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关键词： Glatiramer acetate   Multiple sclerosis   Biomarker   Treatment response   HLA   Genetics  

摘要： Background Glatiramer acetate (GA) is a well-tolerated treatment for multiple sclerosis (MS) and comparable in its efficacy to high-dose interferon beta (IFN). As a lack of validated treatment response biomarkers for MS hampers progress in personalised treatment, the study goal was to search for biomarkers of a successful treatment response utilising the known observation of T-cell expansions after GA treatment. Methods T-cell receptor beta chain (TRB) sequencing was performed in 3021 patients with MS: a discovery cohort of 1627 patients with MS, 204 of whom had previously been treated with GA, and then validated in 1394 patients with MS, 424 of whom had previously been treated with GA. Clinical data from 1987 patients with MS treated with GA or IFN and available HLA information from the NationMS, ACP, EPIC, BIONAT, and CombiRx trial cohorts were used for a subsequent analysis. Findings Common GA-associated TRB expansions were exclusively detected in HLA-A*03:01 or in HLA-DRB1*15:01 backgrounds, within CD8+ effector-or CD4+ central-memory T cells. Both sets of common sequences clonally expanded after GA treatment in a first validation cohort and predicted GA exposure in two further validation cohorts. To evaluate whether restriction of public TRBs to only two HLA alleles is also associated with GA's clinical efficacy, we analysed five cohorts of patients with MS for a potential benefit of the two HLAs concerning the GA response compared to IFN. We consistently found positive interactions with HLA-A*03:01. This included a relative reduction in relapse risk compared to IFN in HLA-A*03:01 carriers of 33% (CombiRx: GA + IFN arm: HR 0.67 [95% CI: 0.47-0.96], p = 0.0269) and 34% (CombiRx: GA arm: HR 0.66 [95% CI: 0.45-0.98], p = 0.0377), and in risk to first relapse of 63% (NationMS: HR 0.37 [95% CI: 0.16-0.88], p = 0.0246), but no positive association with DRB1*15:01. Interpretation HLA-A*03:01 carrying patients with MS specifically benefit from GA treatment and GA signi

关键词： Manganese   D-ribose- L-cysteine   Oxidative damage   ERK pathway   Brain  

摘要： Manganese (Mn), though an essential trace element, can become neurotoxic after excessive exposure. Established mechanisms of Mn neurotoxicity include oxidative stress, apoptotic signalling, and inflammatory responses. D-ribose-L-cysteine (RibCys), a cysteine derivative, is reported to mitigate oxidative damage. In this study, we investigated its effects on B-cell lymphoma 2-associated X protein (Bax)/B-cell lymphoma 2 (Bcl-2) apoptotic signaling, tumor necrosis factor-alpha (TNF-alpha) inflammatory response, and extracellular signal-regulated kinase (ERK) pathway across various brain regions. Adult male Wistar rats were treated with saline (control), Mn (25 mg/kg intraperitoneally for 2 weeks, 8 doses at 48-hour intervals), RibCys (200 mg/kg orally for 2 weeks), or both Mn and RibCys. Biochemical assays for oxidative stress and antioxidant activity, Golgi staining for dendritic morphology, and immunohistochemistry for key protein markers were performed. Results showed that RibCys reduced Mn-induced distortions in brain neurochemistry and dendritic morphology. Mn increased lipid peroxidation, myeloperoxidase, and nitric oxide levels while decreasing glutathione peroxidase and sulfhydryl content, and these effects were attenuated by RibCys. Mn also disrupted dendritic arborization, which improved with RibCys treatment. Furthermore, Mn exposure elevated Bax/Bcl-2, TNF-alpha, and ERK1/2 expression in selected brain regions. RibCys co-administration mitigated these molecular alterations. Our findings suggest that RibCys is a promising therapeutic agent against Mn-induced neurotoxicity with potential for broader application. A notable limitation of this study was the absence of direct measurements of reduced and oxidized glutathione, and cysteine. Future studies should include these key antioxidant markers, assess long-term outcomes of RibCys treatment, and incorporate female animal models to evaluate potential sex-specific responses to Mn toxicity and intervention.

关键词： Diet-induced dyslipidemia   CD1-restricted T cells   Mycolic acid   Mycobacterium tuberculosis   Transgenic mice  

摘要： Dyslipidemia, characterized by altered lipid profiles, influences host immune responses against infections, including Mycobacterium tuberculosis (Mtb). While the effects of dyslipidemia on conventional T cell responses are well documented, its impact on group 1-CD1 restricted T cells, a distinct subset of lipid antigen-specific unconventional T cells, during Mtb infection remains unclear. In this study, we developed a double-transgenic mouse model expressing human group 1 CD1 (hCD1Tg) and mycolic acid (MA)-specific CD1b-restricted T cell receptor (DN1Tg) in a Rag-deficient and low-density lipoprotein receptor-deficient background to investigate how diet-induced dyslipidemia affects the functionality of MA-specific T cells and their role in anti-Mtb immunity. We found that diet-induced dyslipidemia led to increased IFN-gamma production by MA-specific T cells, which promoted mycobacterial clearance in vitro. Mechanistically, this enhanced IFN-gamma production was associated with increased TCR signaling and enhanced glycolysis in DN1 T cells, rather than changes in antigen presentation by dendritic cells. However, dyslipidemia also increased apoptosis in DN1 T cells, which may have impaired their ability to control mycobacterial infection in vivo, resulting in reduced bacterial clearance. These findings highlight a complex interplay between diet-induced dyslipidemia and lipid antigen-specific T-cell responses in Mtb infection, providing insights for potential therapeutic strategies to mitigate dyslipidemia-induced changes in Tcell functions.

