Disease-associated inflammatory biomarker profiles in blood in different subtypes of multiple sclerosis: Prospective clinical and MRI follow-up study
Introduction
Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) that is characterized by complex pathophysiological processes including inflammation, demyelination, axonal loss and remyelination (McQualter and Bernard, 2007). Currently, the clinical assessments used in the treatment of MS are relatively crude and depend mainly on relapses and changes in disability scores. Magnetic resonance imaging (MRI) is the main paraclinical tool used in clinical practice (McFarland, 2009), but clinicoradiological correlations have been generally weak thus far (Barkhof, 2002). Likewise, prognostic markers predicting a risk of transition from clinically isolated syndrome (CIS) to clinically definite MS (CDMS) would have a strong influence on treatment decisions. Up to now, lesion load in the initial MRI of CIS patients has been the best validated prognostic paraclinical measure (Brex et al., 2002, Achiron and Barak, 2000, Fisniku et al., 2008). Due to these reasons, sensitive biomarkers are needed for the evaluation of disease activity and progression, predicting the disease course and optimizing therapeutic responses in MS (Tumani et al., 2009, Harris and Sadiq, 2009).
The majority of blood and CSF markers analyzed thus far in MS reflect both immune-inflammatory and neurodegenerative events, but their correlation with clinical aspects have been relatively weak (Tumani et al., 2009, Harris and Sadiq, 2009). Cytokines and chemokines are major regulators of inflammation that mediate the recruitment of leukocytes into CNS with the subsequent development of tissue damage (McQualter and Bernard, 2007). Several chemokines including CCL2, CCL4, CCL5, CXCL10, CXCL12, and CXCL13 and their receptors including CCR1, CCR2, CCR5, CXCR3, and CXCR4 have been detected in the active MS lesions, as well as in CSF and blood where they were considered to reflect disease activity (Szczucinski and Losy, 2007). Moreover, recently expression of CXCR3+ on circulating CD8+ cells was associated with MRI measurements of inflammatory activity and tissue destruction (Fox et al., 2008). Interestingly, it has been reported that interferon (IFN)-β can modulate the levels of several chemokines (CCL1, CCL2, CCL7, CXCL10 and CXCL11) in blood and CSF, thus limiting the entry of immune cells into the CNS (Cepok et al., 2009, Sellebjerg et al., 2009).
Altered levels of proinflammatory cytokines such as interleukin (IL)-2, IL-12, IL-6, tumor necrosis factor (TNF) -α and IFN-γ, and of regulatory cytokines such as IL-10, IL-4 and transforming growth factor (TGF)-β in the blood and CSF of MS patients have also been reported (Imitola et al., 2005). These were considered to reflect the in vivo activity of inflammatory cells (Sospedra and Martin, 2005). Some of these cytokines are associated with disease activity on MRI (Fassbender et al., 1998, Petereit et al., 2003). In general, markers of inflammation show rather poor correlation with clinical disease progression and there are no data on any sufficiently long period follow up (Tumani et al., 2009).
A failure in the apoptotic cell death of autoreactive T cells is an important pathophysiological mechanism in MS (Zipp, 2000, Pender, 2007). Neuropathological evidence showing enhanced expression of death receptors Fas (CD95), TNF-related apoptosis-inducing ligand receptor 1 (TRAIL-R1), TRAIL-R2, TNF-R1, TNF-R2 and their ligands Fas Ligand (FasL), TRAIL and TNF-α in MS together with expression of apoptotic molecules in blood and CSF favors this concept (D'Souza et al., 1996, Dowling et al., 1996, Bonetti and Raine, 1997, Cannella et al., 2007). However, only a few studies have analyzed the potential of these molecules to predict clinical outcomes of disease.
Our aim in this study was to identify biomarkers in the blood that could reflect pathogenetic processes in MS and be used in clinical practice when treating patients with MS. Therefore, the profiles of several cytokines, chemokines and apoptotic molecules that are considered to be involved in pathogenesis of MS were evaluated with the aim of recognizing such molecules that could be used as biomarkers of disease activity and progression in MS.
Section snippets
Subjects
The study was a one-year prospective follow-up study that included altogether 110 subjects of whom 72 had CDMS according to revised McDonald Criteria (McDonald et al., 2001, Polman et al., 2005), 17 had CIS and the remaining 21 were healthy controls (HC). The CDMS group included 33 patients with relapsing remitting MS (RRMS), 18 patients with secondary progressive MS (SPMS) and 21 with primary progressive MS (PPMS). CIS patients were defined as patients who had their first demyelinating
Clinical follow-up data
RRMS patients had a lower EDSS score than the patients with SPMS and PPMS (Table 1). At one-year follow up, the EDSS score had increased in 8 out of 30 (27%) RRMS patients, in 6 out of 17 (35%) SPMS patients, and 6 out of 17 (35%) of patients with PPMS. Two years before enrollment, 7 of the 33 (21%) RRMS patients were relapse-free, 11 (33%) patients had had one relapse and the remaining 15 (45%) patients had had 2 to 3 relapses. Over the one-year follow up, 18 of 30 (60%) RRMS patients were
Discussion
In this study, the profiles of major cytokines, chemokines, and apoptotic molecules that are thought to be involved in the pathophysiology of MS were correlated with clinical and MRI follow-up characteristics with the aim of identifying the biomarkers of disease activity and progression in MS. Higher levels of sFas, TNF-α and CCL2 in sera of PPMS patients at baseline in comparison to healthy controls indicate the presence of inflammatory activity in this subtype where neurodegenerative changes
Acknowledgments
We would like to thank Raija Paalavuo for her excellent technical assistance. The study was financially supported by the Competitive Research Funding of Tampere University Hospital, Finnish Cultural Foundation, The Finnish MS Foundation and the Finnish Neurological Societies.
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