Recessive NLRC4-Autoinflammatory Disease Reveals an Ulcerative Colitis Locus.

Jorge Kalil, Seth L Masters, Leonardo Oliveira Mendonça, Marco Gattorno, Matthias Geyer, Gunther Hartmann, Thomas Zillinger, Eva Bartok, Florian I Schmidt, Florian N Gohr, Annemarie Steiner, Fabio Fernandes Morato Castro, Alice Grossi, Francesco Caroli, Sophia Davidson, Fiona Moghaddas, Jonas Moecking, Isabella Ceccherini, Alessandra Pontillo, Thomas Reygaerts

Journal: Journal of clinical immunology 2022;42(2):325-335

PMID: 34783940

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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-1β/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-1β therapy partially controlled symptoms. While on treatment, serum IL-1β 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-1β/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.

Address: Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC, 3052, Australia.; Department of Medical Biology, The University of Melbourne, Parkville, VIC, 3010, Australia.; Institute of Structural Biology, Medical Faculty, University of Bonn, 53127, Bonn, Germany.; Immunogenetic Laboratory, Department of Immunology, Biomedical Science Institute, Universidade of São Paulo, São Paulo, Brazil.; Laboratory of Genetics and Genomics of Rare Diseases, IRCCS Istituto Giannina Gaslini, 16147, Genoa, Italy.; Department of Clinical Immunology and Allergy, The Royal Melbourne Hospital, Parkville, VIC, 3052, Australia.; Division of Clinical Immunology and Allergy, Department of Internal Medicine, Universidade of São Paulo, São Paulo, Brazil.; Institute of Innate Immunity, Medical Faculty, University of Bonn, 53127, Bonn, Germany.; Department of Microbiology and Immunology, The University of Melbourne, Parkville, VIC, 3010, Australia.; Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, 53127, Bonn, Germany.; Unit of Experimental Immunology, Department of Biomedical Sciences, Institute of Tropical Medicine, Antwerp, Belgium.; Institute of Immunology, Philipps-University Marburg, BMFZ, 35043, Marburg, Germany.; German Center for Infection Research (DZIF), Partner Site Bonn-Cologne, Cologne, Germany.; Center for Autoinflammatory Diseases and Primary Immunodeficiencies, IRCCS Istituto Giannina Gaslini, 16147, Genoa, Italy.; Center for Rare and Immunological Disorders, DASA-Hospital 9 de Julho, São Paulo, Brazil.; Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC, 3052, Australia. [email protected].; Department of Medical Biology, The University of Melbourne, Parkville, VIC, 3010, Australia. [email protected].

DOI: 10.1007/s10875-021-01175-4