| 1. |
- Ayoglu, Burcu, et al.
(författare)
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Anoctamin 2 identified as an autoimmune target in multiple sclerosis
- 2016
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : National Academy of Sciences of the USA. - 0027-8424 .- 1091-6490. ; 113:8, s. 2188-2193
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Tidskriftsartikel (refereegranskat)abstract
- Multiple sclerosis (MS) is the most common chronic inflammatory disease of the central nervous system and also is regarded as an autoimmune condition. However, the antigenic targets of the autoimmune response in MS have not yet been deciphered. In an effort to mine the autoantibody repertoire within MS, we profiled 2,169 plasma samples from MS cases and population-based controls using bead arrays built with 384 human protein fragments selected from an initial screening with 11,520 antigens. Our data revealed prominently increased autoantibody reactivity against the chloride-channel protein anoctamin 2 (ANO2) in MS cases compared with controls. This finding was corroborated in independent assays with alternative protein constructs and by epitope mapping with peptides covering the identified region of ANO2. Additionally, we found a strong interaction between the presence of ANO2 autoantibodies and the HLA complex MS-associated DRB1*15 allele, reinforcing a potential role for ANO2 autoreactivity in MS etiopathogenesis. Furthermore, immunofluorescence analysis in human MS brain tissue showed ANO2 expression as small cellular aggregates near and inside MS lesions. Thus this study represents one of the largest efforts to characterize the autoantibody repertoire within MS. The findings presented here demonstrate that an ANO2 autoimmune subphenotype may exist in MS and lay the groundwork for further studies focusing on the pathogenic role of ANO2 autoantibodies in MS.
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| 2. |
- Berglund, Rasmus, et al.
(författare)
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Microglial autophagy-associated phagocytosis is essential for recovery from neuroinflammation
- 2020
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Ingår i: Science Immunology. - Stockholm : Karolinska Institutet, Dept of Clinical Neuroscience. - 2470-9468.
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Tidskriftsartikel (refereegranskat)abstract
- Multiple sclerosis (MS) is a leading cause of incurable progressive disability in young adults caused by inflammation and neurodegeneration in the central nervous system (CNS). The capacity of microglia to clear tissue debris is essential for maintaining and restoring CNS homeostasis. This capacity diminishes with age, and age strongly associates with MS disease progression, although the underlying mechanisms are still largely elusive. Here, we demonstrate that the recovery from CNS inflammation in a murine model of MS is dependent on the ability of microglia to clear tissue debris. Microglia-specific deletion of the autophagy regulator Atg7, but not the canonical macroautophagy protein Ulk1, led to increased intracellular accumulation of phagocytosed myelin and progressive MS-like disease. This impairment correlated with a microglial phenotype previously associated with neurodegenerative pathologies. Moreover, Atg7-deficient microglia showed notable transcriptional and functional similarities to microglia from aged wild-type mice that were also unable to clear myelin and recover from disease. In contrast, induction of autophagy in aged mice using the disaccharide trehalose found in plants and fungi led to functional myelin clearance and disease remission. Our results demonstrate that a noncanonical form of autophagy in microglia is responsible for myelin degradation and clearance leading to recovery from MS-like disease and that boosting this process has a therapeutic potential for age-related neuroinflammatory conditions.
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| 3. |
- Bronge, Mattias, et al.
(författare)
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Identification of four novel T cell autoantigens and personal autoreactive profiles in multiple sclerosis
- 2022
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Ingår i: Science Advances. - : American Association for the Advancement of Science (AAAS). - 2375-2548. ; 8:17
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Tidskriftsartikel (refereegranskat)abstract
- Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS), in which pathological T cells, likely autoimmune, play a key role. Despite its central importance, the autoantigen repertoire remains largely uncharacterized. Using a novel in vitro antigen delivery method combined with the Human Protein Atlas library, we screened for T cell autoreactivity against 63 CNS-expressed proteins. We identified four previously unreported autoantigens in MS: fatty acid-binding protein 7, prokineticin-2, reticulon-3, and synaptosomal-associated protein 91, which were verified to induce interferon-gamma responses in MS in two cohorts. Autoreactive profiles were heterogeneous, and reactivity to several autoantigens was MS-selective. Autoreactive T cells were predominantly CD4(+) and human leukocyte antigen-DR restricted. Mouse immunization induced antigen-specific responses and CNS leukocyte infiltration. This represents one of the largest systematic efforts to date in the search for MS autoantigens, demonstrates the heterogeneity of autoreactive profiles, and highlights promising targets for future diagnostic tools and immunomodulatory therapies in MS.
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| 4. |
- Dominguez, Cecilia A, et al.
(författare)
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Variability in C-type lectin receptors regulates neuropathic pain-like behavior after peripheral nerve injury
- 2014
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Ingår i: Molecular Pain. - : SAGE Publications. - 1744-8069. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: Neuropathic pain is believed to be influenced in part by inflammatory processes. In this study we examined the effect of variability in the C-type lectin gene cluster (Aplec) on the development of neuropathic pain-like behavior after ligation of the L5 spinal nerve in the inbred DA and the congenic Aplec strains, which carries seven C-type lectin genes originating from the PVG strain.RESULTS: While both strains displayed neuropathic pain behavior early after injury, the Aplec strain remained sensitive throughout the whole study period. Analyses of several mRNA transcripts revealed that the expression of Interleukin-1β, Substance P and Cathepsin S were more up-regulated in the dorsal part of the spinal cord of Aplec rats compared to DA, indicating a stronger inflammatory response. This notion was supported by flow cytometric analysis revealing increased infiltration of activated macrophages into the spinal cord. In addition, macrophages from the Aplec strain stimulated in vitro displayed higher expression of inflammatory cytokines compared to DA cells. Finally, we bred a recombinant congenic strain (R11R6) comprising only four of the seven Aplec genes, which displayed similar clinical and immune phenotypes as the Aplec strain.CONCLUSION: We here for the first time demonstrate that C-type lectins, a family of innate immune receptors with largely unknown functions in the nervous system, are involved in regulation of inflammation and development of neuropathic pain behavior after nerve injury. Further experimental and clinical studies are needed to dissect the underlying mechanisms more in detail as well as any possible relevance for human conditions.
