Crystallizing a Sense of Danger

Abstract

Classically, activation of the immune response has been viewed as depending on immunological recognition of foreign antigens. An alternative explanation (see Heath and Carbone) postulates that activation of the immune response also depends on "danger" signals released by injured and dying cells. Although the coinjection of dying cells along with antigen appears to act as an adjuvant and primes the T cell response, which provides support for the latter view, the identity of the danger signal has remained unclear. Shi et al. used high-performance liquid chromatography to fractionate the cytoplasm of BALB/c 3T3 cells injured by ultraviolet irradiation. A low-molecular-weight (LMW) fraction was identified that, when injected into mice along with human immunodeficiency virus gp120 antigen, enhanced the subsequent ability of T cells to kill cells bearing that antigen. The authors used gas chromatography together with mass spectrometry to identify uric acid, a product of purine catabolism that is released by dying cells, as the primary component of the LMW fraction. Purified uric acid showed adjuvant activity, whereas treatment of the LMW fraction with uricase, which breaks down uric acid, reduced its effect. Uric acid, at supersaturating concentrations, stimulated primary cultures of dendritic cells to increase expression of T cell costimulatory molecules. Thus, uric acid released from injured cells appears to act as an immunological danger signal. The authors further propose that the activation of dendritic cells after precipitation of uric acid in the joints may contribute to the pathogenesis of gout. Y. Shi, J. E. Evans, K. L. Rock, Molecular identification of a danger signal that alerts the immune system to dying cells. Nature 425 , 516-521 (2003). [Online Journal] W. R. Heath, F. R. Carbone, Dangerous liaisons. Nature 425 , 460-461 (2003). [Online Journal]