TY - JOUR
T1 - Recessive NLRC4-autoinflammatory disease reveals an ulcerative colitis locus
AU - Steiner, Annemarie
AU - Reygaerts, Thomas
AU - Pontillo, Alessandra
AU - Ceccherini, Isabella
AU - Moecking, Jonas
AU - Moghaddas, Fiona
AU - Davidson, Sophia
AU - Caroli, Francesco
AU - Grossi, Alice
AU - Morato Castro, Fabio Fernandes
AU - Kalil, Jorge
AU - Gohr, Florian N.
AU - Schmidt, Florian
AU - Bartok, Eva
AU - Zillinger, Thomas
AU - Hartmann, Gunther
AU - Geyer, Matthias
AU - Gattorno, Marco
AU - Mendonca, Leonardo Oliveira
AU - Masters, Seth L.
N1 - FTX; OGOA; (CC BY 4.0)
PY - 2021
Y1 - 2021
N2 - 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.
AB - 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.
KW - NLRC4-associated autoinflammatory disease
KW - inflammasome
KW - ulcerative colitis
KW - CAUSES AUTOINFLAMMATION
KW - NLRC4 CAUSES
KW - MUTATION
KW - RECRUITMENT
KW - NLRP3
U2 - 10.1007/s10875-021-01175-4
DO - 10.1007/s10875-021-01175-4
M3 - A1: Web of Science-article
SN - 0271-9142
VL - 42
SP - 325
EP - 335
JO - Journal of Clinical Immunology
JF - Journal of Clinical Immunology
ER -