Inflammation-mediated neurodegeneration occurs in the acute and the chronic phases of multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). Classically ...activated (M1) microglia are key players mediating this process. Here, we identified Galectin-1 (Gal1), an endogenous glycan-binding protein, as a pivotal regulator of M1 microglial activation that targets the activation of p38MAPK-, CREB-, and NF-κB-dependent signaling pathways and hierarchically suppresses downstream proinflammatory mediators, such as iNOS, TNF, and CCL2. Gal1 bound to core 2 O-glycans on CD45, favoring retention of this glycoprotein on the microglial cell surface and augmenting its phosphatase activity and inhibitory function. Gal1 was highly expressed in the acute phase of EAE, and its targeted deletion resulted in pronounced inflammation-induced neurodegeneration. Adoptive transfer of Gal1-secreting astrocytes or administration of recombinant Gal1 suppressed EAE through mechanisms involving microglial deactivation. Thus, Gal1-glycan interactions are essential in tempering microglial activation, brain inflammation, and neurodegeneration, with critical therapeutic implications for MS.
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► Gal1 deactivates classically activated M1 microglia ► Gal1-glycan interactions promote retention of CD45 on the surface of microglial cells ► Lack of Gal1 favors classical microglial activation, inflammation, and neurodegeneration ► Astrocytes control microglial activation and neuroinflammation via Gal1
Interleukin 9 (IL-9) is a pleiotropic cytokine that can regulate autoimmune responses by enhancing regulatory CD4+FoxP3+ T regulatory (Treg) cell survival and T helper 17 (Th17) cell proliferation. ...Here, we analyzed the costimulatory requirements for the induction of Th9 cells, and demonstrated that Notch pathway cooperated with TGF-β signaling to induce IL-9. Conditional ablation of Notch1 and Notch2 receptors inhibited the development of Th9 cells. Notch1 intracellular domain (NICD1) recruited Smad3, downstream of TGF-β cytokine signaling, and together with recombining binding protein (RBP)-Jκ bound the Il9 promoter and induced its transactivation. In experimental autoimmune encephalomyelitis (EAE), Jagged2 ligation regulated clinical disease in an IL-9-dependent fashion. Signaling through Jagged2 expanded Treg cells and suppressed EAE when administered before antigen immunization, but worsened EAE when administered concurrently with immunization by favoring Th17 cell expansion. We propose that Notch and Smad3 cooperate to induce IL-9 and participate in regulating the immune response.
► Notch1 and Notch2 receptors are required for the differentiation of Th9 cells ► Jagged2 but not Delta-like1 convert naive T cells into pre-Th9 cells ► NICD binds to Smad3 in Th9 cells and together transactivate the Il9 promoter ► The timing of IL-9 signal and the cytokine milieu in EAE determine the outcome of clinical disease
Interleukin (IL)-9 producing CD4
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T helper cells (Th9) are the newest addition to the T helper cell subsets. IL-9 binds to a heterodimeric receptor consisting of the IL-9 receptor (IL-9R) and a ...common γ chain also presents in IL-2, IL-4, IL-7, and IL-15 receptor complexes. In addition to Th9 cells, Th17 cells secrete smaller amounts of IL-9. Many functional and regulatory roles associated with Th9 cells are currently not fully understood. IL-9 is a pleiotropic cytokine that affects the activity of multiple cell types in the immune compartment as well as in the central nervous system (CNS). Initially implicated in type 2 inflammation, IL-9 has been recently shown to be a key player in regulating autoimmune responses in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). Here, we review the current understanding of the role of Th9/IL-9 signaling in EAE and MS. We summarize the source and regulation of Th9 cells in vivo, the influence of IL-9 signaling on peripheral and CNS-resident cells in EAE, and the association between IL-9 and MS disease activity.
Gendered differences in career paths of medical graduates persist globally. We aim to explore the impact of domestic tethers on the career paths of physicians by studying gendered differences in ...domestic burdens of physicians as well as differences in perceptions around the impact of domestic work on professional advancement.
A web-based survey including 38 questions was sent to all 3866 physician alumni of the top academic medical school in Lebanon. Data was collected between November 2018 and January 2019, with up to three invite reminders. Overall, 382 were included in the final analysis, 124 women (32%), 258 men (68%).
The study had a response rate of 10.4%. Findings show that a greater percentage of men were married and had children (77.5% vs 62.1%, p = 0.004, 77.9% vs 51.6%, <0.001, respectively). Majority of both women and men held full-time positions (82.1% and 87.1%), having children however reduced the odds significantly OR = 0.2, 95% CI: (0.1-0.6), p = 0.01for women, while only older age reduced it for men (OR = 0.1,95% CI: (0.04-0.2), p<0.001. Among full-time physicians, men and women spent similar time on professional activities (60.2hrs/wk vs 58.3hrs/wk, p = 0.32). Women spent more time on parenting and household work (23.5hrs/wk vs 10.4hrs/wk, <0.001; 8.9hrs/wk vs 6.0hrs/wk, p = 0.001, respectively). Women physicians' spouses contributed to 14.5 hours/week of total time on domestic activities whereas men physicians' spouses spent two folds more time on domestic activities (35.0 hours/week, P<0.001). Of physicians with children, a higher percentage of women than men reported that children prevented their career advancement or their participation in development opportunities (43.8% vs 15.9%, p<0.001; 50.0% vs 19.4%, p<0.001, respectively). A greater percentage of women than men scaled back their career after first child (31.3% vs 3.5%, <0.001). Of married/partnered physicians, fewer women than men reported their career took priority over their partner's when conflicts arose, (52.0% vs 86.0%, p<0.001).
