The Soluble Form of Toll-Like Receptor 2 Is Elevated in Serum of Multiple Sclerosis Patients: A Novel Potential Disease Biomarker

Abstract

Multiple sclerosis (MS) is an immune-mediated inflammatory demyelinating disease of the central nervous system. It was previously shown that toll-like receptor (TLR)-2 signaling plays a key role in the murine experimental autoimmune encephalomyelitis (EAE) model of MS, and that TLR2-stimulation of regulatory T cells (Tregs) promotes their conversion to T helper 17 (Th17) cells. Here, we sought potential sources of TLR2 stimulation and evidence of TLR2 activity in MS patient clinical samples. Soluble TLR2 (sTLR2) was found to be significantly elevated in sera of MS patients (n = 21), in both relapse and remission, compared to healthy controls (HC) (n = 24). This was not associated with the acute phase reaction (APR) as measured by serum C-reactive protein (CRP) level, which was similarly increased in MS patients compared to controls. An independent validation cohort from a different ethnic background showed a similar upward trend in mean sTLR2 values in relapsing-remitting MS (RRMS) patients, and significant differences in sTLR2 values between patients and HC were preserved when the data from the two cohorts were pooled together (n = 41 RRMS and 44 HC, P = 0.0006). TLR2-stimulants, measured using a human embryonic kidney (HEK)-293 cells transfectant reporter assay, were significantly higher in urine of MS patients than HC. A screen of several common urinary tract infections (UTI)-related organisms showed strong induction of TLR2-signaling in the same assay. Taken together, these results indicate that two different markers of TLR2-activity—urinary TLR2-stimulants and serum sTLR2 levels—are significantly elevated in MS patients compared to HC.

Melatonin, a toll‐like receptor inhibitor: Current status and future perspectives

“…AP-1: activator protein-1; IRF-2: interferon regulatory factor 2; MAPK: mitogen-activated protein kinase; PI3K: phosphoinositide 3-kinase; RIP1: receptor-interacting protein; TLR: toll-like receptor; TRIF: TIR-domain-containing adapterinducing interferon-β; TRAM: TRIF-related adaptor molecule [Color figure can be viewed at wileyonlinelibrary.com] disorders including AD (E. Gambuzza et al, 2014;F. Su, Bai, Zhou, & Zhang, 2016), multiple sclerosis (Hossain et al, 2018;Ruggiero, 2012), epilepsy (Song et al, 2014;Wen et al, 2018), and stroke (Fadakar, Dadkhahfar, Esmaeili, & Rezaei, 2014;L. Zhang et al, 2012).…”

Urinary Tract Infection in Patients with Multiple Sclerosis: An Overview

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“…As soluble TLR2 is released from excessive TLR2 stimulation, the authors looked for potential stimulants and found data which suggested that bacteria responsible for UTIs were potent TLR2 stimulators (Gram-negative: Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa and Proteus vulgaris; Gram-positive: Enterococcus faecalis and Streptococcus pyogenes), relating recent UTIs to exacerbations of the disease. (Hossain et al, 2018).…”

Biomarkers and Disease Activity in Multiple Sclerosis : A cohort study on patients with clinically isolated syndrome and relapsing remitting multiple sclerosis

“…They are highly specific neuronal proteins that are very stable in vitro [42]. Three major neurofilament subunits exist and based on their molecular mass they are named neurofilament heavy chain (200-220 kDa), neurofilament intermediate chain (145)(146)(147)(148)(149)(150)(151)(152)(153)(154)(155)(156)(157)(158)(159)(160) and neurofilament light chain (68-70 kDa). NFL and NFH can be measured with enzyme-linked immunosorbent assays (ELISA) in CSF.…”