An Autoinflammatory Disease Due to Homozygous Deletion of the IL1RN Locus

Department of Pediatrics, Medical College of Wisconsin and the Children's Research Institute, Milwaukee 53201, USA.
New England Journal of Medicine (Impact Factor: 55.87). 07/2009; 360(23):2438-44. DOI: 10.1056/NEJMoa0809568
Source: PubMed


We describe a patient with an autoinflammatory disease in which the main clinical features are pustular rash, marked osteopenia, lytic bone lesions, respiratory insufficiency, and thrombosis. Genetic studies revealed a 175-kb homozygous deletion at chromosome 2q13, which encompasses several interleukin-1 family members, including the gene encoding the interleukin-1-receptor antagonist (IL1RN). Mononuclear cells, obtained from the patient and cultured, produced large amounts of inflammatory cytokines, with increasing amounts secreted after stimulation with lipopolysaccharide. A similar increase was not observed in peripheral-blood mononuclear cells from a patient with neonatal-onset multisystem inflammatory disorder (NOMID). Treatment with anakinra completely resolved the symptoms and lesions.

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Available from: Shuang Jia, Feb 25, 2014
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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]. "
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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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    • "DIRA is a severe autosomal recessive inherited disease caused by the homozygous loss-of-function mutations in IL1RN leading to the absence of IL-1 receptor antagonist production and subsequent IL-1 overactivity (Aksentijevich et al., 2009; Reddy et al., 2009). Clinically, DIRA manifests itself with perinatal-onset pustular dermatitis, joint swelling, painful osteolytic lesions, and periosteitis. "
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    ABSTRACT: During the past years, significant progress in the understanding of the complexity, regulation, and relevance of innate immune responses underlying several inflammatory conditions with neutrophilic skin involvement has been made. These diseases belong to the novel class of autoinflammatory diseases, and several are caused by mutations in genes regulating the function of innate immune complexes, termed inflammasomes, leading to enhanced secretion of the proinflammatory cytokine IL-1β. Consequently, targeting of IL-1β has proven successful in the treatment of these diseases, and the identification of related pathogenic mechanisms in other more common skin diseases characterized by autoinflammation and neutrophilic tissue damage also provides extended opportunities for therapy by interfering with IL-1 signaling.Journal of Investigative Dermatology advance online publication, 6 March 2014; doi:10.1038/jid.2014.76.
    Full-text · Article · Mar 2014 · Journal of Investigative Dermatology
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    • "Thus, while in CAPS the disease phenotype is mostly linked to hyperactivity of IL-1␤, in DIRA, especially at the skin level, also IL-1␣ could play a relevant role. DIRA, like CAPS, is exquisitely responsive to IL-1 blockade [13] [14], confirming the key role of IL-1/IL-1Ra axis unbalance in the pathophysiology of these syndromes. "
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