These findings highlight the heavier impact of domestic tethers on the career paths of women physicians than men physicians. Men are more likely than women to hold full-time positions in the early advancement defining phases of their careers. Full-time women shoulder more domestic work than men and experience more professional advancement concessions. Closing persistent gender gaps in medicine requires addressing inequities in domestic burdens through strategies that include mentorship on domestic tethers, support of on-site child-care and advocacy for parental leave policies that encourage shared care-work.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The presence of a “central vein sign” (CVS) has been introduced as a biomarker for the diagnosis of multiple sclerosis (MS) and shown to have the ability to accurately differentiate MS from other ...white matter diseases (MS mimics). Following the development of susceptibility‐based magnetic resonance venography that allowed the in vivo detection of CVS, a standard CVS definition was established by introducing the “40% rule” that assesses the number of MS lesions with CVS as a fraction of the total number of lesions to differentiate MS lesions from other types of lesions. The “50% rule,” the “three‐lesion criteria,” and the “six‐lesion criteria” were later introduced and defined. Each of these rules had high levels of sensitivity, specificity, and accuracy in differentiating MS from other diseases, which has been recognized by the Magnetic Resonance Imaging in MS (MAGNIMS) group and the Consortium of MS Centers task force. The North American Imaging in Multiple Sclerosis Cooperative even provided statements and recommendations aiming to refine, standardize and evaluate the CVS in MS. Herein, we review the existing literature on CVS and evaluate its added value in the diagnosis of MS and usefulness in differentiating it from other vasculopathies. We also review the histopathology of CVS and identify available automated CVS assessment methods as well as define the role of vascular comorbidities in the diagnosis of MS.
Abstract Multiple sclerosis (MS) is a chronic disorder of the central nervous system characterized by autoimmune inflammation, demyelination, and axonal damage. MS etiology remains unknown, but ...disease phenotype is most likely the result of an interaction between complex genetic factors and environmental influences. The better understanding of the mechanisms involved in the immunopathogenesis of MS has led to the development of promising new therapeutic strategies for the disease. This review will discuss the key pathogenic steps implicated in the disease and the role of the main cellular populations that drive the immune responses in MS.
The development of T helper (TH)17 and regulatory T (Treg) cells is reciprocally regulated by cytokines. Transforming growth factor (TGF)-β alone induces FoxP3⁺ Treg cells, but together with IL-6 or ...IL-21 induces TH17 cells. Here we demonstrate that IL-9 is a key molecule that affects differentiation of TH17 cells and Treg function. IL-9 predominantly produced by TH17 cells, synergizes with TGF-β1 to differentiate naïve CD4⁺ T cells into TH17 cells, while IL-9 secretion by TH17 cells is regulated by IL-23. Interestingly, IL-9 enhances the suppressive functions of FoxP3⁺ CD4⁺ Treg cells in vitro, and absence of IL-9 signaling weakens the suppressive activity of nTregs in vivo, leading to an increase in effector cells and worsening of experimental autoimmune encephalomyelitis. The mechanism of IL-9 effects on TH17 and Tregs is through activation of STAT3 and STAT5 signaling. Our findings highlight a role of IL-9 as a regulator of pathogenic versus protective mechanisms of immune responses.
In demyelinating diseases including multiple sclerosis (MS), neural stem cells (NSCs) can replace damaged oligodendrocytes if the local microenvironment supports the required differentiation process. ...Although chitinase-like proteins (CLPs) form part of this microenvironment, their function in this differentiation process is unknown. Here, we demonstrate that murine Chitinase 3-like-3 (Chi3l3/Ym1), human Chi3L1 and Chit1 induce oligodendrogenesis. In mice, Chi3l3 is highly expressed in the subventricular zone, a stem cell niche of the adult brain, and in inflammatory brain lesions during experimental autoimmune encephalomyelitis (EAE). We find that silencing Chi3l3 increases severity of EAE. We present evidence that in NSCs Chi3l3 activates the epidermal growth factor receptor (EGFR), thereby inducing Pyk2-and Erk1/2- dependent expression of a pro-oligodendrogenic transcription factor signature. Our results implicate CLP-EGFR-Pyk2-MEK-ERK as a key intrinsic pathway controlling oligodendrogenesis.
Multiple sclerosis (MS) is often associated with cognitive deficits. Accurate evaluation of the MS patients' cognitive performance is essential for diagnosis and treatment recommendation. The Brief ...International Cognitive Assessment in Multiple Sclerosis (BICAMS), widely used cognitive testing battery, examines processing speed, verbal and visuospatial learning, and memory. Our study aims to examine the psychometric properties of an Arabic version of the BICAMS and to provide normative values in a Lebanese sample.
The BICAMS, comprised of the Symbol Digit Modalities Test (SDMT), Brief Visuospatial Memory Test-Revised (BVMT-R), and a newly developed verbal learning/memory test, the Verbal Memory Arabic Test (VMAT), were administered on healthy subjects and MS patients. The sample consisted of 180 healthy individuals, of whom 63 were retested after 2-3 weeks. Forty-three MS patients matched with 43 healthy subjects based on age, sex, and years of education were assessed. A sample of 10 MS patients was also examined on two occasions. Test-retest reliability and criterion-related validity were examined, and regression-based norms were derived.
The test-retest correlations showed good evidence of reliability with coefficients ranging between 0.64 and 0.73 in the healthy sample, and between 0.43 and 0.92 in the MS sample. The BICAMS was able to discriminate between MS patients and matched healthy participants on the SDMT and BVMT-R. Normative data were comparable to other studies.
This new Arabic version of the BICAMS shows initial good psychometric properties. While good evidence of VMAT's reliability was shown in the healthy participants, less test-retest reliability in this tool was seen in the MS group, and partial criterion-related validity was evident. This renders further examination of the VMAT. We provide regression-based norms for a Lebanese sample and encourage the use of this battery in both research and clinical settings.
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