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Showing papers by "Samuel K. Ludwin published in 2015"



Journal ArticleDOI
TL;DR: In vitro and in situ experiments confirm that P2Y12 is selectively expressed on human microglia and elevated under neuropathologic conditions that promote Th2 responses, such as parasitic CNS infection and suggest a mechanism to selectively target a functionally unique population of myeloid cells in the CNS.
Abstract: Objective: To investigate and measure the functional significance of altered P2Y12 expression in the context of human microglia activation. Methods: We performed in vitro and in situ experiments to measure how P2Y12 expression can influence disease-relevant functional properties of classically activated (M1) and alternatively activated (M2) human microglia in the inflamed brain. Results: We demonstrated that compared to resting and classically activated (M1) human microglia, P2Y12 expression is increased under alternatively activated (M2) conditions. In response to ADP, the endogenous ligand of P2Y12, M2 microglia have increased ligand-mediated calcium responses, which are blocked by selective P2Y12 antagonism. P2Y12 antagonism was also shown to decrease migratory and inflammatory responses in human microglia upon exposure to nucleotides that are released during CNS injury; no effects were observed in human monocytes or macrophages. In situ experiments confirm that P2Y12 is selectively expressed on human microglia and elevated under neuropathologic conditions that promote Th 2r esponses, such as parasitic CNS infection. Conclusion: These findings provide insight into the roles of M2 microglia in the context of neuroinflammation and suggest a mechanism to selectively target a functionally unique population of

139 citations


Journal ArticleDOI
TL;DR: The authors specifically address the concept of there being distinct phenotypes of early lesions among MS patients, categorized as patterns 1–4, and acknowledge the controversy that exists regarding this concept, providing rationale for generating more direct evidence.
Abstract: Plenas et al. are to be congratulated on the application of cutting edge cell and molecular biologic techniques to address central issues regarding the immune-pathogenesis multiple sclerosis (MS) of lesions.1 This was a demanding study with regard to acquisition of patient material, experimental design, quality and quantity of labor involved, and cost. As emphasized in this report, a challenge in MS is to define the immunologic events ongoing in actual lesions and then determine whether and how these may be reflected or monitored by analysis of more readily available tissue samples such as cerebrospinal fluid (CSF) or blood. The authors specifically address the concept of there being distinct phenotypes of early lesions among MS patients, categorized as patterns 1–4.2 Pattern 2 lesions have been described to feature immunoglobulin (Ig) and complement deposition in addition to inflammatory cell infiltration and myelin destruction and were the most frequent lesion pattern observed in the initial combined biopsy and autopsy sample. Data supporting the distinct features of pattern 2 lesions include therapeutic responses to plasma exchange therapy3 and potentially presence of unique serum autoantibody signatures.4 The authors acknowledge the controversy that exists regarding this concept, providing rationale for generating more direct evidence as in this study.

2 citations


Journal Article
TL;DR: It is demonstrated thatIL-10 induces expression of M2c specific markers in human microglia in vitro, and that pathological conditions associated with increased IL-10 levels are also likely to induce such expression in situ.
Abstract: OBJECTIVE: To investigate the effect of IL-10 on the phenotypic characteristics of M2 polarized human microglia BACKGROUND: Myeloid cells acquire distinct immunologic phenotypes dependent on their state of ‘polarization’: either ‘M1’ (pro-inflammatory) or ‘M2’ (anti-inflammatory) M2 polarized cells, generated using mCSF/IL-4/IL13, produce increased quantities of anti-inflammatory cytokines and display increased phagocytic activity and expression of scavenger receptors Previous in vitro studies show that mCSF/IL-4/IL13 treated human microglia express more limited M2 phenotypic and functional properties than blood-derived macrophages Rodent-based studies have defined distinct subsets (M2a, M2b and M2c) within the overall M2 population that thus far have not been investigated in the human microglia system Human M2c macrophages induced by treatment with IL-10 in combination with mCSF/IL-4/IL13 (M2a protocol) show enhancement of aforementioned M2-like properties DESIGN/METHODS: Human microglia were cultured from both fetal and adult brain tissue; these cells were polarized in vitro with exposure to mCSF/IL-4/IL13 ± IL-10 (50ng/ml) Phenotypic markers (cell surface and intra-cellular) were assessed by way of multi-colour flow cytometery and qPCR In situ expression of markers of M2 polarized myeloid cells was demonstrated by immunohistochemical staining of post-mortem CNS tissue RESULTS: We were able to demonstrate higher expression of specific M2c markers, CD163 and HMOX-1, in human microglia polarized in the presence of IL-10 compared to M2a conditions alone; M2 markers CD206 and CD209 were comparably expressed Analysis of a case of Schistosoma mekongi parasitic infection confirmed that CD163 is selectively expressed in situ on myeloid cells in the CNS and its expression is elevated under a pathologic condition that promotes Th2 responses CONCLUSIONS: Our findings demonstrate that IL-10 induces expression of M2c specific markers in human microglia in vitro, and that pathological conditions associated with increased IL-10 levels are also likely to induce such expression in situ Disclosure: Dr Healy has nothing to disclose Dr Moore has nothing to disclose Dr Touil has nothing to disclose Dr Ludwin has nothing to disclose Dr Bar-Or has received research support from Amplimmune, EMD Serono, and Novartis Dr Antel has received personal compensation for activities with Biogen Idec, Teva Neuroscience, EMD Serono, Genzyme, Sanofi-Aventis, and Novartis

1 citations


Journal ArticleDOI
TL;DR: With the passing this spring of Margaret Norman, MD, FRCP(C), the American Association of Neuropathologists and indeed the worldwide neuropathology community have lost a wonderful scholar and practitioner and a remarkable human being.
Abstract: With the passing this spring of Margaret Norman, MD, FRCP(C), the American Association of Neuropathologists and indeed the worldwide neuropathology community have lost a wonderful scholar and practitioner and a remarkable human being. Pediatric neuropathologist extraordinaire, author, researcher, mentor, ethicist, confidante, friend, and humanitarian, Margaret's example of personal and professional behavior, achievement, and dedication set a standard to which all of us, and those who follow us, should aspire. Perhaps her upbringing predestined her for a lifetime of selfless service. She was born in Japan as the child of United Church missionaries and grew up in Vancouver. She obtained her medical degree from the University of Toronto and worked as a government doctor in Frobisher Bay in the Northwest Territories among the least advantaged of the Canadian population before returning to Toronto where she specialized in pathology and then pediatric pathology at the Hospital for Sick Children. After a further fellowship in pediatric pathology at Columbia in New York, she specialized in pediatric neuropathology at the Massachusetts General Hospital before returning to Toronto as a staff neuropathologist at the Hospital for Sick Children in 1970. She moved to the Children's Hospital of Eastern Ontario at the University of Ottawa as associate professor and chief pathologist where she remained for 6 years before moving …