Pattern Recognition Receptors in Multiple Sclerosis and Its Animal Models

Abstract

Pattern recognition receptors (PRRs) coordinate the innate immune response and have a significant role in the development of multiple sclerosis (MS). Accumulating evidence has identified both pathogenic and protective functions of PRR signaling in MS and its animal model, experimental autoimmune encephalomyelitis (EAE). Additionally, evidence for PRR signaling in non-immune cells and PRR responses to host-derived endogenous ligands has also revealed new pathways controlling the development of CNS autoimmunity. Many PRRs remain uncharacterized in MS and EAE, and understanding the distinct triggers and functions of PRR signaling in CNS autoimmunity requires further investigation. In this brief review, we discuss the diverse pathogenic and protective functions of PRRs in MS and EAE, and highlight major avenues for future research.

Molecular patterns from a human gut-derived Lactobacillus strain suppress pathogenic infiltration of leukocytes into the central nervous system

“…In support of a major role for Lb-associated molecular patterns in conferring resistance against neuroinflammation, we identify TLR2 as a critical host pattern recognition receptor in the protective mechanism of Lb. MS patients exhibit increased expression of TLR2 in peripheral blood mononuclear cells, cerebrospinal fluid cells, and demyelinating lesions [25], and in line with our own preclinical results, MS patients also exhibit decreased microbiota-derived TLR2 ligands in the blood [26]. Additionally, post-mortem analyses of whole brains from MS patients have identified the presence of peptidoglycan in demyelinating lesions [27,28], evidencing the ability of MAMPs to reach the CNS parenchyma in a neuroinflammatory context.…”

Synergistic Activation of Toll-Like and NOD Receptors by Complementary Antigens as Facilitators of Autoimmune Disease: Review, Model and Novel Predictions

“…Multiple sclerosis (MS) has, once again, a different TLR activation profile than AM or MG. MS results from an autoimmune attack on central nervous system myelinated nerves, destroying their myelin sheaths. The TLR activation profile in MS consists of 2, 4, 9 along with NOD2 [ 39 ]. Animal models of MS fall under the general name of experimental allergic encephalomyelitis (EAE), which has a number of differences from the human disease but is characterized by similar TLR profiles ( Table 1 ).…”

“…EAE animal models generally use one of several myelin antigens such as myelin basic protein (MBP) or myelin oligodendrocyte glycoprotein (MOG) in combination with an appropriate adjuvant. MBP can be combined with CFA, in one formulation, which activates the same TLR as are observed in MS itself [ 39 ]. CFA, which activates TLRs 2, 4 and 9, may be replaced with cytosyl- p -guanosyl oligodeoxynucleotides (CpG-ODN), an adjuvant that activates TLR9 in combination with LPS, at TLR4 activator [ 40 , 41 ].…”

“…However, some comparisons are possible that suggest that the concentrations of antigens involved in human AD are comparable or even significantly greater than those used in the induction of experimental AD. For example, doses of 100–500 μg of inactivated M. tuberculosis are often delivered in Freund’s complete adjuvant (FCA) as part of experimental AD induction [ 26 , 33 , 34 , 37 , 38 , 39 ]. In comparison, a dose of the mycobacterial vaccine BCG (Bacillus Calmette-Guerin) is delivered as 50 μg of the semi-dry mass of live BCG bacilli, which will then replicate to many times this mass.…”

Protective roles for myeloid cells in neuroinflammation

“…35 Innate receptors, for example pattern recognition receptors, are widely expressed and can play pathologic and protective roles in MS and EAE. 36 Triggering innate receptors within the CNS may induce the infiltration of MRCs. As a specific example, G/PMN-MRCs were mobilized in EAE by intrathecal administration of a bispecific microparticle called MIS416, which combines ligands for TLR9 and NOD2 to activate phagocytes.…”