A hive-inducing villain has been convicted and traced back to its headquarters. On page 1029, Lachmann et al. confirm that IL-1β is the sole cytokine to blame for chronic rashes symptomatic of the genetic disorder CAPS (cryopyrin-associated periodic syndrome). And on page 1037, Nakamura et al. track IL-1β to its surprising source: mast cells.

Drugs that block IL-1 are used to relieve antihistamine-resistant rashes—the type typical of patients with CAPS. However, researchers weren't sure whether IL-1α, IL-1β, or both caused the problem. Lachmann et al. now show that IL-1β alone predicts disease severity. By developing an anti-IL-1β antibody (canakinumab), they found that patients with CAPS have abnormally high levels of circulating IL-1β. Treating patients with canakinumab relieved their rashes within a day, along with other symptoms of the disease, such as fevers, headaches, and joint pain.

In a separate report, Nakamura and colleagues showed that IL-1β localized to mast cells in human skin. Before now, IL-1β was thought to be produced primarily by macrophages. In macrophages, microbial infection stimulates inflammasomes, multiprotein complexes that turn on IL-1β along with other inflammatory cytokines. Within these cells, microbial ligands trigger the synthesis of the IL-1β precursor protein. And a second ATP-triggered signal activates the inflammasome, which then turns on caspase-1, the protease that cleaves the precursor into its active form. Here, Nakamura et al. show for the first time that the same process occurs in healthy mast cells.

A mutation in the gene encoding NLRP3, a component of the inflammasome, causes CAPS. Mast cells expressing mutated NLRP3 were trigger happy, according to Nakamura's study, producing active IL-1β in the absence of an inflammasome-activating signal. When the authors injected mast cells expressing mutant NLRP3 into the skin of normal mice, the mice developed CAPS-like symptoms, including neutrophil recruitment and vascular leakage.

Perhaps a normally benign environmental cue triggers the constitutive production of the IL-1β precursor in patients, suggest Nakamura et al. This might explain why CAPS patients usually develop hives within the first few weeks after birth, when newborn skin is first exposed to microbes and other inflammatory stimuli.

As for canakinumab, it is awaiting approval from regulatory agencies in the US and in Europe for the treatment of CAPS-associated rashes.