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Blood, 1 February 2008, Vol. 111, No. 3, pp. 1472-1479.
Prepublished online as a Blood First Edition Paper on November 20, 2007; DOI 10.1182/blood-2007-10-117184.
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Submitted October 10, 2007
Accepted November 12, 2007
The endogenous danger signal, crystalline uric acid, signals for enhanced antibody immunity
Marshall D Behrens, Wolfgang M. Wagner, Christopher J Krco, Courtney L Erskine, Kimberly R Kalli, James Krempski, Ekram A Gad, Mary L. Disis, and Keith L Knutson*
Department of Immunology, Mayo Clinic College of Medicine, Rochester, MN
Tumor Vaccine Group, Center for Translational Medicine in Women's Health, Seattle, WA
* Corresponding author; email: knutson.keith{at}mayo.edu.
Studies have shown that the immune system can recognize self antigens under conditions (e.g. cell injury) in which the self tissue might elaborate immune-activating endogenous danger signals. Uric acid (UA) is an endogenous danger signal recently identified to be released from dying cells. Prior work has shown that UA activates immune effectors of both the innate and adaptive immune system, including neutrophils and cytotoxic T cell immunity. However, it was unclear whether UA could enhance antibody immunity which was examined in this study. When added to dying tumor cells or with whole protein antigen, UA increased IgG1-based humoral immunity. Further, UA blocked growth of tumor in subsequent tumor challenge experiments, which depended on CD4, but not CD8 T cells. Sera derived from UA-treated animals enhanced tumor growth suggesting it had little role in the anti-tumor response. UA did not signal for T cell expansion or altered tumor-infiltrating leukocyte populations. Consistent with the lack of T cell expansion, when applied to dendritic cells, UA suppressed T cell growth factors but upregulated B cell-activating cytokines. Understanding the nature of endogenous danger signals released from dying cells may aid in a better understanding of mechanisms of immune recognition of self.
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