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Exploratory proteomic analysis implicates the alternative complement cascade in primary CNS vasculitis.

ABSTRACT: OBJECTIVE:To identify molecular correlates of primary angiitis of the CNS (PACNS) through proteomic analysis of CSF from a biopsy-proven patient cohort. METHODS:Using mass spectrometry, we quantitatively compared the CSF proteome of patients with biopsy-proven PACNS (n = 8) to CSF from individuals with noninflammatory conditions (n = 11). Significantly enriched molecular pathways were identified with a gene ontology workflow, and high confidence hits within enriched pathways (fold change >1.5 and concordant Benjamini-Hochberg-adjusted p < 0.05 on DeSeq and t test) were identified as differentially regulated proteins. RESULTS:Compared to noninflammatory controls, 283 proteins were differentially expressed in the CSF of patients with PACNS, with significant enrichment of the complement cascade pathway (C4-binding protein, CD55, CD59, properdin, complement C5, complement C8, and complement C9) and neural cell adhesion molecules. A subset of clinically relevant findings were validated by Western blot and commercial ELISA. CONCLUSIONS:In this exploratory study, we found evidence of deregulation of the alternative complement cascade in CSF from biopsy-proven PACNS compared to noninflammatory controls. More specifically, several regulators of the C3 and C5 convertases and components of the terminal cascade were significantly altered. These preliminary findings shed light on a previously unappreciated similarity between PACNS and systemic vasculitides, especially anti-neutrophil cytoplasmic antibody-associated vasculitis. The therapeutic implications of this common biology and the diagnostic and therapeutic utility of individual proteomic findings warrant validation in larger cohorts.

SUBMITTER: Mandel-Brehm C

PROVIDER: S-EPMC6693432 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Exploratory proteomic analysis implicates the alternative complement cascade in primary CNS vasculitis.

Mandel-Brehm Caleigh C Retallack Hanna H Knudsen Giselle M GM Yamana Alex A Hajj-Ali Rula A RA Calabrese Leonard H LH Tihan Tarik T Sample Hannah A HA Zorn Kelsey C KC Gorman Mark P MP Madan Cohen Jennifer J Sreih Antoine G AG Marcus Jacqueline F JF Josephson S Andrew SA Douglas Vanja C VC Gelfand Jeffrey M JM Wilson Michael R MR DeRisi Joseph L JL

Neurology 20190703 5

<h4>Objective</h4>To identify molecular correlates of primary angiitis of the CNS (PACNS) through proteomic analysis of CSF from a biopsy-proven patient cohort.<h4>Methods</h4>Using mass spectrometry, we quantitatively compared the CSF proteome of patients with biopsy-proven PACNS (n = 8) to CSF from individuals with noninflammatory conditions (n = 11). Significantly enriched molecular pathways were identified with a gene ontology workflow, and high confidence hits within enriched pathways (fold ...[more]

PMID: 31270218

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Exploratory proteomic analysis implicates the alternative complement cascade in primary CNS vasculitis.

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Exploratory proteomic analysis implicates the alternative complement cascade in primary CNS vasculitis.

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