Protein based receptor ligand interactions are universally regarded as the initiating point of immune activation. However, it is questionable if it is applicable to immune recognition of solid structures. Binding of particulate antigens by antigen presenting cells (APC) is a critical step in immune activation. Previously, we demonstrated that uric acid 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 crystals can directly engage cellular membranes, particularly the cholesterol components, 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 arthropathies, inflammation and adjuvanticity. In this proposal, we extend our work to study how alum interacts with the immune system and to reveal if such a lipid based mechanism is applicable in alum's adjuvanticity. We will also study the association between cell surface lipid sorting and Nalp3 inflammasome activation, a critical step in uric acid crystal mediated cell activation. We will further study a set of immune activation events unrelated to inflammasome regulation in order to establish a complete picture of alum's immune regulating capacities. The outcome of this work will impact vaccine development and our understanding of crystal related diseases.

Public Health Relevance

This project deals with the basic mechanism for the immune recognition of alum. It has high relevance in the vaccine development and crystal related diseases. Its outcomes will lead to better understanding of the immune system and suggest new methods for population based immunizations.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI089963-02
Application #
8085825
Study Section
Vaccines Against Microbial Diseases (VMD)
Program Officer
Leitner, Wolfgang W
Project Start
2010-06-15
Project End
2013-05-31
Budget Start
2011-06-01
Budget End
2013-05-31
Support Year
2
Fiscal Year
2011
Total Cost
$160,380
Indirect Cost
Name
University of Calgary
Department
Type
DUNS #
207663915
City
Calgary
State
AB
Country
Canada
Zip Code
T2 1-N4
Geng, Shuang; Zhong, Yiwei; Zhou, Xiaoyu et al. (2017) Induced Regulatory T Cells Superimpose Their Suppressive Capacity with Effector T Cells in Lymph Nodes via Antigen-Specific S1p1-Dependent Egress Blockage. Front Immunol 8:663
Chen, Jiahuan; Ganguly, Anutosh; Mucsi, Ashley D et al. (2017) Strong adhesion by regulatory T cells induces dendritic cell cytoskeletal polarization and contact-dependent lethargy. J Exp Med 214:327-338
Hari, Aswin; Ganguly, Anutosh; Mu, Libing et al. (2015) Redirecting soluble antigen for MHC class I cross-presentation during phagocytosis. Eur J Immunol 45:383-95
Shi, Yan (2012) To forge a solid immune recognition. Protein Cell 3:564-70
Ghaemi-Oskouie, Faranak; Shi, Yan (2011) The role of uric acid as an endogenous danger signal in immunity and inflammation. Curr Rheumatol Rep 13:160-6
Flach, Tracy L; Ng, Gilbert; Hari, Aswin et al. (2011) Alum interaction with dendritic cell membrane lipids is essential for its adjuvanticity. Nat Med 17:479-87
Malik, Ahsan F; Hoque, Rafaz; Ouyang, Xinshou et al. (2011) Inflammasome components Asc and caspase-1 mediate biomaterial-induced inflammation and foreign body response. Proc Natl Acad Sci U S A 108:20095-100