TAGAP instructs Th17 differentiation by bridging Dectin activation to EPHB2 signaling in innate antifungal response.
- 作者列表："Chen J","He R","Sun W","Gao R","Peng Q","Zhu L","Du Y","Ma X","Guo X","Zhang H","Tan C","Wang J","Zhang W","Weng X","Man J","Bauer H","Wang QK","Martin BN","Zhang CJ","Li X","Wang C
:The TAGAP gene locus has been linked to several infectious diseases or autoimmune diseases, including candidemia and multiple sclerosis. While previous studies have described a role of TAGAP in T cells, much less is known about its function in other cell types. Here we report that TAGAP is required for Dectin-induced anti-fungal signaling and proinflammatory cytokine production in myeloid cells. Following stimulation with Dectin ligands, TAGAP is phosphorylated by EPHB2 at tyrosine 310, which bridges proximal Dectin-induced EPHB2 activity to downstream CARD9-mediated signaling pathways. During Candida albicans infection, mice lacking TAGAP mount defective immune responses, impaired Th17 cell differentiation, and higher fungal burden. Similarly, in experimental autoimmune encephalomyelitis model of multiple sclerosis, TAGAP deficient mice develop significantly attenuated disease. In summary, we report that TAGAP plays an important role in linking Dectin-induced signaling to the promotion of effective T helper cell immune responses, during both anti-fungal host defense and autoimmunity.
METHODS:PURPOSE:The aim of the study was to assess dual-task cost to spatio-temporal gait parameters in people with multiple sclerosis and a matched control group. METHOD:The multiple sclerosis group was composed of 17 participants with a diagnosis of multiple sclerosis and an Expanded Disability Status Scale score of less than 6. A total of 17 healthy participants were allocated to the control group by stratification. Controls were matched on the basis of age, sex, sociocultural habits, and body structure. Dual-task cost was determined by within-group repeated-measures analysis of variance. Participants were instructed to ambulate under normal conditions and perform a discrimination and decision-making task concurrently. Then, between-group analysis of variance was used to assess differences in mean dual-task cost between groups and determine dual-task cost differential. Testing was performed using three-dimensional photogrammetry and an electronic walkway. RESULTS:Based on dual-task cost differential, gait cycle time increase (-5.8%) and gait speed decrease (6.3%) because of multiple sclerosis-induced impairment. CONCLUSIONS:During single- and dual-task conditions, gait speed was lower in multiple sclerosis participants, because of a shorter step length and increased swing time. Increased gait time might be the result of compensatory mechanisms adopted to maintain stability while walking specially during the double-support phases.
METHODS:OBJECTIVE:The aims of the study were to compare mobility in multiple sclerosis, Parkinson disease, and stroke, and to quantify the relationship between mobility and participation restrictions. DESIGN:This is a multicenter cross-sectional study. Included were compliant subjects with Parkinson disease, multiple sclerosis, and stroke seen for rehabilitation, with no comorbidities interfering with mobility. Functional scales were applied to each subject to investigate gait speed (10-meter walking test), balance while maintaining body position (Berg Balance Scale), dynamic balance and mobility (Timed Up and Go and Dynamic Gait Index), and participation (Community Integration Questionnaire). RESULTS:Two hundred ninety-nine patients (111 multiple sclerosis, 94 Parkinson disease, and 94 stroke) were enrolled. Stroke had the slowest gait speed (mean gait speed = 0.9 m/sec) compared with Parkinson disease (1.1 m/sec), and multiple sclerosis (1.2 m/sec) (P < 0.001). Multiple sclerosis was more limited than Parkinson disease and stroke in dynamic balance both in the Timed Up and Go Test (multiple sclerosis = 16.7 secs, Parkinson disease = 11.4 secs, stroke = 14.0 secs; P < 0.001) and Dynamic Gait Index (multiple sclerosis = 11.6 points, Parkinson disease = 12.9 points, stroke = 13.6 points; P = 0.03); ability to maintain balance and body position (Berg Balance Scale) was more affected in stroke and Parkinson disease than multiple sclerosis (multiple sclerosis = 42.6 points, Parkinson disease = 39.4 points, stroke = 39.7 points; P = 0.03). Balance disorders were associated with participation restrictions but not gait speed. CONCLUSIONS:Neurological conditions have differing impacts on gait and balance, leading to different levels of participation restriction.
METHODS:OBJECTIVES:Cerebrospinal fluid (CSF) and blood neurofilaments (NFLs) are markers of axonal damage and are being investigated, mostly in relapsing-remitting (RR) MS, as a marker of disease activity and of response to treatment, while there are less data in progressive MS patients. Primary aim was to measure NFL in plasma samples of untreated patients with primary (PP) and secondary (SP) progressive MS and to correlate them with disability, disease severity, and prior/subsequent disability progression. MATERIALS AND METHODS:Neurofilament concentrations were measured using SIMOA (Single Molecule Array, Simoa HD-1 Analyzer; Quanterix). RESULTS:Neurofilament concentrations were measured on plasma samples of 70 progressive (27 PP and 43 SP), 21 RRMS patients, and 10 HCs. Longitudinal plasma NFL (pNFL) concentrations (median interval between sampling: 25 months) were available for nine PP/SP patients. PNFL concentrations were significantly higher in PP/SP compared to RRMS patients. They correlated with EDSS and MS Severity Score values. There was no difference in pNFL levels between PP/SP patients with EDSS progression in the preceding year (14% of patients) or during a median follow-up of 27 months (41%). In the longitudinal sub-study, pNFL levels increased in all patients between sampling by a mean value of 23% while EDSS mostly remained stable (77% of cases). CONCLUSION:In PP/SP progressive MS patients, pNFL levels correlate with disability and increase over time, but are not associated with prior/subsequent disability progression, as measured by EDSS, which may not be a sufficiently sensitive tool in this context.