ecessive NLRC4-Autoinflammatory Disease Reveals an Ulcerative Colitis Locu

Author(s):Show less -

Steiner, Annemarie ^{[1, 2, 3]} ; Reygaerts, Thomas ^{[1, 2]} ; Pontillo, Alessandra ^[4] ; Ceccherini, Isabella ^[5] ; Moecking, Jonas ^{[1, 2, 3]} ; Moghaddas, Fiona ^{[1, 2, 6]} ; Davidson, Sophia ^{[1, 2]} ; Caroli, Francesco ^[5] ; Grossi, Alice ^[5] ; Morato Castro, Fabio Fernandes ^[7] ; Kalil, Jorge ^[7] ; Gohr, Florian N. ^{[8, 9]} ; Schmidt, I, Florian ; Bartok, Eva ^{[10, 11]} ; Zillinger, Thomas ^{[10, 12]} ; Hartmann, Gunther ^{[10, 13]} ; Geyer, Matthias ^[3] ; Gattorno, Marco ^[14] ; Mendonca, Leonardo Oliveira ^{[4, 5, 7, 14, 15]} ; Masters, Seth L. ^{[1, 2]}

Affiliation:Show less -

^[1] Walter & Eliza Hall Inst Med Res, Inflammat Div, 1G Royal Parade, Parkville, Vic 3052 - Australia

^[2] Univ Melbourne, Dept Med Biol, Parkville, Vic 3010 - Australia

^[3] Univ Bonn, Med Fac, Inst Struct Biol, D-53127 Bonn - Germany

^[4] Univ Sao Paulo, Biomed Sci Inst, Dept Immunol, Immunogenet Lab, Sao Paulo - Brazil

^[5] IRCCS Ist Giannina Gaslini, Lab Genet & Genom Rare Dis, I-16147 Genoa - Italy

^[6] Royal Melbourne Hosp, Dept Clin Immunol & Allergy, Parkville, Vic 3052 - Australia

^[7] Univ Sao Paulo, Dept Internal Med, Div Clin Immunol & Allergy, Sao Paulo - Brazil

^[8] I, Univ Bonn, Med Fac, Inst Innate Immun, D-53127 Bonn - Germany

^[9] Univ Melbourne, Dept Microbiol & Immunol, Parkville, Vic 3010 - Australia

^[10] Univ Hosp Bonn, Inst Clin Chem & Clin Pharmacol, D-53127 Bonn - Germany

^[11] Inst Trop Med, Dept Biomed Sci, Unit Expt Immunol, Antwerp - Belgium

^[12] Philipps Univ Marburg, Inst Immunol, BMFZ, D-35043 Marburg - Germany

^[13] German Ctr Infect Res DZIF, Partner Site Bonn Cologne, Cologne - Germany

^[14] IRCCS Ist Giannina Gaslini, Ctr Autoinflammatory Dis & Primary Immunodeficien, I-16147 Genoa - Italy

^[15] DASA Hosp 9 Julho, Ctr Rare & Immunol Disorders, Sao Paulo - Brazil

• Document type: Journal article
• Source: JOURNAL OF CLINICAL IMMUNOLOGY; v. 42, n. 2 NOV 2021.
• Web of Science Citations: 0

Abstract

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-1 beta/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-1 beta therapy partially controlled symptoms. While on treatment, serum IL-1 beta 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-1 beta/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. (AU)

• FAPESP's process: 15/50650-7 - Characterization of novel molecular players in the control of obesity and obesity-induced inflammation
• Grantee: Alessandra Pontillo
• Support Opportunities: Regular Research Grants
• FAPESP's process: 15/23395-6 - Immunogenetics of the inflammasome and translational study "from bed to bench and back": analysis of variations in inflammasome genes in monogenic and multifactorial autoinflammatory diseases for differential diagnosis and therapeutic applications
• Grantee: Alessandra Pontillo
• Support Opportunities: Regular Research Grants