A clinical trial involving 19 autoinflammatory syndrome patients reveals some key findings (Schuh et al., 2019): 1) peripheral blood mononuclear cells from patients with NLRP3 low penetrance variants are more likely to release NLRP3-specific IL-1β, which is demonstrated by inhibition of NLRP3 with MCC950; 2) these patients present NLRP3-independent release of IL-6 and TNF-α; and 3) patients with NLRP3 low penetrance variants may present with severe CNS manifestations and partially respond to IL-1 targeting therapies. The gene discussed is TNF; the disease is autoinflammatory syndrome.