Microglia, immune cells of the central nervous system (CNS), are important for tissue development and maintenance and are implicated in CNS disease, but we lack understanding of human fetal... Show moreMicroglia, immune cells of the central nervous system (CNS), are important for tissue development and maintenance and are implicated in CNS disease, but we lack understanding of human fetal microglia development. Single-cell gene expression and bulk chromatin profiles of microglia at 9 to 18 gestational weeks (GWs) of human fetal development were generated. Microglia were heterogeneous at all studied GWs. Microglia start to mature during this developmental period and increasingly resemble adult microglia with CNS-surveilling properties. Chromatin accessibility increases during development with associated transcriptional networks reflective of adult microglia. Thus, during early fetal development, microglia progress toward a more mature, immune-sensing competent phenotype, and this might render the developing human CNS vulnerable to environmental perturbations during early pregnancy. Show less
Background: Several studies suggested an important role of the gut microbiota in the pathophysiology of neurological disorders, implying that alteration of the gut microbiota might serve as a... Show moreBackground: Several studies suggested an important role of the gut microbiota in the pathophysiology of neurological disorders, implying that alteration of the gut microbiota might serve as a treatment strategy. Fecal microbiota transplantation (FMT) is currently the most effective gut microbiota intervention and an accepted treatment for recurrent Clostridioides difficile infections. To evaluate indications of FMT for patients with neurological disorders, we summarized the available literature on FMT. In addition, we provide suggestions for future directions.Methods: In July 2019, five main databases were searched for studies and case descriptions on FMT in neurological disorders in humans or animal models. In addition, the website was consulted for registered planned and ongoing trials.Results: Of 541 identified studies, 34 were included in the analysis. Clinical trials with FMT have been performed in patients with autism spectrum disorder and showed beneficial effects on neurological symptoms. For multiple sclerosis and Parkinson's disease, several animal studies suggested a positive effect of FMT, supported by some human case reports. For epilepsy, Tourette syndrome, and diabetic neuropathy some studies suggested a beneficial effect of FMT, but evidence was restricted to case reports and limited numbers of animal studies. For stroke, Alzheimer's disease and Guillain-Barre syndrome only studies with animal models were identified. These studies suggested a potential beneficial effect of healthy donor FMT. In contrast, one study with an animal model for stroke showed increased mortality after FMT. For Guillain-Barre only one study was identified. Whether positive findings from animal studies can be confirmed in the treatment of human diseases awaits to be seen. Several trials with FMT as treatment for the above mentioned neurological disorders are planned or ongoing, as well as for amyotrophic lateral sclerosis.Conclusions: Preliminary literature suggests that FMT may be a promising treatment option for several neurological disorders. However, available evidence is still scanty and some contrasting results were observed. A limited number of studies in humans have been performed or are ongoing, while for some disorders only animal experiments have been conducted. Large double-blinded randomized controlled trials are needed to further elucidate the effect of FMT in neurological disorders. Show less
Kramer, G.; Wegdam, W.; Donker-Koopman, W.; Ottenhoff, R.; Gaspar, P.; Verhoek, M.; ... ; Eijk, M.C. van 2016
Gaucher disease is caused by inherited deficiency of lysosomal glucocerebrosidase. Proteome analysis of laser-dissected splenic Gaucher cells revealed increased amounts of glycoprotein... Show moreGaucher disease is caused by inherited deficiency of lysosomal glucocerebrosidase. Proteome analysis of laser-dissected splenic Gaucher cells revealed increased amounts of glycoprotein nonmetastatic melanoma protein B (gpNMB). Plasma gpNMB was also elevated, correlating with chitotriosidase and CCL18, which are established markers for human Gaucher cells. In Gaucher mice, gpNMB is also produced by Gaucher cells. Correction of glucocerebrosidase deficiency in mice by gene transfer or pharmacological substrate reduction reverses gpNMB abnormalities. In conclusion, gpNMB acts as a marker for glucosylceramide-laden macrophages in man and mouse and gpNMB should be considered as candidate biomarker for Gaucher disease in treatment monitoring. Show less
