Enhanced TLR2 responses in multiple sclerosis

Abstract

SummaryThe roles of the microbiome and innate immunity in the pathogenesis of multiple sclerosis (MS) remain unclear. We have previously documented abnormally low levels of a microbiome‐derived Toll‐like receptor (TLR)2‐stimulating bacterial lipid in the blood of MS patients and postulated that this is indicative of a deficiency in the innate immune regulating function of the microbiome in MS. We postulated further that the resulting enhanced TLR2 responsiveness plays a critical role in the pathogenesis of MS. As proof‐of‐concept, we reported that decreasing systemic TLR2 responsiveness by administering very low‐dose TLR2 ligands attenuated significantly the mouse model of MS, experimental autoimmune encephalomyelitis. Studies of Toll‐like receptor responses in patients with MS have been conflicting. Importantly, most of these investigations have focused on the response to TLR4 ligation and few have characterized TLR2 responses in MS. In the present study, our goal was to characterize TLR2 responses of MS patients using multiple approaches. Studying a total of 26 MS patients and 32 healthy controls, we now document for the first time that a large fraction of MS patients (50%) demonstrate enhanced responsiveness to TLR2 stimulation. Interestingly, the enhanced TLR2 responders include a significant fraction of those with progressive forms of MS, a subset of patients considered unresponsive to adaptive immune system‐targeting therapies. Our results suggest the presence of a pathologically relevant TLR2 related innate immune abnormality in patients with both relapsing–remitting and progressive MS. These findings may have significant implications for understanding the role of innate immunity in the pathogenesis of MS.

Herpes Simplex Virus Type 1 Infection of the Central Nervous System: Insights Into Proposed Interrelationships With Neurodegenerative Disorders

“…Although this response is responsible for Aβ clearance, a sustained pro-inflammatory environmental could be detrimental for the host (Heneka et al, 2013; Chen L. et al, 2016; Go et al, 2016). Additionally, TLR2 and TLR7 responses are over-stimulated in PBMCs in MS patients when compared with healthy controls (Hamid et al, 2016; Fujiwara et al, 2018).…”

The expression profile of virus-recognizing toll-like receptors in natural killer cells of Cypriot multiple sclerosis patients

“…Upon stimulation using a TLR2 agonist, reduction of Treg function and Th17-like phenotype skewing occurred in MS patients more than in HCs [38]. Enhanced TLR2 responsiveness to its agonist was reported in monocytes and PBMCs of MS patients [31]. The same study found no differences in TLR2 expression in monocytes of MS patients compared to HCs [31].…”

“…Enhanced TLR2 responsiveness to its agonist was reported in monocytes and PBMCs of MS patients [31]. The same study found no differences in TLR2 expression in monocytes of MS patients compared to HCs [31]. In the murine model of MS, experimental autoimmune encephalomyelitis (EAE), the lack of TLR2 in CD4 + T cells was shown to ameliorate EAE [32], while inducing TLR2 tolerance via low-levels of a microbiome-derived TLR2 agonist resulted in amelioration of EAE [39].…”

“…In fact, studies have focused on specific TLRs in different cell subsets of the immune system in association with MS [31][32][33][34][35][36][37]. For instance, Nyirenda et al found that TLR2 expression is higher in Treg cells of MS patients compared to HCs [38].…”

C-type lectin receptors Mcl and Mincle control development of multiple sclerosis–like neuroinflammation

“…A growing body of evidence suggests a role for pattern recognition receptors (PRRs) in autoimmune inflammatory responses (5). Previous studies have primarily focused on Tolllike receptors (TLRs), showing their potential role in modulating pathogenic disease pathways (6)(7)(8); however, little is known about the role of C-type lectin receptors (CLRs) in autoimmunity and particularly in MS (9).…”