Date of Completion

4-24-2018

Embargo Period

4-24-2018

Keywords

Multiple Sclerosis; immune tolerance; Toll-like receptor tolerance

Major Advisor

Robert B. Clark

Associate Advisor

Frank Nichols

Associate Advisor

Anthony Vella

Associate Advisor

Lauren Sansing

Associate Advisor

Thiruchandurai V. Rajan

Field of Study

Biomedical Science

Degree

Doctor of Philosophy

Open Access

Open Access

Abstract

We have reported that a microbiome-derived Toll-like receptor 2 (TLR2) ligand, Lipid 654 (L654), is decreased in the circulation of MS patients. This led us to ask 1) why is a TLR ligand low in an inflammatory disease like MS, 2) what are the properties of L654 that might be biologically relevant and 3) can serum L654 be used as a biomarker for MS disease status or activity?

We proposed that microbiome products routinely accessing the circulation maintain a state of immune tolerance. TLR tolerance is a mechanism that, through low-level, tonic ligation of TLRs, establishes the threshold and magnitude of TLR signaling. Therefore, we proposed that a loss of micribiome-mediated TLR tolerance plays a role in the pathogenesis of MS. As proof of concept we asked whether low-level administration of a TLR2 ligand in EAE could induce TLR2-tolerance and attenuate disease. Indeed, administration of a cannonical TLR2 ligand and L654 both induced TLR2-tolerance and attenuated EAE. Additionally, suggesting this is a normal mechanism of immune tolerance that is deficient in MS, we showed that monocytes from active MS patients are hyper-responsive to a TLR2 ligand. Next, as L654 is a newly described molecule, we posited that studying the chemical and biological properties of L654 would provide insight into its role in MS. We found that L654 exists in multiple isoforms, and there is preferential hydrolysis of L654 by Phospholipase A2 (PLA2) for one isoform. We also have data suggesting that the ratio of isoforms determines the TLR2 activity. Additionally, there is greater breakdown of L654 in serum of MS patients compared to controls, suggesting a potential role for PLA2 in MS. Importantly, we found serum L654 levels may correlate with MS disease activity.

Overall, our results suggest that systemic exposure to low-level microbiome products can inhibit CNS autoimmunity and that restoring this microbiome function in patients with MS may offer a new approach to treating this autoimmune disease. Additionally, the relationship between PLA2 and L654 may provide insight into why serum L654 is lower in MS. Lastly, L654 has potential to be utilized as a serum biomarker for MS.

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