen E, Vanderlocht J, Ryck LD, Gelan J, Stinissen P, and Adriaensens P
- Subjects
- Animals, Antigens, CD metabolism, Antigens, Differentiation, Myelomonocytic metabolism, Cell Migration Assays, Macrophage, Encephalomyelitis, Autoimmune, Experimental physiopathology, Female, Ferric Compounds pharmacokinetics, Macrophages drug effects, Myelin Basic Protein adverse effects, Rats, Rats, Inbred Lew, Time Factors, Encephalomyelitis, Autoimmune, Experimental pathology, Macrophages physiology, Magnetic Resonance Imaging
- Abstract
Macrophages are considered to be the predominant effector cells in multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE). Ultra small particles of iron oxide (USPIO) can be used to detect macrophage infiltrates in the CNS with magnetic resonance imaging (MRI). Here, we investigated whether the kinetics of lesion formation in EAE can be visualised by altering the time point of USPIO injection and the time interval between particle injection and MRI. When USPIO are systemically injected 24 h before MRI, hypo intense regions are detected in different brain regions depending on the disease stage. These regions correspond to sites of macrophage infiltration. A more complete visualisation of sites of inflammation is accomplished by USPIO injection at disease onset and postponing MRI to top of disease. This study demonstrates that the distribution pattern and amount of inflammatory lesions detected with USPIO, depends on timing of USPIO administration and subsequent MRI. These findings are important for a correct application and interpretation of USPIO dependent contrast imaging of CNS inflammation.
- Published
- 2008
- Full Text
- View/download PDF
41. Cost-effectiveness of a nurse-led telemonitoring intervention based on peak expiratory flow measurements in asthmatics: results of a randomised controlled trial.
- Author
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Willems DC, Joore MA, Hendriks JJ, Wouters EF, and Severens JL
- Abstract
Background: Asthma is a chronic lung disease in which recurrent asthma symptoms create a substantial burden to individuals and their families. At the same time the economic burden associated with asthma is considerable., Methods: The cost-effectiveness study was part of a single centre prospective randomised controlled trial comparing a nurse-led telemonitoring programme to usual care in a population of asthmatic outpatients. The study included 109 asthmatic outpatients (56 children; 53 adults). The duration of follow-up was 12 months, and measurements were performed at baseline, 4, 8, and 12 months. Patients were asked to transfer their monitor data at least twice daily and by judging the received data and following a stepwise intervention protocol a nurse was able to act as the main caregiver in the intervention group. In both groups the EQ-5D and the SF-6D were used to obtain estimates of health state utilities. One year health care costs, patient and family costs, and productivity losses were calculated. The mean incremental costs were weighted against the mean incremental effect in terms of QALY., Results: The study population generally represented mild to moderate asthmatics. No significant differences were found between the groups with regard to the generic quality of life. Overall, the mean health care costs per patient were higher in the intervention group than in the control group. The intervention costs mainly caused the cost difference between the groups. The intervention costs the society euro 31,035/QALY gained with regard to adults and with regard to children euro 59,071/QALY gained., Conclusion: If the outcome is measured by generic quality of life the nurse-led telemonitoring programme is of limited cost-effectiveness in the study population. From the societal perspective the probability of the programme being cost-effective compared to regular care was 85% at a ceiling ratio of euro 80,000/QALY gained among the adults and 68% among the children. A decrease in the price of the asthma monitor will substantial increase the probability of the programme to be cost-effective.
- Published
- 2007
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42. The ambivalent nature of T-cell infiltration in the central nervous system of patients with multiple sclerosis.
