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.

• Authors: Caleigh Mandel-Brehm, Hanna Retallack, Giselle M Knudsen, Alex Yamana, Rula A Hajj-Ali, Leonard H Calabrese, Tarik Tihan, Hannah A Sample, Kelsey C Zorn, Mark P Gorman, Jennifer Madan Cohen, Antoine G Sreih, Jacqueline F Marcus, S Andrew Josephson, Vanja C Douglas, Jeffrey M Gelfand, Michael R Wilson, Joseph L DeRisi
• Journal: Neurology (Neurology) Vol. 93 Issue 5 Pg. e433-e444 (07 30 2019) ISSN: 1526-632X [Electronic] United States
• PMID: 31270218 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2019 American Academy of Neurology.

Chemical References

• CD55 Antigens
• CD59 Antigens
• Complement C4b-Binding Protein
• Complement C5
• Complement C8
• Complement C9
• Neural Cell Adhesion Molecules
• CD59 protein, human
• Properdin
• Complement System Proteins

Topics

• Adolescent
• Adult
• Biopsy
• Brain (pathology)
• CD55 Antigens (cerebrospinal fluid)
• CD59 Antigens (cerebrospinal fluid)
• Case-Control Studies
• Cohort Studies
• Complement C4b-Binding Protein (cerebrospinal fluid)
• Complement C5 (cerebrospinal fluid)
• Complement C8 (cerebrospinal fluid)
• Complement C9 (cerebrospinal fluid)
• Complement Pathway, Alternative
• Complement System Proteins (cerebrospinal fluid)
• Female
• Gene Ontology
• Humans
• Male
• Mass Spectrometry
• Middle Aged
• Neural Cell Adhesion Molecules (cerebrospinal fluid)
• Properdin (cerebrospinal fluid)
• Proteomics
• Vasculitis, Central Nervous System (cerebrospinal fluid, pathology)