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: 55.87). 07/2009; 360(23):2426-37. DOI: 10.1056/NEJMoa0807865
Source: PubMed


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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    • "We indeed found that high circulating IL-6 levels are present during active disease. In vivo, neutralization of excessive IL-1β in cryopyrinopathies and in deficiency of interleukin-1 receptor antagonist (DIRA) results in decrease in IL-6 production [10-12]. "
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    ABSTRACT: Background This study aims to investigate the inflammasome response in peripheral blood mononuclear cells (PBMCs) and the expression of inflammasome components in bone biopsies from patients with chronic recurrent multifocal osteomyelitis (CRMO). Methods The expression of inflammasome components mRNAs was evaluated in PBMCs isolated from 15 CRMO patients and 13 healthy controls by quantitative real-time PCR. The Interleukin (IL)-1β released in the medium of PBMC cultures after treatment with lipopolysaccharides (LPS) alone or LPS and ATP was measured by ELISA. Immunohistochemical staining for Apoptosis-associated Speck-like protein (ASC), caspase-1 (CASP-1), Nod-like receptor protein-3 (NLRP3) and IL-1β expression was performed in bone biopsies from CRMO patients. Results mRNA levels of ASC, CASP-1 and IL-1β were significantly higher in freshly isolated PBMCs from CRMO patients in active disease than in healthy controls. CASP-1 and IL-1β transcript levels were significantly higher also in PBMCs from CRMO patients in remission compared to healthy controls. PBMCs from CRMO patients in active disease stimulated in vitro with LPS showed a significant increase in IL-1β release compared to healthy control cells. Immunohistochemistry staining of bone tissue revealed the expression of inflammasome components in CRMO osteoclasts. Conclusions Our data suggest that an abnormal regulation of IL-1β axis may be involved in CRMO pathogenesis.
    Full-text · Article · Jul 2014 · Pediatric Rheumatology
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    • "Deficiency of the IL-1-receptor antagonist (DIRA) is an autosomal-recessive disorder secondary to homozygous missense and nonsense loss-of-function mutations in the IL1RN gene, located on the long arm of chromosome 2, which codifies the IL-1 receptor antagonist [120], physiologically antagonizing the effect of the proinflammatory cytokines IL-1α and IL-1β. Aksentijevich et al. identified IL1RN mutations in 9 individuals, all displaying an abnormal function of the IL-1 receptor antagonist protein and leading to uninhibited signaling of IL-1 [121]. This condition starts at birth and is characterized by multifocal osteomyelitis, periostitis with heterotopic nuclei of ossification, pustular, and/or ichthyosis skin lesions. "
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    ABSTRACT: The innate immune system is involved in the pathophysiology of systemic autoinflammatory diseases (SAIDs), an enlarging group of disorders caused by dysregulated production of proinflammatory cytokines, such as interleukin-1β and tumor necrosis factor-α, in which autoreactive T-lymphocytes and autoantibodies are indeed absent. A widely deranged innate immunity leads to overactivity of proinflammatory cytokines and subsequent multisite inflammatory symptoms depicting various conditions, such as hereditary periodic fevers, granulomatous disorders, and pyogenic diseases, collectively described in this review. Further research should enhance our understanding of the genetics behind SAIDs, unearth triggers of inflammatory attacks, and result in improvement for their diagnosis and treatment.
    Full-text · Article · Jul 2014 · Mediators of Inflammation
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    • "IL-1RA competitively binds to IL-1RI with IL-1 and thus decoys the inflammatory effects of IL-1. Deletion of IL-1RA leaves IL-1β unopposed and thus causes fetal inflammation systemically [154]. Under conditions with lung injury, IL-1 releases and triggers inflammation and IL-1RA releases to encounter this process. "
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    ABSTRACT: Obesity becomes pandemic, predisposing these individuals to great risk for lung injury. In this review, we focused on the anti-inflammatories and addressed the following aspects: adipocytokines and obesity, inflammation and other mechanisms, adipocytokines and lung injury in obesity bridged by inflammation, and potential therapeutic targets. To sum up, the majority of evidence supported that adiponectin, omentin, and secreted frizzled-related protein 5 (SFRP5) were reduced significantly in obesity, which is associated with increased inflammation, indicated by increase of TNF α and IL-6, through activation of toll-like receptor (TLR4) and nuclear factor light chain κ B (NF- κ B) signaling pathways. Administration of these adipocytokines promotes weight loss and reduces inflammation. Zinc- α 2-glycoprotein (ZAG), vaspin, IL-10, interleukin-1 receptor antagonist (IL-1RA), transforming growth factor β (TGF- β 1), and growth differentiation factor 15 (GDF15) are also regarded as anti-inflammatories. There were controversial reports. Furthermore, there is a huge lack of studies for obesity related lung injury. The effects of adiponectin on lung transplantation, asthma, chronic obstructive pulmonary diseases (COPD), and pneumonia were anti-inflammatory and protective in lung injury. Administration of IL-10 agonist reduces mortality of acute lung injury in rabbits with acute necrotizing pancreatitis, possibly through inhibiting proinflammation and strengthening host immunity. Very limited information is available for other adipocytokines.
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