An Autoinflammatory Disease with Deficiency of the Interleukin-1-Receptor Antagonist

National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, MD 20892, USA.
New England Journal of Medicine (Impact Factor: 54.42). 07/2009; 360(23):2426-37. DOI: 10.1056/NEJMoa0807865
Source: PubMed

ABSTRACT Autoinflammatory diseases manifest inflammation without evidence of infection, high-titer autoantibodies, or autoreactive T cells. We report a disorder caused by mutations of IL1RN, which encodes the interleukin-1-receptor antagonist, with prominent involvement of skin and bone.
We studied nine children from six families who had neonatal onset of sterile multifocal osteomyelitis, periostitis, and pustulosis. Response to empirical treatment with the recombinant interleukin-1-receptor antagonist anakinra in the first patient prompted us to test for the presence of mutations and changes in proteins and their function in interleukin-1-pathway genes including IL1RN.
We identified homozygous mutations of IL1RN in nine affected children, from one family from Newfoundland, Canada, three families from The Netherlands, and one consanguineous family from Lebanon. A nonconsanguineous patient from Puerto Rico was homozygous for a genomic deletion that includes IL1RN and five other interleukin-1-family members. At least three of the mutations are founder mutations; heterozygous carriers were asymptomatic, with no cytokine abnormalities in vitro. The IL1RN mutations resulted in a truncated protein that is not secreted, thereby rendering cells hyperresponsive to interleukin-1beta stimulation. Patients treated with anakinra responded rapidly.
We propose the term deficiency of the interleukin-1-receptor antagonist, or DIRA, to denote this autosomal recessive autoinflammatory disease caused by mutations affecting IL1RN. The absence of interleukin-1-receptor antagonist allows unopposed action of interleukin-1, resulting in life-threatening systemic inflammation with skin and bone involvement. ( number, NCT00059748.)

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    • "The activation of inflammatory responses and immunity by ILRs or TLRs signaling is tightly regulated at different levels. For instance, IL-1Ra and IL-36Ra are polypeptide antagonists for IL-1RI and IL-1Rrp2, respectively (Towne et al., 2004; Costelloe et al., 2008; Aksentijevich et al., 2009; Dinarello, 2009; Reddy et al., 2009). Decoy receptors , such as IL-1RII, bind ligands that are no longer available for the transducing receptors or form dominant negative nonsignaling complexes with AcPs (Mantovani et al., 2001). "
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