Familial cold autoinflammatory syndrome (FCAS), Muckle–Wells syndrome (MWS) and neonatal onset multi-system inflammatory disease (NOMID) [also called chronic infantile neurologic cutaneous articular syndrome (CINCA)] are different manifestations of one disease, in that they are all caused by autosomal-dominant mutations in NLRP3. Therefore, FCAS, MWS and NOMID are now collectively called cryopyrin-associated periodic syndromes (CAPS) [69,70]. FCAS represents the less severe manifestation of CAPS and is characterized by cold-induced fever and urticaria-like rashes. MWS is more severe, and patients have also sensorineural hearing loss and arthritis. NOMID is the most severe form of CAPS, and patients have epiphyseal overgrowth of the long bones and chronic aseptic meningitis . Mutations that lead to CAPS are clustered inside or in the vicinity of the NOD domain (also referred as the NACHT domain), a module that is thought to be important in promoting the oligomerization of NLR proteins (Fig. 1). Initial experiments indicated that NLRP3 mutations in CAPS are gain-of-function mutations, in that over-expression of disease-associated mutants leads to increased secretion of IL-1β and macrophages from MWS patients secrete more IL-1β than healthy individuals [71,72] (Fig. 1). These early studies uncovered the molecular basis on CAPS and paved the way to the treatment of CAPS with biologicals that target IL-1β-induced signalling. However, the mechanism through which disease-associated mutations led to increased production of IL-1β is still poorly understood. One feature of the NOD domain that is thought to be important to induce the oligomerization of NLRP3 is its ability to bind to and hydrolyze ATP. This activity is required for CAPS-associated mutations to induce IL-1β secretion, suggesting that the gain-of function mutations in NLRP3 do not affect NLRP3 binding to ATP . One possibility is that inhibitory signals that normally act on NLRP3 to repress its function fail to do so if the NOD domain of NLRP3 is mutated. In agreement with this possibility, cytosolic K+ that normally prevents activation of the NLRP3-inflammasome fails to do so if cells harbour NLRP3-associated mutations [74,75]. One alternative possibility is that disease-associated NLRP3 mutations remove an inhibitory loop, making the NLRP3 variant constitutively active. In agreement with this possibility, stimulation with LPS that induces the up-regulation of NLRP3 is not sufficient to induce the activation of wild-type NLRP3, but is sufficient to induce caspase-1 activation and IL-1β production in macrophages harbouring the NLRP3 mutations associated with CAPS [74,75]. Furthermore, production of IL-1β in monocytes from CAPS patients stimulated with PAMPs is maximal in the absence of ATP stimulation that is required instead to induce maximal production of IL-1β in monocytes from healthy individuals . Recently, a mouse model of CAPS has been developed independently by two groups. Strober et al. generated a knock-in mouse harbouring the R258W mutation that corresponds to the R260W substitution found in patients with MWS and FCAS . Hoffman et al. generated mouse strains carrying mutations (A350V that corresponds to the A352V variant found in MWS and L351P that corresponds to the L353P variant found in FCAS patients) downstream of a LoxP-flanked neomycin resistance cassette in a reverse orientation . With this strategy the expression of the mutated NLRP3 protein is conditional to the expression of Cre-recombinase (Cre), and the authors were able to generate conditional knock-in mice expressing NLRP3 mutant in selected tissues by crossing the mice with mice expressing Cre under different promoters. Although the phenotypes of these mice show different severities of inflammation, all were characterized by the infiltration of neutrophils in the inflamed tissues [74,75]. Furthermore, the inflammatory response was due to the expression of NLRP3 mutants in the myeloid compartment and overproduction of IL-1β[74,75]. Importantly, Hoffman et al.'s work showed that disease manifestation is independent of the presence of T cells or B cells, thus providing experimental evidence that autoinflammatory syndromes are primarily disorders of the innate immune system . It must be noted, however, that overproduction of IL-1β led to a T helper type 17 (Th17)-skewed phenotype. Interestingly, anti-IL-17 antibodies were found to ameliorate skin pathology, suggesting that certain disease manifestation may be exacerbated by Th17 cells . This mouse model can help to address some unresolved questions. First, as this disease is not caused by an infection and the cells from these mice do not secrete IL-1β spontaneously, which are the stimuli that are triggering the production of IL-1β? Secondly, as IL-1β is produced by different cells of myeloid origin, such as macrophages, dendritic cells and mast cells, which of these cells (and in which organ) are responsible for the pathological production of IL-1β? Thirdly, why are several organs affected by the disease but others, such as the lung and the intestine, do not show any abnormality? Fourthly, why does the overproduction of IL-1β not predispose to autoimmune responses, when IL-1β is an effective adjuvant?
The important role of IL-1β in CAPS patients is underscored by the efficacy of biologicals that target IL-1β in the treatment of those patients. Recombinant IL-1Ra (anakinra), soluble IL-1 receptor (rilonacept)  and a human monoclonal antibody against IL-1β (canakinumab)  promote the rapid resolution of symptoms. Remarkably, biologicals that target IL-1β also proved to be effective in ameliorating the neurological symptoms in NOMID patients.