Elevated Concentrations of Soluble Fas and FasL in Multiple Sclerosis Patients with Antinuclear Antibodies.

Josip Sremec,Nataša Kovačić,Nada Tomić Sremec,Sanja Tomasović,Koraljka Bačić Baronica,Danka Grčević,Jelena Košćak Lukač,Alan Šućur

doi:10.3390/jcm9123845

Abstract

Antinuclear antibodies (ANA) are currently considered as an epiphenomenon of apoptotic processes, possibly in control of autoreactivity in patients with multiple sclerosis (MS). Apoptosis of reactive lymphocytes by the Fas/FasL system is described as an effective control mechanism for autoreactivity in MS. We aimed to provide a context to the potential link between ANA and peripheral lymphocyte apoptosis in MS. The presence of ANA was detected in sera by immunofluorescence assay, and concentrations of sFas and sFasL were determined in the sera of 44 and cerebrospinal fluid (CSF) of 11 relapsing-remitting (RR) MS patients using cytometric bead-based array, and their association with the disease characteristics was determined. ANA were detected in the sera of 43.2% of RRMS patients, and their frequency was the highest in patients with disease duration of less than one year (88,89%). In addition, the number of experienced relapses was lower in ANA-positive patients. Concentrations of sFasL were inversely associated with patients’ expanded disability status scale (EDSS) scores. Low concentrations of both soluble factors strongly discriminated patients with moderate to severe disability, from patients with mild or absent disability only in a group of patients with prolonged disease duration (>10 years). Both soluble mediators were significantly higher in ANA-positive patients. FasL concentrations were inversely associated with the number of relapses. There is a potential link between the presence of ANA and peripheral lymphocyte apoptosis mediated by Fas/FasL system in MS, whose precise role and significance needs to be determined by future mechanistic studies.

Highlights

Multiple sclerosis (MS) is a chronic, demyelinating immune-mediated disorder [1] characterized by multiple alterations in various components of the immune system
There is a potential link between the presence of Antinuclear antibodies (ANA) and peripheral lymphocyte apoptosis mediated by Fas/FasL system in multiple sclerosis (MS), whose precise role and significance needs to be determined by future mechanistic studies
This explanation would be in concordance with the current knowledge about the pathogenic mechanisms of ANA production in other autoimmune diseases, of systemic autoimmune rheumatic diseases (SARD) spectrum of diseases, where ANA production in autoimmune diseases is thought to be a result of excessive apoptosis of cytotoxic lymphocytes [21,22], and a reduction in those events could remove the substrate for their production

Summary

Introduction

Multiple sclerosis (MS) is a chronic, demyelinating immune-mediated disorder [1] characterized by multiple alterations in various components of the immune system. Antinuclear antibodies (ANA), which are frequently found in systemic autoimmune rheumatic diseases (SARD), such as systemic lupus erythematosus (SLE), Sjögren’s syndrome, and systemic sclerosis, have been recognized in higher frequencies in MS patients than in healthy individuals [8,9,10]. Earlier studies considered ANA positivity in MS as a false positive finding [11], or recommended their exclusion during evaluation of clinically isolated syndrome (CIS) and MS, argumenting that their presence in the context of MS was not indicative of an alternative diagnosis, such as a disease from the SARD spectrum [12]. There are reports on the development of signs of SARD diseases in only a small fraction of ANA positive patients with CIS [15]. ANA positivity is commonly detected in neuromyelitis optica disease spectrum (NMOSD), which partially corresponds to MS [17,18], and seems to be associated with milder disease course and fewer relapses [19]

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