- Author
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Vanderlocht J, Hellings N, Hendriks JJ, and Stinissen P
- Subjects
- Antigen Presentation, Autoimmunity, Cell Movement, Humans, Leukemia Inhibitory Factor physiology, Nerve Growth Factors physiology, Brain immunology, Multiple Sclerosis immunology, T-Lymphocytes physiology
- Abstract
Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) of presumed autoimmune origin. On the basis of the pathophysiology of MS, inflammatory reactions in the CNS are considered detrimental. Recent evidence suggests that the injured CNS can also benefit from immune activity. In this review, we will first provide an overview of the mechanisms by which immune cells contribute to CNS injury in MS. We will further review evidence supporting a neuroprotective role of CNS inflammation with special focus on the protective properties of autoimmune reactions. Finally, we discuss the proposed mechanisms by which autoreactive T cells exert protection in the CNS and how this protection is regulated.
- Published
- 2007
- Full Text
- View/download PDF
43. Process evaluation of a nurse-led telemonitoring programme for patients with asthma.
- Author
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Willems DC, Joore MA, Hendriks JJ, van Duurling RA, Wouters EF, and Severens JL
- Subjects
- Adolescent, Adult, Aged, Child, Female, Humans, Male, Middle Aged, Patient Compliance, Peak Expiratory Flow Rate, Program Evaluation, Reproducibility of Results, Asthma nursing, Patient Satisfaction statistics & numerical data, Telemetry
- Abstract
We performed a process evaluation of a nurse-led telemonitoring programme for patients with asthma. The indicators used to evaluate the programme were feasibility, consistency of peak expiratory flow (PEF) tests, compliance and patient satisfaction. Patients in the intervention group received a home monitor in which spirometry results and symptoms could be recorded. They were asked to measure PEF in the morning and evening. A nurse studied the home monitoring data and took stepwise actions in accordance with the intervention protocol. During a 12-month study period, 55 patients were allocated to the intervention group (26 adults and 29 children). Although technical and logistical problems did occur, the dropout rate was low. At least 75% of the PEF manoeuvres were valid for two-thirds of the patients. Compliance with the study protocol was high. The average number of recorded PEF tests was 1.5 per day, which was less than the two tests per day that were required by the protocol. Patient satisfaction was high and, after one year, less than 20% of the participants chose to discontinue their participation. The results indicate that nurse-led telemonitoring for a motivated group of patients with mild to moderate asthma is feasible and reliable, and satisfying to patients.
- Published
- 2007
- Full Text
- View/download PDF
44. Current trends in multiple sclerosis research: an update on pathogenic concepts.
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Vanderlocht J, Hellings N, Hendriks JJ, and Stinissen P
- Subjects
- Animals, Autoimmunity immunology, Axons immunology, Axons pathology, CD8-Positive T-Lymphocytes immunology, Humans, Immunosuppression Therapy methods, Immunosuppression Therapy trends, Immunotherapy methods, Immunotherapy trends, Lymphocyte Activation genetics, Lymphocyte Activation immunology, Multiple Sclerosis genetics, Multiple Sclerosis immunology, Wallerian Degeneration genetics, Wallerian Degeneration immunology, Wallerian Degeneration physiopathology, Autoimmunity genetics, Genetic Predisposition to Disease genetics, Multiple Sclerosis physiopathology
- Abstract
Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) of presumed autoimmune origin which develops in a genetic susceptible individual triggered by additional environmental factors. In this review we will provide an update of basic pathogenic concepts. In addition, we will discuss newly evolving concepts in MS pathogenesis such as pathogenic heterogeneity, importance of axonal loss and the role of CD8+ T lymphocytes in tissue injury. In the last part of this review we will briefly describe currently approved MS treatments and summarize some promising therapeutic approaches that are currently under evaluation.