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| 5. |
- Guerreiro Cacais, Andre Ortlieb
(författare)
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Immunological consequences of Epstein-Barr virus replication
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Epstein-Barr virus (EBV) is a ubiquitous human herpesvirus involved in the pathogenesis of a wide spectrum of malignant and non-malignant diseases. In healthy EBV carriers, the virus is believed to infect two major cellular targets - B lymphocytes and epithelial cells. While EBV latency is established predominantly, if not exclusively, in B-lymphocytes, virus replication can take place both in B cells and epithelial cells. Lytic replication ensures virus transmission to new carriers and replenishes the cellular reservoirs of virus persistence. The generally asymptomatic and harmless persistence of EBV relies on a tightly controlled immune response and distinct modes of virus/cell interactions observed at different stages of EBV life cycle. The aim of this thesis was to characterize the mutual influence of the host immune system and EBV at the replicative stage of virus infection. We showed that EBV enters monocytes and inhibits their differentiation into dendritic cells (DCs) without the need of viral gene expression. The sensitivity of the cells to virus-induced apoptosis progressively decreases along the process of DC maturation and is strongly dependent on the cell type in which the virus replicated before infecting DC precursors, since epithelial-cells derived viruses exhibited a significantly stronger pro-apoptotic activity than their B cell-derived counterparts. The capacity of the virus to suppress DC development might help in delaying the establishment of EBV specific immunity before the pool of infected B cells reaches the size sufficient for long-term virus persistence. During virus replication, both B cells and epithelial cells may escape recognition by cytotoxic CD8+ T cells through downregulation of MHC class I molecules. Our work demonstrated that MHC class I heavy-chain and beta2m mRNA and protein synthesis are inhibited during EBV replication. Several other characteristic changes observed in the MHC class I processing and presentation pathway during the lytic cycle were recapitulated by chemical inhibition of protein synthesis. These results were recently confirmed by others and the viral protein responsible for host-cell global protein synthesis shutdown was shown to be encoded by the BGLF5 open reading frame of the EBV genome. Triggering of receptors of the tumor necrosis factor (TNF) superfamily participates both in determining the fate of B-lymphocytes during the process of their differentiation and in immunologic clearance of virus infected targets. Initiation of EBV lytic cycle counteracted sensitization to death induced by TNF-related apoptosis-inducing ligand (TRAIL) that resulted from B-cell receptor (BCR) triggering in Burkitt s lymphoma cells. Differential modulation of death-transmitting and decoy TRAIL receptors was associated with sensitization to TRAIL in response to BCR-triggering or protection from TRAIL by EBV lytic cycle. Interference with TRAIL-mediated checkpoints in B-cell differentiation may account for the involvement of EBV in autoimmune diseases. Decreased sensitivity to TRAIL may also protect EBV infected cells from recognition by CTL and NK-cells. B-cell homeostasis is severely perturbed during malaria infection. We showed that the CIDR1á domain of P. falciparum erythrocyte membrane protein 1 (PfEMP1), a multiadhesive protein expressed during the erythrocytic phase of the parasite life cycle, binds to B cells and induces EBV replication. This might partly explain the increased EBV viral load during malaria infection and the increased risk of B cell immortalization in the ontogenesis of endemic Burkitt s lymphoma. Results presented in this thesis strengthen the notion that EBV replication actively modulates the functioning of the immune system at different levels through complex interactions of viral products with several types of cells and contributes to immune suppression, autoimmunity and tumorogenesis through a number of mechanisms whose details require further characterization. Research lines defined by this work may lead to new approaches towards management of EBV associated diseases.
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| 6. |
- Thomas, Olivia G., et al.
(författare)
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Cross-reactive EBNA1 immunity targets alpha-crystallin B and is associated with multiple sclerosis
- 2023
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Ingår i: Science Advances. - : American Association for the Advancement of Science (AAAS). - 2375-2548. ; 9:20
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Tidskriftsartikel (refereegranskat)abstract
- Multiple sclerosis (MS) is an inflammatory disease of the central nervous system, for which and Epstein-Barr virus (EBV) infection is a likely prerequisite. Due to the homology between Epstein-Barr nuclear antigen 1 (EBNA1) and alpha-crystallin B (CRYAB), we examined antibody reactivity to EBNA1 and CRYAB peptide libraries in 713 persons with MS (pwMS) and 722 matched controls (Con). Antibody response to CRYAB amino acids 7 to 16 was associated with MS (OR = 2.0), and combination of high EBNA1 responses with CRYAB positivity markedly in-creased disease risk (OR = 9.0). Blocking experiments revealed antibody cross-reactivity between the homolo-gous EBNA1 and CRYAB epitopes. Evidence for T cell cross-reactivity was obtained in mice between EBNA1 and CRYAB, and increased CRYAB and EBNA1 CD4+ T cell responses were detected in natalizumab-treated pwMS. This study provides evidence for antibody cross-reactivity between EBNA1 and CRYAB and points to a similar cross-reactivity in T cells, further demonstrating the role of EBV adaptive immune responses in MS development.
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