Universität zu Köln

Steiner, Annemarie, Reygaerts, Thomas, Pontillo, Alessandra, Ceccherini, Isabella, Moecking, Jonas, Moghaddas, Fiona, Davidson, Sophia, Caroli, Francesco ORCID: 0000-0003-1828-6900, Grossi, Alice, Morato Castro, Fabio Fernandes, Kalil, Jorge, Gohr, Florian N., Schmidt, Florian, I, Bartok, Eva ORCID: 0000-0003-0556-1950, Zillinger, Thomas, Hartmann, Gunther, Geyer, Matthias, Gattorno, Marco, Mendonca, Leonardo Oliveira and Masters, Seth L. (2022). Recessive NLRC4-Autoinflammatory Disease Reveals an Ulcerative Colitis Locus. J. Clin. Immunol., 42 (2). S. 325 - 336. NEW YORK: SPRINGER/PLENUM PUBLISHERS. ISSN 1573-2592

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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-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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Steiner, Annemarie UNSPECIFIED UNSPECIFIED UNSPECIFIED Reygaerts, Thomas UNSPECIFIED UNSPECIFIED UNSPECIFIED Pontillo, Alessandra UNSPECIFIED UNSPECIFIED UNSPECIFIED Ceccherini, Isabella UNSPECIFIED UNSPECIFIED UNSPECIFIED Moecking, Jonas UNSPECIFIED UNSPECIFIED UNSPECIFIED Moghaddas, Fiona UNSPECIFIED UNSPECIFIED UNSPECIFIED Davidson, Sophia UNSPECIFIED UNSPECIFIED UNSPECIFIED Caroli, Francesco UNSPECIFIED orcid.org/0000-0003-1828-6900 UNSPECIFIED Grossi, Alice UNSPECIFIED UNSPECIFIED UNSPECIFIED Morato Castro, Fabio Fernandes UNSPECIFIED UNSPECIFIED UNSPECIFIED Kalil, Jorge UNSPECIFIED UNSPECIFIED UNSPECIFIED Gohr, Florian N. UNSPECIFIED UNSPECIFIED UNSPECIFIED Schmidt, Florian, I UNSPECIFIED UNSPECIFIED UNSPECIFIED Bartok, Eva UNSPECIFIED orcid.org/0000-0003-0556-1950 UNSPECIFIED Zillinger, Thomas UNSPECIFIED UNSPECIFIED UNSPECIFIED Hartmann, Gunther UNSPECIFIED UNSPECIFIED UNSPECIFIED Geyer, Matthias UNSPECIFIED UNSPECIFIED UNSPECIFIED Gattorno, Marco UNSPECIFIED UNSPECIFIED UNSPECIFIED Mendonca, Leonardo Oliveira UNSPECIFIED UNSPECIFIED UNSPECIFIED Masters, Seth L. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-600943
DOI:	10.1007/s10875-021-01175-4
Journal or Publication Title:	J. Clin. Immunol.
Volume:	42
Number:	2
Page Range:	S. 325 - 336
Date:	2022
Publisher:	SPRINGER/PLENUM PUBLISHERS
Place of Publication:	NEW YORK
ISSN:	1573-2592
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language CAUSES AUTOINFLAMMATION; NLRC4 CAUSES; MUTATION; RECRUITMENT; NLRP3 Multiple languages Immunology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/60094