Caleigh Mandel-Brehm1, Hanna Retallack1, Giselle M Knudsen1, Alex Yamana1, Rula A Hajj-Ali1, Leonard H Calabrese1, Tarik Tihan1, Hannah A Sample1, Kelsey C Zorn1, Mark P Gorman1, Jennifer Madan Cohen1, Antoine G Sreih1, Jacqueline F Marcus1, S Andrew Josephson1, Vanja C Douglas1, Jeffrey M Gelfand1, Michael R Wilson1, Joseph L DeRisi2. 1. From the Departments of Biochemistry and Biophysics (C.M.-B., H.R., H.A.S., K.C.Z., J.L.D.), Pharmaceutical Chemistry (G.M.K., A.Y.), Pathology and Laboratory Medicine (T.T.), and Neurology (S.A.J., V.C.D., J.M.G., M.R.W.), University of California, San Francisco; Department of Rheumatology/Immunology (R.A.H.-A., L.H.C.), Cleveland Clinic, OH; Department of Neurology (M.P.G.), Boston Children's Hospital, MA; Division of Neurology (J.M.C.), Connecticut Children's Medical Center, Hartford; Division of Rheumatology (A.G.S.), University of Pennsylvania, Philadelphia; Kaiser Permanente (J.F.M.), San Francisco Medical Center; UCSF Weill Institute for Neurosciences (S.A.J., V.C.D., J.M.G., M.R.W.); and Chan Zuckerberg Biohub (J.L.D.), San Francisco, CA. 2. From the Departments of Biochemistry and Biophysics (C.M.-B., H.R., H.A.S., K.C.Z., J.L.D.), Pharmaceutical Chemistry (G.M.K., A.Y.), Pathology and Laboratory Medicine (T.T.), and Neurology (S.A.J., V.C.D., J.M.G., M.R.W.), University of California, San Francisco; Department of Rheumatology/Immunology (R.A.H.-A., L.H.C.), Cleveland Clinic, OH; Department of Neurology (M.P.G.), Boston Children's Hospital, MA; Division of Neurology (J.M.C.), Connecticut Children's Medical Center, Hartford; Division of Rheumatology (A.G.S.), University of Pennsylvania, Philadelphia; Kaiser Permanente (J.F.M.), San Francisco Medical Center; UCSF Weill Institute for Neurosciences (S.A.J., V.C.D., J.M.G., M.R.W.); and Chan Zuckerberg Biohub (J.L.D.), San Francisco, CA. joe@derisilab.ucsf.edu.
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.
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.
Authors: Boris Zybailov; Amber L Mosley; Mihaela E Sardiu; Michael K Coleman; Laurence Florens; Michael P Washburn Journal: J Proteome Res Date: 2006-09 Impact factor: 4.466
Authors: Dylan V Miller; Carlo Salvarani; Gene G Hunder; Robert D Brown; Joseph E Parisi; Teresa J Christianson; Caterina Giannini Journal: Am J Surg Pathol Date: 2009-01 Impact factor: 6.394
Authors: Pirow Bekker; Daniel Dairaghi; Lisa Seitz; Manmohan Leleti; Yu Wang; Linda Ertl; Trageen Baumgart; Sarah Shugarts; Lisa Lohr; Ton Dang; Shichang Miao; Yibin Zeng; Pingchen Fan; Penglie Zhang; Daniel Johnson; Jay Powers; Juan Jaen; Israel Charo; Thomas J Schall Journal: PLoS One Date: 2016-10-21 Impact factor: 3.240
Authors: Milani Deb-Chatterji; Christian W Keller; Simon Koch; Heinz Wiendl; Christian Gerloff; Tim Magnus; Jan D Lünemann Journal: Cells Date: 2021-05-08 Impact factor: 6.600