Abstract
34 Mutations in the interleukin-1 receptor antagonist cause a new autoinflammatory disease
Cytokine (Philadelphia, Pa.), Vol.43(3), pp.244-245
09/2008
DOI: 10.1016/j.cyto.2008.07.075
Abstract
Two patients presented as neonates with a previously unrecognized syndrome characterized by multifocal osteomyelitis, periosteitis and pustulosis. A very rapid and dramatic recovery was observed upon initiation of an empiric trial of treatment with anakinra (recombinant human interleukin-1 receptor antagonist, IL-1Rα). For this reason we sequenced the gene encoding IL-1Rα and in fact found that these two unrelated patients have unique homozygous mutations that result in premature truncation of the IL-1Rα protein (N52KfsX25 and E77X). The 25 amino acid leader sequence of IL-1Rα is normally cleaved when the cytokine is secreted, however when the mutant protein is overexpressed in vitro, it is only detected intracellularly with the leader sequence still attached and no mutant protein is secreted. Furthermore cells from the patient with the N52KfsX25 mutation did not secrete IL-1Rα, and mutant protein was not detected in serum. This was consistent with a very low RNA expression of the mutant gene in patient leukocytes. The loss of IL-1Rα has a pronounced effect on IL-1 signaling ex vivo, as shown by the increased number of patient T-cells that proliferate when in co-culture with autologous monocytes than compared to controls. We also find that patient’s leukocytes are hyper-responsive to stimulation with IL-1β, resulting in increased expression of the pro-inflammatory cytokines TNF-α, MCP-1, MIP-1α, MIP-1β, IL-6 and IL-8. This reveals signaling pathways that are likely to cause the inflammation and neutrophil activation that lead to osteolytic bone lesions and skin pustulosis as observed in this disease. This also implicates the IL-1 pathway in other conditions that present with these disease manifestations, and highlights the critical physiological requirement of IL-1Rα to control IL-1 mediated inflammation in vivo. We therefore suggest a novel nomenclature for this clinical entity, DIRA, as an autoinflammatory disease that results from deficiency of the interleukin-1 receptor antagonist.
Details
- Title: Subtitle
- 34 Mutations in the interleukin-1 receptor antagonist cause a new autoinflammatory disease
- Creators
- Seth L Masters - Genetics and Genomics Branch, Bethesda, MD, USAIvona Aksentijevich - Genetics and Genomics Branch, Bethesda, MD, USAPolly J Ferguson - Department of Pediatrics, University of Iowa, Iowa City, IA, USAMatthew G Booty - Genetics and Genomics Branch, Bethesda, MD, USAArian Laurence - Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, MD, USAHang Pham - Office of the Clinical Director, Bethesda, MD, USADeborah L Stone - Office of the Clinical Director, Bethesda, MD, USAEdward W Cowen - Dermatology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USANicole Plass - Office of the Clinical Director, Bethesda, MD, USAXinyu Bing - Department of Pediatrics, University of Iowa, Iowa City, IA, USAGillian I Clarke - Division of Dermatology, Eastern Health, St Johns, Nfld, CanadaKamal Ohson - Department of Medicine, Memorial University of Newfoundland, Nfld, CanadaHatem I El-Shanti - Department of Pediatrics, University of Iowa, Iowa City, IA, USAAnnet van Royen - Department of General Pediatrics, Division of Pediatrics, University Medical Center, Utrecht, The NetherlandsJoost Frenk - Department of Pediatrics, Nfld, Canada
- Resource Type
- Abstract
- Publication Details
- Cytokine (Philadelphia, Pa.), Vol.43(3), pp.244-245
- Publisher
- Elsevier Ltd
- DOI
- 10.1016/j.cyto.2008.07.075
- ISSN
- 1043-4666
- eISSN
- 1096-0023
- Language
- English
- Date published
- 09/2008
- Academic Unit
- Critical Care; Medical Genetics and Genomics; Iowa Neuroscience Institute; Stead Family Department of Pediatrics; Rheumatology, Allergy, and Immunology
- Record Identifier
- 9984071729102771
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