- Published
- 2006
45. Cost-effectiveness of self-management in asthma: a systematic review of peak flow monitoring interventions.
- Author
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Willems DC, Joore MA, Hendriks JJ, Wouters EF, and Severens JL
- Subjects
- Asthma economics, Cost Savings, Cost-Benefit Analysis, Humans, Outcome Assessment, Health Care, Peak Expiratory Flow Rate, Self Care methods, Asthma therapy, Self Care economics, Technology Assessment, Biomedical economics
- Abstract
Objectives: It is generally accepted that home peak flow monitoring increases patients' self-management and could lead to cost savings. The aim of this review was to analyze costs and the cost-effectiveness of self-management based on peak flow monitoring interventions in asthma., Methods: Twenty-one studies were included in this review. Data were extracted, and methodological and economic quality were assessed. These studies presented economic information regarding self-management interventions based on peak flow monitoring in asthmatics. The mean methodological quality was 4.6 (maximum 8), and the mean economic quality was 12.0 (maximum 15)., Results: In eighteen studies, the interventions led to net savings compared with usual care or less intensive intervention. Only three studies found the total costs to be higher in the intervention group. In thirteen of the seventeen studies that analyzed health outcomes, at least one of the reported health outcomes improved statistically significantly after the intervention. However, the methods of economic evaluation differed among the studies and were not always in line with the standard methodology., Conclusions: The interventions, costs, and outcomes were very diverse. The results emphasize the need for guidelines to increase the comparability of cost-effectiveness evaluations relating to asthma. Only then will it be possible to conclude whether interventions for asthmatics, such as self-management based on peak flow monitoring interventions, are cost-effective.
- Published
- 2006
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46. Effects of IFN-beta, leptin and simvastatin on LIF secretion by T lymphocytes of MS patients and healthy controls.
- Author
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Vanderlocht J, Hendriks JJ, Venken K, Stinissen P, and Hellings N
- Subjects
- Adult, Aged, CD4-Positive T-Lymphocytes drug effects, CD4-Positive T-Lymphocytes immunology, CD4-Positive T-Lymphocytes metabolism, Cells, Cultured, Cytokines drug effects, Cytokines metabolism, Cytoprotection drug effects, Cytoprotection immunology, Down-Regulation drug effects, Down-Regulation immunology, Female, Humans, Leukemia Inhibitory Factor, Male, Middle Aged, Multiple Sclerosis blood, Neuroprotective Agents immunology, Neuroprotective Agents pharmacology, Reference Values, T-Lymphocytes immunology, T-Lymphocytes metabolism, Up-Regulation drug effects, Up-Regulation immunology, Interferon-beta pharmacology, Interleukin-6 metabolism, Leptin pharmacology, Multiple Sclerosis immunology, Simvastatin pharmacology, T-Lymphocytes drug effects
- Abstract
In multiple sclerosis (MS), oligodendrocyte injury is believed to be caused by an aberrant immune response initiated by autoreactive T cells. Increasing evidence indicates that inflammatory responses in the central nervous system are not exclusively detrimental, but may also exert protective effects. Such protective effects are potentially mediated by the local secretion of neurotrophic factors by immune cells. We previously reported that T cells and monocytes in vitro and in inflammatory MS lesions produce leukaemia inhibitory factor (LIF), a member of the neuropoietic family of neurotrophins. In the present study, we report a reduced LIF production by CD4+ T cells of relapsing remitting MS patients as compared to healthy controls. Furthermore, immunomodulatory agents such as leptin, IFN-beta and simvastatin were studied for their potential to alter LIF and secretion of other cytokines by T cells and monocytes of relapsing remitting MS patients and healthy controls. Low doses of simvastatin, but not IFN-beta or leptin enhanced LIF secretion by CD4+ T cells of RR-MS patients. We further demonstrated that LIF did not influence viability, proliferation and cytokine secretion of T cells. Together these data provide new information on the regulation of LIF secretion by immune cells. Further insights into the complex regulation of neurotrophic factors such as LIF may prove useful for treatment of MS.
- Published
- 2006
- Full Text
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47. Leukemia inhibitory factor is produced by myelin-reactive T cells from multiple sclerosis patients and protects against tumor necrosis factor-alpha-induced oligodendrocyte apoptosis.
