Microfibrillar-associated protein 4 as a potential marker of acute relapse in inflammatory demyelinating diseases of the central nervous system: Pathological and clinical aspects

Abstract

Background: Microfibrillar-associated protein 4 (MFAP4) is an extracellular matrix protein not previously described in the human central nervous system (CNS). Objectives: We determined MFAP4 CNS expression and measured cerebrospinal fluid (CSF) and serum levels. Methods: Tissue was sampled at autopsy from patients with acute multiple sclerosis (MS) ( n = 3), progressive MS ( n = 3), neuromyelitis optica spectrum disorder (NMOSD) ( n = 2), and controls ( n = 9), including 6 healthy controls (HC). MFAP4 levels were measured in 152 patients: 49 MS, 62 NMOSD, 22 myelin oligodendrocyte glycoprotein-associated disease (MOGAD), and 19 isolated optic neuritis (ION). Results: MFAP4 localized to meninges and vascular/perivascular spaces, intense in the optic nerve. At sites of active inflammation, MFAP4 reactivity was reduced in NMOSD and acute MS and less in progressive MS. CSF MFAP4 levels were reduced during relapse and at the onset of diseases (mean U/mL: MS 14.3, MOGAD 9.7, and ION 14.6 relative to HC 17.9. ( p = 0.013, p = 0.000, and p = 0.019, respectively). Patients with acute ON ( n = 68) had reduced CSF MFAP4 (mean U/mL: 14.5, p = 0.006). CSF MFAP4 levels correlated negatively with relapse severity (rho = −0.41, p = 0.017). Conclusion: MFAP4 immunoreactivity was reduced at sites of active inflammation. CSF levels of MFAP4 were reduced following relapse and may reflect disease activity.

Microfibrillar-associated protein 4 interaction with inflammation and clinical characteristics in neuropsychiatric systemic lupus erythematosus

“…Notably, in autopsy samples from patients with acute multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD), we observed a downregulation of MFAP4 immunoreactivity at sites of active inflammation documented by the presence of inflammatory infiltrates. In line with these pathology data, cerebrospinal fluid (CSF) MFAP4 levels were reduced in active disease stages (27). The data suggested that inflammation changes the composition of ECM, perhaps due to the secretion of proteolytic enzymes e.g., MMPs in inflammatory conditions.…”

“…MFAP4 is measurable in serum, serum levels increase in specific conditions characterized by aberrant tissue remodeling (26) while ECM-bound MFAP4 is predominantly located in arteries and arterioles in most tissues (17). Very recently our group reported data on expression of MFAP4 in the CNS and alteration of the levels of soluble MFAP4 in cerebrospinal fluid (CSF) in patients with acute neuroinflammation and relapse (27). These data suggest that MFAP4 may serve as a potential biomarker of disease activity.…”