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Recessive NLRC4-Autoinflammatory Disease Reveals an Ulcerative Colitis Locus.
Steiner, Annemarie; Reygaerts, Thomas; Pontillo, Alessandra; Ceccherini, Isabella; Moecking, Jonas; Moghaddas, Fiona; Davidson, Sophia; Caroli, Francesco; Grossi, Alice; Castro, Fabio Fernandes Morato; Kalil, Jorge; Gohr, Florian N; Schmidt, Florian I; Bartok, Eva; Zillinger, Thomas; Hartmann, Gunther; Geyer, Matthias; Gattorno, Marco; Mendonça, Leonardo Oliveira; Masters, Seth L.
Afiliación
  • Steiner A; Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC, 3052, Australia.
  • Reygaerts T; Department of Medical Biology, The University of Melbourne, Parkville, VIC, 3010, Australia.
  • Pontillo A; Institute of Structural Biology, Medical Faculty, University of Bonn, 53127, Bonn, Germany.
  • Ceccherini I; Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC, 3052, Australia.
  • Moecking J; Department of Medical Biology, The University of Melbourne, Parkville, VIC, 3010, Australia.
  • Moghaddas F; Immunogenetic Laboratory, Department of Immunology, Biomedical Science Institute, Universidade of São Paulo, São Paulo, Brazil.
  • Davidson S; Laboratory of Genetics and Genomics of Rare Diseases, IRCCS Istituto Giannina Gaslini, 16147, Genoa, Italy.
  • Caroli F; Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC, 3052, Australia.
  • Grossi A; Department of Medical Biology, The University of Melbourne, Parkville, VIC, 3010, Australia.
  • Castro FFM; Institute of Structural Biology, Medical Faculty, University of Bonn, 53127, Bonn, Germany.
  • Kalil J; Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC, 3052, Australia.
  • Gohr FN; Department of Medical Biology, The University of Melbourne, Parkville, VIC, 3010, Australia.
  • Schmidt FI; Department of Clinical Immunology and Allergy, The Royal Melbourne Hospital, Parkville, VIC, 3052, Australia.
  • Bartok E; Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC, 3052, Australia.
  • Zillinger T; Department of Medical Biology, The University of Melbourne, Parkville, VIC, 3010, Australia.
  • Hartmann G; Laboratory of Genetics and Genomics of Rare Diseases, IRCCS Istituto Giannina Gaslini, 16147, Genoa, Italy.
  • Geyer M; Laboratory of Genetics and Genomics of Rare Diseases, IRCCS Istituto Giannina Gaslini, 16147, Genoa, Italy.
  • Gattorno M; Division of Clinical Immunology and Allergy, Department of Internal Medicine, Universidade of São Paulo, São Paulo, Brazil.
  • Mendonça LO; Division of Clinical Immunology and Allergy, Department of Internal Medicine, Universidade of São Paulo, São Paulo, Brazil.
  • Masters SL; Institute of Innate Immunity, Medical Faculty, University of Bonn, 53127, Bonn, Germany.
J Clin Immunol ; 42(2): 325-335, 2022 02.
Article en En | MEDLINE | ID: mdl-34783940
PURPOSE: NLRC4-associated autoinflammatory disease (NLRC4-AID) is an autosomal dominant condition presenting with a range of clinical manifestations which can include macrophage activation syndrome (MAS) and severe enterocolitis. We now report the first homozygous mutation in NLRC4 (c.478G > A, p.A160T) causing autoinflammatory disease with immune dysregulation and find that heterozygous carriers in the general population are at increased risk of developing ulcerative colitis. METHODS: Circulating immune cells and inflammatory markers were profiled and historical clinical data interrogated. DNA was extracted and sequenced using standard procedures. Inflammasome activation assays for ASC speck formation, pyroptosis, and IL-1ß/IL-18 secretion confirmed pathogenicity of the mutation in vitro. Genome-wide association of NLRC4 (A160T) with ulcerative colitis was examined using data from the IBD exomes portal. RESULTS: A 60-year-old Brazilian female patient was evaluated for recurrent episodes of systemic inflammation from six months of age. Episodes were characterized by recurrent low-grade fever, chills, oral ulceration, uveitis, arthralgia, and abdominal pain, followed by diarrhea with mucus and variable skin rash. High doses of corticosteroids were somewhat effective in controlling disease and anti-IL-1ß therapy partially controlled symptoms. While on treatment, serum IL-1ß and IL-18 levels remained elevated. Genetic investigations identified a homozygous mutation in NLRC4 (A160T), inherited in a recessive fashion. Increased ASC speck formation and IL-1ß/IL-18 secretion confirmed pathogenicity when NLRC4 (A160T) was analyzed in human cell lines. This allele is significantly enriched in patients with ulcerative colitis: OR 2.546 (95% 1.778-3.644), P = 0.01305. CONCLUSION: NLRC4 (A160T) can either cause recessively inherited autoinflammation and immune dysregulation, or function as a heterozygous risk factor for the development of ulcerative colitis.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Colitis Ulcerosa / Enfermedades Autoinflamatorias Hereditarias Tipo de estudio: Diagnostic_studies / Prognostic_studies / Risk_factors_studies Límite: Female / Humans / Middle aged Idioma: En Revista: J Clin Immunol Año: 2022 Tipo del documento: Article País de afiliación: Australia Pais de publicación: Países Bajos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Colitis Ulcerosa / Enfermedades Autoinflamatorias Hereditarias Tipo de estudio: Diagnostic_studies / Prognostic_studies / Risk_factors_studies Límite: Female / Humans / Middle aged Idioma: En Revista: J Clin Immunol Año: 2022 Tipo del documento: Article País de afiliación: Australia Pais de publicación: Países Bajos