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- Kaufmann, M., et al.
(författare)
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Identification of early neurodegenerative pathways in progressive multiple sclerosis
- 2022
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Ingår i: Nature Neuroscience. - : Springer Nature. - 1097-6256 .- 1546-1726. ; 25:7, s. 944-955
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Tidskriftsartikel (refereegranskat)abstract
- Progressive multiple sclerosis (MS) is characterized by unrelenting neurodegeneration, which causes cumulative disability and is refractory to current treatments. Drug development to prevent disease progression is an urgent clinical need yet is constrained by an incomplete understanding of its complex pathogenesis. Using spatial transcriptomics and proteomics on fresh-frozen human MS brain tissue, we identified multicellular mechanisms of progressive MS pathogenesis and traced their origin in relation to spatially distributed stages of neurodegeneration. By resolving ligand–receptor interactions in local microenvironments, we discovered defunct trophic and anti-inflammatory intercellular communications within areas of early neuronal decline. Proteins associated with neuronal damage in patient samples showed mechanistic concordance with published in vivo knockdown and central nervous system (CNS) disease models, supporting their causal role and value as potential therapeutic targets in progressive MS. Our findings provide a new framework for drug development strategies, rooted in an understanding of the complex cellular and signaling dynamics in human diseased tissue that facilitate this debilitating disease.
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- Huang, J., et al.
(författare)
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Inflammation-related plasma and CSF biomarkers for multiple sclerosis
- 2020
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 117:23, s. 12952-12960
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Tidskriftsartikel (refereegranskat)abstract
- Effective biomarkers for multiple sclerosis diagnosis, assessment of prognosis, and treatment responses, in particular those measur-able in blood, are largely lacking. We have investigated a broad set of protein biomarkers in cerebrospinal fluid (CSF) and plasma using a highly sensitive proteomic immunoassay. Cases from two independent cohorts were compared with healthy controls and patients with other neurological diseases. We identified and replicated 10 cerebrospinal fluid proteins including IL-12B, CD5, MIP-1a, and CXCL9 which had a combined diagnostic efficacy sim-ilar to immunoglobulin G (IgG) index and neurofilament light chain (area under the curve [AUC] = 0.95). Two plasma proteins, OSM and HGF, were also associated with multiple sclerosis in compari-son to healthy controls. Sensitivity and specificity of combined CSF and plasma markers for multiple sclerosis were 85.7% and 73.5%, respectively. In the discovery cohort, eotaxin-1 (CCL11) was asso-ciated with disease duration particularly in patients who had sec-ondary progressive disease (P-CSF < 4 x 10(-5) , P plasma < 4 x 10-5 ), and plasma CCL20 was associated with disease severity (P = 4 x 10(-5) ), although both require further validation. Treatment with natalizumab and fingolimod showed different compartmental changes in protein levels of CSF and peripheral blood, respectively, including many disease-associated markers (e.g., IL12B, CD5) showing potential application for both diagnosing disease and monitoring treatment efficacy. We report a number of multiple sclerosis biomarkers in CSF and plasma for early disease detection and potential indicators for disease activity. Of particular impor-tance is the set of markers discovered in blood, where validated biomarkers are lacking.
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- Iversen, AKN, et al.
(författare)
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Limited protective effect of the CCR5 Delta 32/CCR5 Delta 32 genotype on human immunodeficiency virus infection incidence in a cohort of patients with hemophilia and selection for genotypic X4 virus
- 2003
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Ingår i: Journal of Infectious Diseases. - 1537-6613. ; 187:2, s. 215-225
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Tidskriftsartikel (refereegranskat)abstract
- The relationship among CCR5 genotype, cytomegalovirus infection, and disease progression and death was studied among 159 human immunodeficiency virus (HIV)-infected patients with hemophilia. One patient (0.6%) had the CCR5Delta32/CCR5Delta32 genotype (which occurs in similar to2% of the Scandinavian population) and a rapid disease course. His HIV V3 region contained genotypic features attributable to X4 virus and resembled functionally verified X4 virus and virus from patients treated with a CD4 cell-stimulating drug, tucaresol. Age-related differences in disease progression rate and survival time were seen for CCR5/CCR5 patients. Surprisingly, no protective effect of the CCR5/CCR5Delta32 genotype on disease progression or survival was seen for children but was evident for adults. Age group-related immunologic differences might explain this variation, and transmission route and/or viral phenotype variation within donor virus may be related to the limited protection of the CCR5Delta32/ CCR5Delta32 genotype. Sequence comparisons indicate that X4 virus can be selected in vivo due to either absence of CCR5 receptors or relative increase of CXCR4 receptors.
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- Regev, A, et al.
(författare)
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The Human Cell Atlas
- 2017
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Ingår i: eLife. - : ELIFE SCIENCES PUBLICATIONS LTD. - 2050-084X. ; 6
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Tidskriftsartikel (refereegranskat)
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- Svendsen, P, et al.
(författare)
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Tracking of proinflammatory collagen-specific T cells in early and late collagen-induced arthritis in humanized mice
- 2004
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Ingår i: Journal of Immunology. - 1550-6606. ; 173:11, s. 7037-7045
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Tidskriftsartikel (refereegranskat)abstract
- Rheumatoid arthritis is a chronic inflammatory disease associated with certain HLA-DR4 subtypes. The target autoantigen(s) is unknown, but type II collagen (CII) is a candidate, with a single immunodominant DR4-restricted 261-273 T cell epitope (CII(261273)). In the present study, we have prepared HLA-DR4:CII(261-273) tetramers and analyzed peripheral blood, lymph node, and synovial fluid cells from DR4-transgenic mice with early and late collagen-induced arthritis to draw a fuller picture of the role of CII-reactive Th cells in disease development. Their frequencies increased similar to20-fold in blood 1-2 wk postimmunization, and even more in acutely arthritic joints. Our data strongly suggest that CII-specific Th cells are necessary, but not sufficient for collagen-induced arthritis. The CII-specific Th cells displayed an activated proinflammatory Th1 phenotype, and their expansion correlated with onset and severity of arthritis and also with anti-CII Ab levels. Surprisingly, shortly after the first clinical signs of arthritis, activated HLA-DR4:CII tetramer(+) cells became undetectable in the synovial fluid and rare in the blood, but persisted in lymph nodes. Consequently, future human studies should focus on patients with early arthritis, and on their synovial cells, to re-evaluate the occurrence and pathogenic importance of CII-specific or other Th cells in rheumatoid arthritis.
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