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

Abstract

Persistent activation of toll-like receptors (TLR) and nucleotide-binding oligomerization domain-containing proteins (NOD) in the innate immune system is one necessary driver of autoimmune disease (AD), but its mechanism remains obscure. This study compares and contrasts TLR and NOD activation profiles for four AD (autoimmune myocarditis, myasthenia gravis, multiple sclerosis and rheumatoid arthritis) and their animal models. The failure of current AD theories to explain the disparate TLR/NOD profiles in AD is reviewed and a novel model is presented that explains innate immune support of persistent chronic inflammation in terms of unique combinations of complementary AD-specific antigens stimulating synergistic TLRs and/or NODs. The potential explanatory power of the model is explored through testable, novel predictions concerning TLR- and NOD-related AD animal models and therapies.

Innate Receptor Activation Patterns Involving TLR and NLR Synergisms in COVID-19, ALI/ARDS and Sepsis Cytokine Storms: A Review and Model Making Novel Predictions and Therapeutic Suggestions

“…The DAMPs activating NLRP3 include cholesterol crystals and amyloid proteins such as those found in Alzheimer’s disease and diabetes [ 47 ]. Thus, once an innate immune response has been activated by the presence of foreign antigens, it may be maintained by the release of host antigens if the foreign antigens stimulate ongoing cellular damage or if an autoimmune disease process is initiated [ 51 ].…”

“…While any particular PAMP or DAMP activates only one or two innate receptor pathways, every innate receptor synergizes with some limited set of other receptors, so that combinations of PAMPs and DAMPs can initiate far greater releases of cytokines than individual ones. Figure 2 A,B summarize the currently known sets of innate receptor synergisms based on two previous reviews [ 51 , 56 ] supplemented by additional sources that were found during the process of researching the present paper [ 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 ]. For example, TLR4 synergizes with multiple TLR, especially TLR2 and TLR9, as well as NLRP3 [ 51 , 56 ].…”

“…For example, RIG1 and TLR2 are antagonists; NOD2 pretreatment antagonizes TLRs2, 4, 5 and 9 [ 64 ]; NOD2 inhibits TLR1/2 [ 66 , 67 ], as well as TLR4, TLR9 and RIG1 [ 56 ]; TLR2, TLR4 and TLR5 inhibit TLR8 [ 68 ] and TLR9 inhibits TLR4 [ 69 ]. Sometimes, the same pair of receptors may, under one set of conditions, synergize with each other and, in another set of conditions, antagonize each other [ 51 , 56 ]. In the vast majority of cases, where both synergy and antagonism occur in the same pair of receptors, the synergy occurs when both receptors are activated simultaneously while the antagonism results when one receptor is activated significantly in advance (several hours to days) of the other.…”

“…In the vast majority of cases, where both synergy and antagonism occur in the same pair of receptors, the synergy occurs when both receptors are activated simultaneously while the antagonism results when one receptor is activated significantly in advance (several hours to days) of the other. Thus, an agonist for one receptor may act as an antagonist for another [ 51 , 56 ]. These complications may explain some cases of conflicting data that will be discussed below with regard to whether particular sets of innate receptors are activated during cytokine storms of varying causes.…”

“…The result is a very complex system of feedforward and feedback loops, many of which involve bacterial antigens with each other (TLR2 and 4 and NOD 1 and 2), bacterial antigens with viral antigens (NOD1 and NOD2 with TLR9 and TLR3 with RIG1) and between viral antigens (TLR3 and RIG1). This figure is based on less-complete versions in [ 51 , 56 ] that were augmented with reference to the following studies [ 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 ]. The different line styles have no intrinsic meaning but are used to help the reader more easily trace the pairs of interactions, in the case of synergisms, and the source and direction of the interactions, in the case of antagonisms.…”