Abstract
Complement activation has been implicated in the pathogenesis of many vasculitic syndromes such as anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides. Using an array-based multiplex system, we simultaneously quantified serum and CSF levels of activated and regulatory complement system proteins in patients with primary CNS vasculitis (PACNS; n = 20) compared to patients with non-inflammatory conditions (n = 16). Compared to non-inflammatory controls, levels of C3a, C5a, and SC5b-9, indicative for general activation of the complement system, of C4a, specific for the activation of the classical pathway, Ba and Bb, reflective for alternative complement activation as well as concentrations of complement-inhibitory proteins factor H and factor I were unchanged in patients with PACNS. Our study does not support the hypothesis that complement activation is systemically increased in patients with PACNS.
Highlights
Primary angiitis of the central nervous system (PACNS) is a severe inflammatory disease affecting medium or small vessels of the CNS and is an important differential diagnosis in stroke of young adults
A recent exploratory proteomic study identified a significant enrichment of complement pathway proteins in the cerebrospinal fluid (CSF) of patients with PACNS compared to patients with non-inflammatory neurological diseases (NIND) and controls with reversible cerebral vasoconstriction syndrome (RCVS) [1], indicating that sustained complement activation contributes to PACNS pathology
Formation of the terminal complement complex, i.e., membrane attack complex, can be triggered by two separate proteolytic pathways, the classical pathway and the alternative pathway. Signaling events from both pathways converge onto a common effector pathway, known as the terminal cascade, which enables lysis and phagocytosis of tagged target cells. Both CSF and serum levels of C3a, C5a, and the soluble terminal complement complex SC5b-9, indicative for general activation of the complement system, of C4a, specific for the activation of the classical pathway, Ba and Bb, reflective for alternative complement activation as well as concentrations of complementinhibitory proteins factor H and factor I were unchanged in patients with PACNS as compared to patients with NIND (Figure 1)
Summary
Primary angiitis of the central nervous system (PACNS) is a severe inflammatory disease affecting medium or small vessels of the CNS and is an important differential diagnosis in stroke of young adults. A recent exploratory proteomic study identified a significant enrichment of complement pathway proteins in the cerebrospinal fluid (CSF) of patients with PACNS compared to patients with non-inflammatory neurological diseases (NIND) and controls with RCVS [1], indicating that sustained complement activation contributes to PACNS pathology. Hyperactivation of the complement system associated with severe inflammatory responses in numerous organs including the CNS is frequently observed in several autoimmune diseases or in subjects with dysfunctional complement regulatory proteins.
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