Identification of potential biomarkers in Multiple Sclerosis

Abstract

Multiple sclerosis (MScl) is an inflammatory, autoimmune, demyelinating disease of the central nervous system (CNS). Thesis describes the identification of potential MScl biomarker research, with emphasis on distinguishing subtypes, first event of CNS demyelination in children, pathogenic IgG antibodies and pregnancy MScl. Chapter 2 highlights the differences and similarities of CSF proteome profile between primary-progressive (PP) and relapsing- remitting (RR) MScl. Our research indicated that the proteome profiles of these two major subtypes of MScl overlap to a large extent. However, few differences were seen and confirmed by independent techniques for two proteins- Protein jagged-1 (more abundant in RR MScl as compared to PP MScl) and Vitamin D-binding protein (only detected in the RR MScl samples). In Chapter 3, study aimed at the identification of protein markers linked to diagnosis of MScl after the first demyelinating event. Twenty one proteins differentiated childhood-onset MScl and children presenting with monophasic acquired demyelinating syndromes (ADS). Proteomics analysis revealed that the CSF of childhood onset MScl is associated with the increased abundance of 14 CNS grey matter related proteins as compared to the children presenting with monophasic ADS. Whereas, seven proteins related to the innate immune system were abundant in children with monophasic ADS (such as haptoglobin and CD14). In Chapter 4, we focused on humoral immune responses in CSF of MScl patients. In this study, our main objective was to identify specific proteomic profiles of mutated complementarity determining regions (CDR) of IgG present in MScl patients but absent in controls. We found five CDR shared in three or more patients and not in controls. Interestingly, one CDR with a single mutation was found to be in common in six patients. The result of the study provides leads concerning the question of whether common antigenic stimuli are accountable for the recruitment of intrathecal B cells in MScl. In Chapter 5, we performed a study to monitor the effect of Natalizumab treatment on MScl patients. We addressed its effects on CSF proteome before and after one year of the treatment. This study revealed a number of proteins that were significantly differentially abundant between the before and after treatment groups. Subsequently, three proteins (Ig mu chain C region, haptoglobin and chitinase-3-like protein 1) were validated in an independent sample set and by means of an independent method. In Chapter 6, we performed proteomics approach on alterations of the proteome of urine from MScl patients during third trimester of pregnancy and at first postpartum period. We found that pregnancy related peptides, were significantly elevated in MScl patients compared to controls. When comparing the pregnancy relate changes, we found 43 disease associated peptides identified with increased or decreased difference ratio in MScl compared to control. Our findings indicated that the peptides that relate strongly to pregnancy are linked with or involved in innate and adaptive immune response either directly or indirectly or were immunosuppressive. Our studies show that we add new information to MScl biomarker field and such biomarkers are of substantial interest with respect to the disease pathology, general understanding, diagnosis and for novel therapeutic targets.