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.
J Clin Immunol. 2022 Feb;42(2):325-335. doi: 10.1007/s10875-021-01175-4. Epub 2021 Nov 16.
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.
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.
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.
NLRC4 (A160T) can either cause recessively inherited autoinflammation and immune dysregulation, or function as a heterozygous risk factor for the development of ulcerative colitis.
NLRC4 相关自身炎症性疾病（NLRC4-AID）是一种常染色体显性遗传病，其临床表现多样，包括巨噬细胞活化综合征（MAS）和严重肠炎。我们现报道首例 NLRC4 纯合突变（c.478G > A，p.A160T）导致自身炎症性疾病伴免疫失调，并发现该突变的杂合携带者在普通人群中溃疡性结肠炎的发病风险增加。
分析循环免疫细胞和炎症标志物，调查既往临床数据。采用标准方法提取和测序 DNA。体外采用 ASC 斑点形成、细胞焦亡和 IL-1β/IL-18 分泌测定法验证该突变的致病性。采用 IBD 外显子组门户的数据，对 NLRC4（A160T）与溃疡性结肠炎的全基因组关联进行研究。
一名 60 岁的巴西女性患者从 6 个月大时开始出现反复发作的全身炎症。发作时表现为反复发作的低热、寒战、口腔溃疡、葡萄膜炎、关节炎和腹痛，随后出现伴有粘液的腹泻和多变的皮疹。大剂量皮质类固醇在一定程度上有效控制了疾病，抗 IL-1β 治疗部分缓解了症状。在治疗过程中，血清 IL-1β 和 IL-18 水平仍然升高。遗传研究发现 NLRC4 存在纯合突变（A160T），呈隐性遗传。在人细胞系中分析 NLRC4（A160T）时，ASC 斑点形成和 IL-1β/IL-18 分泌增加证实了其致病性。该等位基因在溃疡性结肠炎患者中显著富集：OR 2.546（95%CI 1.778-3.644），P=0.01305。
NLRC4（A160T）既可以导致隐性遗传的自身炎症和免疫失调，也可以作为溃疡性结肠炎发生的杂合风险因素。
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