- Author
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Vanderlocht J, Hellings N, Hendriks JJ, Vandenabeele F, Moreels M, Buntinx M, Hoekstra D, Antel JP, and Stinissen P
- Subjects
- Animals, Apoptosis drug effects, Apoptosis immunology, Brain immunology, Brain metabolism, Brain pathology, Ciliary Neurotrophic Factor immunology, Ciliary Neurotrophic Factor metabolism, Ciliary Neurotrophic Factor pharmacology, Cytokines immunology, Dose-Response Relationship, Drug, Humans, Immunohistochemistry, Interleukin-6 immunology, Interleukin-6 pharmacology, Leukemia Inhibitory Factor, Multiple Sclerosis physiopathology, Oligodendroglia drug effects, Oligodendroglia immunology, Rats, Reverse Transcriptase Polymerase Chain Reaction, T-Lymphocytes metabolism, Tumor Necrosis Factor-alpha immunology, Tumor Necrosis Factor-alpha metabolism, Interleukin-6 metabolism, Multiple Sclerosis immunology, Myelin Sheath immunology, Oligodendroglia pathology, T-Lymphocytes immunology
- Abstract
In multiple sclerosis (MS), damage to oligodendrocytes is believed to be caused by an aberrant immune response initiated by autoreactive T cells. Increasing evidence indicates that these T cells are not exclusively detrimental but might also exert protective effects. We report for the first time that myelin-reactive T-cell clones from eight MS patients (6/19) and five healthy controls (4/11) produce leukemia inhibitory factor (LIF), a member of the neuropoietic family of neurotrophins. In addition, T-cell clones specific for tetanus toxoid, CD4(+) and CD8(+) T cells, and monocytes, but not B cells, secreted LIF. LIF-producing T lymphocytes and macrophages were also identified immunohistochemically in both active and chronic-active MS lesions. We further demonstrated dose-dependent protective effects of LIF on tumor necrosis factor-alpha-induced apoptosis of oligodendrocytes. In conclusion, our data demonstrate that peripheral and CNS-infiltrating T cells from MS patients produce LIF, a protective factor for oligodendrocytes. This study emphasizes that secretion of LIF may contribute to the neuroprotective effects of autoreactive T cells.
- Published
- 2006
- Full Text
- View/download PDF
48. Macrophages and neurodegeneration.
- Author
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Hendriks JJ, Teunissen CE, de Vries HE, and Dijkstra CD
- Subjects
- Animals, Axons chemistry, Axons pathology, Cytokines physiology, Encephalomyelitis, Autoimmune, Experimental etiology, Encephalomyelitis, Autoimmune, Experimental immunology, Encephalomyelitis, Autoimmune, Experimental pathology, Free Radicals metabolism, Humans, Models, Biological, Multiple Sclerosis etiology, Multiple Sclerosis immunology, Multiple Sclerosis pathology, Nerve Degeneration complications, Nerve Degeneration pathology, Peptide Hydrolases physiology, Axons immunology, Macrophages physiology, Nerve Degeneration immunology
- Abstract
Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS). Demyelination is a classical feature of MS lesions, and neurological deficits are often ascribed to the reduced signal conduction by demyelinated axons. However, recent studies emphasize that axonal loss is an important factor in MS pathogenesis and disease progression. Axonal loss is found in association with cellular infiltrates in MS lesions. In this review, we discuss the possible contribution of the innate immune system in this process. In particular, we describe how infiltrated macrophages may contribute to axonal loss in MS and in experimental autoimmune encephalomyelitis (EAE), the animal model for MS. An overview is given of the possible effects of mediators, which are produced by activated macrophages, such as such as pro-inflammatory cytokines, free radicals, glutamate and metalloproteases, on axonal integrity. We conclude that infiltrated macrophages, which are activated to produce pro-inflammatory mediators, may be interesting targets for therapeutic approaches aimed to prevent or reduce axonal loss during exacerbation of inflammation. Interference with the process of infiltration and migration of monocytes across the blood-brain barrier is one of the possibilities to reduce the damage by activated macrophages.