关键词： autoantibody dynamics   biologic therapy   bullous pemphigoid   IL-23p19 inhibitors   immunopathogenesis   psoriasis   psoriatic arthritis  

关键词： eosinophilic chronic rhinosinusitis   epithelial cells   IL-13   nasal polyps   periostin  

摘要： Background: Periostin is an extracellular matrix protein that is highly expressed in nasal polyp (NP) tissues in patients with chronic rhinosinusitis (CRS). This study investigated the cellular source of periostin in sinonasal tissues and the mechanism of IL-13-induced periostin production in nasal epithelial cells. Methods: The amount and localization of the periostin protein and mRNA were examined via immunohistochemistry and in situ hybridization analysis in control subjects and subjects with eosinophilic chronic rhinosinusitis (ECRS) and non-ECRS. The expression levels of periostin and type 2 inflammatory cytokines in the tissue were measured by protein and mRNA levels. Normal human nasal epithelial cells were cultured in the presence of IL-13, and the effect of the specific inhibitors, leflunomide, PD98059, or PS1145, on periostin production was evaluated. Results: Periostin was mainly deposited in the subepithelial region of NP tissues in ECRS and was more highly expressed than in non-ECRS (p < 0.01) and control subjects (p < 0.001). The number of periostin mRNA-positive basal epithelial cells was significantly increased in NP tissues in ECRS. The IL-13 concentration was strongly correlated with periostin expression in the tissues (p < 0.0001, r = 0.8802). Periostin production was much greater in differentiated cells under long-term stimulation with IL-13 than in ciliated cells, and this effect was attenuated by leflunomide and PD98059, but not by PS1145. Conclusion: NP tissues from ECRS patients exhibit increased type 2 inflammatory cytokines and periostin. Nasal epithelial cells, particularly basal cells, are an important source of periostin. Exposure to IL-13 is important for periostin production from nasal epithelial cells.

关键词： Leishmania mexicana   Skin lesion   UV-B radiation   Immunosuppression   Mast cells   CD4   CD8   IFN-gamma  

摘要： In mice, susceptibility or resistance to Leishmania spp. infection is associated with distinct CD4+ T-helper cell responses. A predominant Th2 response, characterized by chronic disease, contrasts with a Th1 response, which promotes healing and parasite clearance. Ultraviolet B (UVB) radiation induces local and systemic immunosuppression by impairing antigen-presenting cell function, stimulating IL-10 production, and skewing the Th1/ Th2 balance towards a Th2 phenotype dominated by IL-4 and IL-10. This study investigated disease progression and early local immune responses in UVB-immunosuppressed C57BL/6 mice infected with Leishmania mexicana. Mice were exposed to immunosuppressive doses of UVB radiation and subsequently infected with L. mexicana promastigotes. Lesion size, parasite load, histopathology, and the presence of IL-10+, IFN-gamma+, mast cells, macrophages (MOMA2+), CD4+, and CD8+ T cells at the lesion site were evaluated. UVB-exposed, L. mexicana-infected mice exhibited altered tissue architecture, increased numbers of both intact and degranulated mast cells, and elevated IL-10+ and MOMA2+ cell infiltration in skin lesions, compared to wild-type, L. mexicana-infected controls. Conversely, CD4+, CD8+, and IFN-gamma+ cells were decreased in the UVB-exposed group. These findings suggest that exposure to UVB radiation acts as a risk factor for cutaneous leishmaniasis (LCL), as these findings indicate it can exacerbate lesions and increase parasite load through the induction of an unfavorable immune microenvironment.

摘要： Persistent germinal center (GC) responses show increased benefit in optimal responses to influenza infection. Follicular helper T (TFH) cells provide the essential signals and help for maintenance of GCs and require IL-1β signaling for establishment and maintenance. We observe a preferential upregulation of IL-1β within GC B cells and coexpression of NLRP3 and caspase-1 with IL-1β confirms that GC B cells process IL-1β using a canonical NLRP3/caspase-1 mechanism. Using B cell specific ablation of IL-1β production and IL-1β signaling we further confirm that, GC B cells are the primary source of vital IL-1β within the GC and that IL-1β processing by GC B cells post influenza infection is driven by NLRP3 inflammasomes. We observe significant reduction of GC B cells and TFH cells in the absence of B cell derived IL-1β and our analysis of human B cells suggests similar mechanisms in human GC B cells. Our data present GC B cells in two novel roles, the first in producing IL-1β, which is associated with innate functions, within the GC and the second is providing helper cytokine to the TFH cell. Our findings add to the known complexity of the GC providing a target to enhance GC function and persistence.

关键词： HLA-B27   season   uveitis