Multiple Sclerosis (MS) is an immune-mediated disease of the central nervous system (CNS) that is characterized by a variable clinical course and heterogeneous and complex pathology. Pathophysiological processes in MS contribute to the disease course and clinical manifestations, and therefore biomarkers that are indicative of these events would provide significant potential for diagnostics, prediction of disease course and optimization of therapeutic responses.
The goal of this thesis was to identify biomarkers in the blood that could reflect pathogenetic processes in MS and be used as biomarkers of disease activity and progression. In this regard, the aims were to: 1) define immune profiles in different clinical subtypes of MS and clinically isolated syndrome (CIS); 2) search for biomarkers for disease activity and disability; 3) search for prognostic biomarkers for CIS to MS, and 4) explore whether the postpartum disease activation of MS is related to changes in the apoptotic molecules in the blood. The study included patients with different subtypes of MS, CIS and healthy controls that underwent neurological, magnetic resonance imaging (MRI) and immunological examinations.
Altered expression of immune profiles in MS subtypes were found on both the protein and gene levels. Immune profiles in sera of primary progressive MS (PPMS) were characterized by elevated levels of tumor necrosis factor (TNF)-a, soluble Fas (sFas) and C-C chemokine motif ligand 2 (CCL2). Decreased serum levels of macrophage migration inhibitory factor (MIF) were found in relapsing-remitting MS (RRMS). Aberrant expression of six apoptosis-related genes (BAD, BBC3, BCL2L14, TNFRSF25, IKBKE, NFKBID), including B-cell lymphoma 2 (Bcl-2) and nuclear factor kappa B (NF-kB) families and death receptor pathway, were found in RRMS patients. Interestingly, atypical expression profiles of apoptosis-related genes were also seen in CIS (BNIP3, TNFRSF25, IKBKE).
Active disease course was associated with upregulation of serum MIF and TNF-related apoptosis inducing ligand (TRAIL), and disease progression was associated with increased TRAIL mRNA, MIF and sTRAIL. In CIS, elevated expression of three apoptosis-related genes (APAF, BIRC6, CFLAR) was found in those patients who fulfilled the diagnostic criteria for MS over the two-year follow up.
In the study of the immunomodulatory effect of pregnancy on MS, sTRAIL and sFasL were upregulated in both MS patients and healthy women from late pregnancy to postpartum. The increase in sTRAIL was significantly smaller in the MS patients in comparison with the controls.
In summary, this thesis focusing on the identification of biomarkers in MS showed that PPMS was characterized by elevated levels of TNF-a, sFas and CCL2 indicating inflammatory activity in this subtype. Abnormal expression of apoptosis-related genes in RRMS and CIS suggested an enhanced potential for apoptosis in immune cells directed at controlling MS disease activity. Disease activity was associated with increased levels of serum TRAIL and MIF and disease progression was associated with upregulated levels of sFas, MIF and TRAIL mRNA, suggesting these molecules to be candidate biomarkers for disease activity and progression. Interestingly, three new prognostic biomarkers for conversion to MS were found. Increased MS disease activity postpartum may be related to inadequate inhibition of T-cell reactivation after pregnancy. Currently we are validating these findings using larger patient series and longer follow-up periods.
