Several autoinflammatory disorders such as Muckle-Wells syndrome are characterized by mutations in the NALP3/cryopyrin gene. NALP3 and NALP1 proteins can assemble to inflammasomes that activate caspase-1, resulting in the processing of pro-inflammatory cytokines IL-1beta and IL-18. The present study was designed to determine which cells and tissues express NALP1 and NALP3. Monoclonal antibodies were developed and their use revealed distinct distribution profiles of NALP1 and NALP3. Granulocytes, monocytes (very weakly), dendritic cells, and B and T cells all express NALP1 and NALP3. Highest levels of NALP1 are found in T cells and Langerhans cells. Furthermore, NALP1 is present in glandular epithelial structures such as stomach, gut, lung, and, surprisingly, in neurons and testis. In contrast to NALP1, NALP3 shows a more restricted tissue distribution with expression mainly in non-keratinizing epithelia in the oropharynx, esophagus, and ectocervix. Moreover, NALP3 expression is found in the urothelial layer in the bladder. Likewise, a difference in subcellular distribution between NALP1 and NALP3 is observed because NALP1 is localized mainly in the nucleus, whereas NALP3 is predominantly cytoplasmic. We propose that the presence of NALP3 in epithelial cells lining the oral and genital tracts allows the rapid sensing of invading pathogens, thereby triggering an innate immune response.

Objective. Mevalonate kinase deficiency (MKD) is an autosomal-recessive disorder characterized by recurring episodes of inflammation. MK catalyzes the phosphorylation of mevalonic acid, which is an early step in isoprenoid biosynthesis. The goal of our study was to determine whether a temporary shortage of certain isoprenoid end products and/or the accumulation of mevalonic acid is the cause of interleukin-1␤ (IL-1␤) secretion in MKD.Methods. We studied the effect of the addition of intermediate metabolites and inhibitors of the isoprenoid biosynthesis pathway on IL-1␤ secretion by peripheral blood mononuclear cells (PBMCs) of patients with MKD and healthy controls.Results. Inhibition of enzymes involved in geranylgeranyl pyrophosphate (GGPP) synthesis or geranylgeranylation of proteins led to a marked increase of lipopolysaccharide-stimulated IL-1␤ secretion in PBMCs of control subjects. Furthermore, the increased IL-1␤ secretion by PBMCs of patients with MKD was reversed by supplementation with GGPP as well as with mevalonic acid. IL-1␤ secretion was increased only when control PBMCs were incubated with excessive amounts of mevalonic acid. Finally, a reduction in IL-1␤ secretion by MKD PBMCs was also observed when sterol biosynthesis was inhibited, favoring nonsterol isoprenoid biosynthesis. Conclusion.Our results indicate that a shortage of geranylgeranylated proteins, rather than an excess of mevalonate, is likely to cause increased IL-1␤ secretion by PBMCs of patients with MKD.

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On-demand treatment with anakinra in HIDS decreases the duration and severity of fever attacks. Because of the burden of daily injections and relatively long asymptomatic intervals of HIDS, all patients with HIDS preferred on-demand treatment.

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