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.
Highlights
Most research concerning the initiation of autoimmune diseases focuses on the role of the adaptive immune system in carrying out a specific attack upon some host autoantigen
I have been working for some time on a theory of autoimmunity that turns the problem on its head, starting with the assumption that there is no defect in tolerance nor defect in the functioning of the immune system during the induction of autoimmune disease (AD)
These results suggest that timing of toll-like receptors (TLR) activation may be important: costimulation with TLR2-3 and TLR2-4 is synergistic, yet TLR2 followed by TLR3 or TLR4 is antagonistic
Summary
Most research concerning the initiation of autoimmune diseases focuses on the role of the adaptive immune system in carrying out a specific attack upon some host autoantigen. I have been working for some time on a theory of autoimmunity that turns the problem on its head, starting with the assumption that there is no defect in tolerance nor defect in the functioning of the immune system (adaptive or innate) during the induction of AD. This study reviews one aspect of that unusual activation—toll-like receptor (TLR) and nucleotide-binding oligomerization domain-containing proteins (NOD) activation and signaling—and provides a model to explain its function in initiating autoimmune disease. This model is applied to four AD and their animal models: autoimmune myocarditis, myasthenia gravis, multiple sclerosis and rheumatoid arthritis. The implications for the model are extrapolated to several other AD and a series of experimentally testable predictions are made that can differentiate the proposed model from other theories of how innate immunity supports AD pathogenesis
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