Omics-Based Approach Reveals Complement-Mediated Inflammation in Chronic Lymphocytic Inflammation With Pontine Perivascular Enhancement Responsive to Steroids (CLIPPERS).

Autor:	Blaabjerg M; Department of Neurology, Odense University Hospital, Odense, Denmark.; Department of Clinical Research, BRIDGE, University of Southern Denmark, Odense, Denmark., Hemdrup AL; Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark., Drici L; Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark., Ruprecht K; Clinical and Experimental Multiple Sclerosis Research Center, Charité - Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.; Department of Neurology, Charité - Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany., Garred P; Laboratory of Molecular Medicine, Department of Clinical Immunology, Sect. 7631, Rigshospitalet, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Höftberger R; Institute of Neurology, Medical University of Vienna, Vienna, Austria., Kristensen BW; Department of Clinical Research, BRIDGE, University of Southern Denmark, Odense, Denmark.; Department of Pathology, Odense University Hospital, Odense, Denmark., Kondziella D; Department of Neurology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark., Sejbaek T; Department of Neurology, Odense University Hospital, Odense, Denmark., Hansen SW; Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark., Nielsen HH; Department of Neurology, Odense University Hospital, Odense, Denmark.; Department of Clinical Research, BRIDGE, University of Southern Denmark, Odense, Denmark., Jensen P; Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark., Meyer M; Department of Neurology, Zealand University Hospital, Roskilde, Denmark.; Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark., Paul F; Clinical and Experimental Multiple Sclerosis Research Center, Charité - Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.; Department of Neurology, Charité - Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.; NeuroCure Clinical Research Center, Charité - Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.; Experimental and Clinical Research Center, Charite - Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany., Lassmann H; Center for Brain Research, Medical University of Vienna, Vienna, Austria., Larsen MR; Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark., Illes Z; Department of Neurology, Odense University Hospital, Odense, Denmark.; Department of Clinical Research, BRIDGE, University of Southern Denmark, Odense, Denmark.; Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark.
Jazyk:	angličtina
Zdroj:	Frontiers in immunology [Front Immunol] 2018 Apr 23; Vol. 9, pp. 741. Date of Electronic Publication: 2018 Apr 23 (Print Publication: 2018).
DOI:	10.3389/fimmu.2018.00741
Abstrakt:	Objective: Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is a rare syndrome with relapsing brainstem/cerebellar symptoms. To examine the pathogenic processes and investigate potential biomarkers, we analyzed combined materials of brain and cerebrospinal fluid (CSF) by comprehensive methodologies. Materials and Methods: To identify major pathways of perivascular inflammation in CLIPPERS, we first compared the CSF proteome ( n  = 5) to a neurodegenerative condition, Alzheimer's disease (AD, n  = 5). Activation of complement was confirmed by immunohistochemistry (IHC) on CLIPPERS brain samples ( n  = 3) and by ELISA in the CSF. For potential biomarkers, we used biomarker arrays, and compared inflammatory and vessel-associated proteins in the CSF of CLIPPERS ( n  = 5) with another inflammatory relapsing CNS disease, multiple sclerosis (RMS, n  = 9) and healthy subjects (HS, n  = 7). Results: Two hundred and seven proteins in the CSF discriminated CLIPPERS from AD. The complement cascade, immunoglobulins, and matrix proteins were among the most frequently represented pathways. Pathway analysis of upstream regulators suggested the importance of vascular cell adhesion protein 1 (VCAM1), IFN-γ, interleukin (IL)-1, and IL-10. Differential regulation of more than 10 complement proteins of the 3 complement pathways in the CSF pointed to the role of complement activation. IHC on brain samples confirmed the perivascular complement activation, i.e., deposition of C3bc, C3d, and the terminal C5b-9 complement complex that partially overlapped with accumulation of IgG in the vessel wall. Besides endothelial cell damage, reactivity to smooth muscle actin was lost in the walls of inflamed vessels, but the glia limitans was preserved. The semi-quantitative array indicated that increased level of IL-8/CXCL8 ( p  < 0.05), eotaxin/CCL11 ( p  < 0.01), and granulocyte colony-stimulating factor ( p  < 0.05) in CSF could distinguish CLIPPERS from HS. The quantitative array confirmed elevated concentration of IL-8/CXCL8 and eotaxin/CCL11 compared to HS ( p  < 0.05, respectively) besides increased levels of ICAM-1 ( p  < 0.05) and VCAM-1 ( p  < 0.001). The increased concentration of VCAM-1 were able to differentiate CLIPPERS from RMS ( p  < 0.01), and a trend of elevated levels of ICAM-1 and IL-8/CXCL8 compared to RMS was also observed ( p  = 0.06, respectively). Conclusion: Complement activation, IgG deposition, and alterations of the extracellular matrix may contribute to inflammation in CLIPPERS. VCAM1, ICAM1, and IL-8 in the CSF may differentiate CLIPPERS from RMS.
Databáze:	MEDLINE
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