Mice injected with antigens mixed with alum produce uric acid that then attracts monocytes.

For more than 70 years, alum has been used as a trusty aide to improve antibody responses to vaccines. But how this aluminum-containing compound boosts the response to vaccines has been a mystery. On page 869, Kool et al. expose its mysterious mechanism; they find that alum causes cells to produce a stimulator of dendritic cells (DCs).

DCs were once the favored hypothetical link between alum and B cells, as they activate CD4+ T cells, which can then enhance B cell activation and antibody production. But DCs were later dismissed when it was found that they were not stimulated by alum in vitro.

These in vitro results are now shown to be a red herring by Kool et al., who find that alum activates DCs in vivo by provoking the secretion of uric acid—a molecule that is triggered by tissue and cell trauma. The injection of alum, the group found, induced an influx of neutrophils and inflammatory cytokines and chemokines—a combination that was previously seen in response to the injection of uric acid into mice.

In mice injected with antigens mixed with alum, uric acid levels increased within hours. The uric acid might be released by the cells' lining the body's cavities that turn necrotic after contacting the alum. The absence of these uric acid sources in in vitro assays might have led to the previous misleading results.

In response to the uric acid, inflammatory monocytes flocked to the injection site, took up the antigens, and broke them down into T cell–stimulating epitopes. The monocytes then migrated to lymph nodes, where they matured into DCs and activated CD4+ T cells.

Without alum, the antigens were not taken up at the injection site. Still, they eventually reached lymph nodes via the flowing lymph. The resident node DCs, however, did not process the alum-free antigens efficiently or express T cell costimulating receptors. The resulting subdued immunity was similar to that seen in mice that were depleted of inflammatory monocytes or those injected with enzymes that degrade uric acid.