- Published
- 2005
- Full Text
- View/download PDF
49. [Allergic bronchopulmonary aspergillosis in asthma and cystic fibrosis].
- Author
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van Hoorn JH, Hendriks JJ, Dompeling E, and Jöbsis Q
- Subjects
- Adolescent, Aspergillosis, Allergic Bronchopulmonary diagnosis, Aspergillosis, Allergic Bronchopulmonary drug therapy, Diagnosis, Differential, Female, Humans, Male, Prednisone adverse effects, Treatment Outcome, Antifungal Agents therapeutic use, Aspergillosis, Allergic Bronchopulmonary etiology, Asthma complications, Cystic Fibrosis complications, Itraconazole therapeutic use, Prednisone therapeutic use
- Abstract
Three children developed allergic bronchopulmonary aspergillosis (ABPA) as a complication of either asthma or cystic fibrosis (CF). The first patient was a 14-year-old boy with CF who presented with an episode of haemoptysis and a decrease in lung function. He was initially treated with intravenous antibiotics but there was no improvement of his lung function. After starting prednisone-itraconazole his condition improved substantially. The second patient was a 16-year-old girl with CF complicated by ABPA. She was treated for 2 years with prednisone-itraconazole. Although the symptoms worsened when the prednisone dosage was gradually reduced, her growth retardation and increased weight decided us to stop prednisone treatment. Two years later, her CF was once again complicated by ABPA. The third patientwas a 16-year-old boy with asthma who had initially been treated for an asthma exacerbation. In retrospect, the cause of his pulmonary exacerbation was probably an ABPA episode. These cases illustrate how important but also how difficult the early diagnosis of ABPA is, and the dilemmas faced in treatment to prevent the fibrotic end stage.
- Published
- 2005
50. Flavonoids influence monocytic GTPase activity and are protective in experimental allergic encephalitis.
- Author
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Hendriks JJ, Alblas J, van der Pol SM, van Tol EA, Dijkstra CD, and de Vries HE
- Subjects
- Animals, Axons metabolism, Axons pathology, Blood-Brain Barrier metabolism, Blood-Brain Barrier pathology, Encephalomyelitis, Autoimmune, Experimental metabolism, Encephalomyelitis, Autoimmune, Experimental pathology, Endothelium, Vascular metabolism, Endothelium, Vascular pathology, Guinea Pigs, Monocytes pathology, Multiple Sclerosis metabolism, Multiple Sclerosis pathology, Myelin Sheath metabolism, Myelin Sheath pathology, Rats, Rats, Inbred Lew, Reactive Oxygen Species metabolism, Signal Transduction drug effects, Cell Movement drug effects, Encephalomyelitis, Autoimmune, Experimental drug therapy, Luteolin administration & dosage, Monocytes metabolism, rho GTP-Binding Proteins metabolism
- Abstract
In the chronic disabling disease multiple sclerosis (MS), migration of monocytes across the blood-brain barrier is a crucial step in the formation of new lesions in the central nervous system (CNS). Infiltrating monocyte-derived macrophages secrete inflammatory mediators such as oxygen radicals, which contribute to axonal demyelination and damage, resulting in neurological deficits. Flavonoids are compounds occurring naturally in food, which scavenge oxygen radicals and have antiinflammatory properties. To investigate whether they might suppress clinical symptoms in MS, we treated rats sensitized for acute and chronic experimental allergic encephalomyelitis, an experimental model of MS, with flavonoids. We demonstrated that the flavonoid luteolin substantially suppressed clinical symptoms and prevented relapse when administered either before or after disease onset. Luteolin treatment resulted in reduced inflammation and axonal damage in the CNS by preventing monocyte migration across the brain endothelium. Luteolin influenced migration by modulating the activity of Rho GTPases, signal transducers involved in transendothelial migration. Oral administration of luteolin also significantly reduced clinical symptoms.
- Published
- 2004
- Full Text
- View/download PDF
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