The decision whether or not to mount a productive immune response to an antigen is determined largely by environmental factors such as the presence or absence of microbial products. These molecules provide signals to alert the immune system to the presence of potentially dangerous antigens and many are thought to function by stimulating dendritic cells (DCs) to mature. Dying cells, when co-injected into mice with antigen, have the same immunostimulatory properties, inducing strong cytolytic CD8+ T-lymphocyte (CTL) responses to the antigen.

The factor present in dying cells that facilitates this CTL priming to antigen has been shown to reside in the cytosol, and now using chromatography and mass spectrometry, Shi et al. have identified uric acid as one of the main agents responsible for this effect. This was confirmed by showing that purified uric acid could induce a similar CTL response to co-injected antigen as the active cytosolic fractions obtained by chromatography, and that treatment of either these fractions or the immunized mice with uricase — a highly specific enzyme that mediates the degradation of uric acid — markedly reduced their ability to promote a measurable CTL response.

Increased uric-acid production was observed to be a general characteristic of cells undergoing death, and as the CTL response generated in animals depleted of uric acid was substantially less than that detected in control mice, it is probably a key immunoactivating signal produced by dying cells.

Soluble uric acid was unable to support DC maturation in vitro, however, monosodium urate (MSU) crystals increased the expression of co-stimulatory molecules by bone-marrow-derived DCs in culture and facilitated CTL priming to antigen in vivo. By contrast, MSU crystals did not affect the uptake of antigen by DCs. Uric acid has been reported to precipitate in vivo at the concentrations used in these studies and so the authors suggest, during cell death, the levels of uric acid produced locally could increase sufficiently to cause this endogenous metabolite to precipitate and promote DC maturation and activation. If the dying cell contained antigen to which the host was not tolerant then such DC activation would lead to the induction of a productive immune response to these antigens.

This study identifies uric acid as an endogenous mediator of immune activation, implicating it as crucial for surveillance by the adaptive immune system. As such, it is possible that uric acid could act as a type of adjuvant, stimulating an immune response to antigens to which the immune system was previously non-responsive, such as virus infections and tumours. Furthermore, these studies are also important to our understanding of the pathogenesis of gout — an inflammatory disease initiated by the precipitation of MSU in the joints — and raise the possibility that uric acid has a central role in the inflammatory response to tissue damage.