EBV is the major infectious environmental risk factor for multiple sclerosis (MS), but the underlying mechanisms remain obscure. Patient studies do not allow manipulation in vivo. We used the... Show moreEBV is the major infectious environmental risk factor for multiple sclerosis (MS), but the underlying mechanisms remain obscure. Patient studies do not allow manipulation in vivo. We used the experimental autoimmune encephalomyelitis (EAE) models in the common marmoset and rhesus monkey to model the association of EBV and MS. We report that B cells infected with EBV-related lymphocryptovirus (LCV) are requisite APCs for MHC-E-restricted autoaggressive effector memory CTLs specific for the immunodominant epitope 40-48 of myelin oligodendrocyte glycoprotein (MOG). These T cells drive the EAE pathogenesis to irreversible neurologic deficit. The aim of this study was to determine why LCV infection is important for this pathogenic role of B cells. Transcriptome comparison of LCV-infected B cells and CD20(+) spleen cells from rhesus monkeys shows increased expression of genes encoding elements of the Ag cross-presentation machinery (i.e., of proteasome maturation protein and immunoproteasome subunits) and enhanced expression of MHC-E and of costimulatory molecules (CD70 and CD80, but not CD86). It was also shown that altered expression of endolysosomal proteases (cathepsins) mitigates the fast endolysosomal degradation of the MOG40-48 core epitope. Finally, LCV infection also induced expression of LC3-II(+) cytosolic structures resembling autophagosomes, which seem to form an intracellular compartment where the MOG40-48 epitope is protected against proteolytic degradation by the endolysosomal serine protease cathepsin G. In conclusion, LCV infection induces a variety of changes in B cells that underlies the conversion of destructive processing of the immunodominant MOG40-48 epitope into productive processing and cross-presentation to strongly autoaggressive CTLs. Show less
Background: Various cytokines and inflammatory mediators are known to be involved in the pathogenesis of rheumatoid arthritis (RA). We hypothesized that polymorphisms in selected inflammatory... Show moreBackground: Various cytokines and inflammatory mediators are known to be involved in the pathogenesis of rheumatoid arthritis (RA). We hypothesized that polymorphisms in selected inflammatory response and tissue repair genes contribute to the susceptibility to and severity of RA. Methods: Polymorphisms in TNFA, IL1B, IL4, IL6, IL8, IL10, PAI1, NOS2a, C1INH, PARP, TLR2 and TLR4 were genotyped in 376 Caucasian RA patients and 463 healthy Caucasian controls using single base extension. Genotype distributions in patients were compared with those in controls. In addition, the association of polymorphisms with the need for anti-TNF-alpha treatment as a marker of RA severity was assessed. Results: The IL8 781 CC genotype was associated with early onset of disease. The TNFA -238 G/A polymorphism was differentially distributed between RA patients and controls, but only when not corrected for age and gender. None of the polymorphisms was associated with disease severity. Conclusions: We here report an association between IL8 781 C/T polymorphism and age of onset of RA. Our findings indicate that there might be a role for variations in genes involved in the immune response and in tissue repair in RA pathogenesis. Nevertheless, additional larger genomic and functional studies are required to further define their role in RA. Show less
In its rare occurrence, Langerhans cell histiocytosis (LCH) is a dangerous but intriguing deviation of mononuclear phagocytes, especially dendritic cells (DCs). Clinically, the disease ranges from... Show moreIn its rare occurrence, Langerhans cell histiocytosis (LCH) is a dangerous but intriguing deviation of mononuclear phagocytes, especially dendritic cells (DCs). Clinically, the disease ranges from self-resolving or well manageable to severe and even fatal. LCH lesions in skin, bone, and other sites contain high numbers of cells with phenotypic features resembling LCs admixed with macrophages, T cells, eosinophils, and multinucleated giant cells. Here we review current progress in the LCH field based on two central questions: (i) are LCH cells intrinsically aberrant, and (ii) how does the lesion drive pathogenesis? We argue that LCH cells may originate from different sources, including epidermal LCs, tissue Langerin(+) DCs, or mononuclear phagocyte precursors. Current and prospective in vitro and in vivo models are discussed. Finally, we discuss recent insights into plasticity of T-helper cell subsets in light of the lesion microenvironment. LCH continues to provide urgent clinical questions thereby inspiring innovative DC lineage research. Show less
In its rare occurrence, Langerhans cell histiocytosis (LCH) is a dangerous but intriguing deviation of mononuclear phagocytes, especially dendritic cells (DCs). Clinically, the disease ranges from... Show moreIn its rare occurrence, Langerhans cell histiocytosis (LCH) is a dangerous but intriguing deviation of mononuclear phagocytes, especially dendritic cells (DCs). Clinically, the disease ranges from self-resolving or well manageable to severe and even fatal. LCH lesions in skin, bone, and other sites contain high numbers of cells with phenotypic features resembling LCs admixed with macrophages, T cells, eosinophils, and multinucleated giant cells. Here we review current progress in the LCH field based on two central questions: (i) are LCH cells intrinsically aberrant, and (ii) how does the lesion drive pathogenesis? We argue that LCH cells may originate from different sources, including epidermal LCs, tissue Langerin+ DCs, or mononuclear phagocyte precursors. Current and prospective in vitro and in vivo models are discussed. Finally, we discuss recent insights into plasticity of T-helper cell subsets in light of the lesion microenvironment. LCH continues to provide urgent clinical questions thereby inspiring innovative DC lineage research. Show less
Breemen, M.J. van; Fost, M. de; Voerman, J.S.A.; Laman, J.D.; Boot, R.G.; Maas, M.; ... ; Rezaee, F. 2007