Modifications like Citrulination and MDA Adducts, Lipidation and the Immune System; A Menage a Trois Gone Wrong in Multiple Sclerosis

Background:

In several autoimmune diseases peroxidation products have been suggested as biomarkers. However, the nature of formation of them and their role in stimulating the immune response, is not understood.

In Multiple Sclerosis (MS) peroxidation derived oxidized lipids have shown to be significantly upregulated and can be exploited to monitor pathogenic mechanisms in cerebrospinal fluid and serum samples¹. Several studies report similar results, but no significant differences in these peroxidation products have been found between relapsing remitting MS and secondary progressive MS, where the inflammatory responses play different roles. This could suggest that peroxidation products are important for the general inflammatory process, but not directly for disease specificity. Resent research in other autoimmune diseases such as Rheumatoid Arthritis suggested that protein adducts deriving from the peroxidation of lipids may function as epitopes for T and B cells, and thereby potentially leading to breakage of tolerance to the unmodified protein in a process called altered peptide ligand response.

Objectives:

This project seeks to investigate more of  the etiology behind MS focusing on the role of peroxidation, the interaction between myelin basic protein (MBP) and lipids as well as how lipid peroxidation potentially affect formation of the complexes of MBP with the lipids or adduct hereof.

Methods:

The analysis is based on both a target and discovery based approaches using Mass spectrometry, and samples derived from Experimental Autoimmune Encephalomyelitis models of MS.

Results:

Working with the hypothesis of lipid derived epitopes, the interaction between MBP and lipids was investigated including the influence of post translational modification on this interaction. A novel hypothesis considering the identification of lipids which covalently bind to MBP has been tested and confirmed using mass spectrometry. We have focussed on the lipid adducts and protein modification like citrullination, especially hypercitrulination in MS lesions, and based on these data propose a revised disease induction and progression model involving these different findings

Conclusions:

This expansion of knowledge in metabolism interaction with inflammation focusing on protein and lipid modifications, crosstalk in MS will tribute to the understanding of the disease etiology, which potentially could provide retrospective information leading to diagnostic as well as prognostic biomarker discovery and thereby to potential target molecules for novel drug discovery.