Multiple Toll-Like Receptor Agonists Act as Potent Adjuvants in the Induction of Autoimmunity



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Multiple sclerosis (MS) is an inflammatory disease of the CNS. Infections can trigger or exacerbate the course of MS, and many agents, both bacterial and viral, have been implicated. These agents are recognized by the innate immune system via pathogen-associated molecular patterns (PAMPs) activating Toll-like receptors (TLRs) on host cells. I investigated the role that PAMPs play in Experimental Autoimmune Encephalomyelitis (EAE), an animal model of MS. Both genetic and environmental influences contribute to the pathogenesis of MS. I used various PAMPs as the environmental input to imitate infection and activate TLRs in an effort to induce EAE in a resistant mouse strain. To further elucidate the impact of infection on EAE, I examined the role of various TLR agonists in the development of autoimmunity using direct immunization and adoptive transfer of encephalitogenic T cells. Mice developed EAE following immunization with myelin antigen emulsified in IFA with various PAMPs, indicating that various PAMPs can participate as the adjuvant necessary to induce EAE. I also examined the effect of PAMPs on APC activation and found that DCs pulsed with antigen and activated with the TLR agonist LPS enhanced the stimulation of antigen-specific immune cells. Conversely, tolerizing mice to a particular PAMP inhibited the ability of those mice to develop EAE following direct immunization with that PAMP and Ag. To determine the role of the Toll/IL-1 pathway in the target organ, Myelin Basic Protein (MBP) Ac1-11-specific T cells were adoptively transferred into both wild type and IRAK1-deficient mice and disease was monitored in both groups, with the results suggesting that signaling through TLR is not required in the target organ to develop disease. These results suggest that PAMPs play an important role in priming of autoreactive T cells in EAE and potentially MS.