Adjuvants' mechanisms

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DESCRIPTION (provided by applicant): Protein based receptor ligand interactions are universally regarded as the initiating point of immune activation. However, it is questionable if i is applicable to immune recognition of solid structures. This issue is particularly relevant in vaccine design as some of the best known adjuvants are solid crystals, such as alum and monosodium urate. Binding of particulate antigens by antigen presenting cells (APC) is a critical step in immune activation. It has been demonstrated that uric acid and alum crystals are potent adjuvants, initiating a robust adaptive immune response. However, the mechanisms of activation are unknown. Using atomic force microscopy as a tool for real time single cell activation analysis, we have collected evidence that uric acid and alum crystals can directly engage cellular membranes, with a force substantially stronger than protein based cellular contacts. Binding of particulate substances activates Syk kinase-dependent signaling in dendritic cells (DCs). These observations suggest a mechanism whereby immune cell activation can be triggered by solid structures via membrane lipid alteration without the requirement for specific cell surface receptors, and a testable hypothesis for crystal-associated inflammation and adjuvanticity. In this proposal, we extend the findings to study the signaling mechanisms involved, particularly the association between cell surface lipid sorting and downstream signal transduction, critical steps in crystal mediated immune activation, as well as how this mechanism affects antigen presentation. The outcome of this work will impact vaccine development and our understanding of crystal related diseases. PUBLIC HEALTH RELEVANCE: We propose here to study how lipids in the immune cell membrane can sense solid structures like crystals and beads. This is an important topic related to vaccine development, implant research, drug delivery and inflammatory responses to air pollution. Specifically, we will study what type of signaling events follow lipid binding in respone to these solid structures and how they impact immune outcomes.