SOCS1 Haploinsufficiency in a Patient with Granulomatous Interstitial Lung Disease and Inflammatory Bowel Disease-like Disease.

IF 3.8 3区医学 Q3 IMMUNOLOGY

Clinical and experimental immunology Pub Date : 2026-05-08 DOI:10.1093/cei/uxag023

Gamze Sonmez, Ismail Yaz, Ceren Ustun, Ali Şahin, Gulnar Aliyeva, Elif Babaoglu, Guzin Özden, Sevil Oskay Halacli, Deniz Cagdas

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引用次数: 0

Abstract

Introduction: SOCS1 haploinsufficiency is an inborn error of immunity with dysregulated JAK-STAT signaling and heterogeneous autoimmune, infectious, and inflammatory phenotypes; its spectrum and management remain unclear.

Methods: We report a 29-year-old woman with a novel heterozygous SOCS1 variant (c.494C>T; p.Pro165Arg) identified by whole-exome sequencing. Variant impact was assessed in silico (CADD, conservation mapping, AlphaFold3, PremPS) and functionally by measuring total and phosphorylated STAT1 expression in patient vs control cells at baseline and after IFN-γ stimulation. We also reviewed data from 20 previously reported SOCS1-deficient patients.

Results: The patient had granulomatous lymphocytic interstitial lung disease (GLILD), rheumatoid arthritis, IBD-like enteropathy, and hypogammaglobulinemia, initially diagnosed with CVID. GLILD responded to rituximab; sirolimus was ineffective for enteropathy. Segregation revealed an asymptomatic father carrying the same variant. The patient was found to have an additional heterozygous TACI gene variant. Post-stimulation flow cytometry showed higher STAT1 (24.7 vs 5.8 MFI) and p-STAT1 (43.4 vs 2.4 MFI) levels; however, these differences were not statistically significant (p>0.05). Structural modeling predicted SH2-domain destabilization (ΔΔG +1.16 kcal/mol). Literature synthesis for SOCS1 deficiency patients (n=21) showed median symptom onset of 8 years (range 5 months-44 years), autoimmune diseases (immune thrombocytopenia, psoriasis, etc.), and frequent immunophenotypic abnormalities: lymphopenia 4/8 (50%); high IgE 5/7 (71.4%); low CD3+ 11/17 (64.7%); CD4+ 6/19 (31.5%); CD8+ 5/17 (29.4%); B cells 5/17 (29.4%); and NK cells 4/19 (21%).

Conclusion: SOCS1 haploinsufficiency presents heterogeneous phenotypes with variable penetrance. Early genetic testing and targeted interventions, such as JAK inhibitors or cytokine-blocking biologics, may improve outcomes.

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肉芽肿性间质性肺疾病和炎症性肠病样疾病患者的SOCS1单倍性不全

SOCS1单倍体功能不全是一种先天性免疫错误，伴有JAK-STAT信号失调和异质自身免疫、感染和炎症表型；其业务范围和管理仍不明朗。方法：我们报告了一名29岁女性，通过全外显子组测序鉴定出一种新的杂合SOCS1变异（c.494C>T; p.Pro165Arg）。通过计算机（CADD，保守图谱，AlphaFold3, PremPS）评估变异影响，并通过测量患者与对照细胞在基线和IFN-γ刺激后的总和磷酸化STAT1表达来功能上评估变异影响。我们还回顾了20例先前报道的socs1缺陷患者的数据。结果：患者有肉芽肿性淋巴细胞间质性肺疾病（GLILD）、类风湿性关节炎、ibd样肠病和低γ球蛋白血症，最初诊断为CVID。GLILD对利妥昔单抗有反应；西罗莫司对肠病无效。分离显示一个无症状的父亲携带相同的变异。患者被发现有一个额外的杂合TACI基因变异。刺激后流式细胞术显示较高的STAT1 （24.7 vs 5.8 MFI）和p-STAT1 （43.4 vs 2.4 MFI）水平；但差异无统计学意义（p < 0.05）。结构模型预测sh2结构域失稳（ΔΔG +1.16 kcal/mol）。SOCS1缺乏症患者（n=21）的文献综合显示，中位症状发作时间为8年（范围5个月-44年），伴有自身免疫性疾病（免疫性血小板减少症、牛皮癣等），免疫表型异常频繁：淋巴细胞减少4/8 (50%)；IgE 5/7高（71.4%）；CD3+ 11/17低（64.7%）；Cd4 + 6/19 (31.5%)；Cd8 + 5/17 (29.4%)；B细胞5/17 (29.4%)；NK细胞4/19（21%）。结论：SOCS1单倍不足表现为异质表型，外显率不同。早期基因检测和有针对性的干预，如JAK抑制剂或细胞因子阻断生物制剂，可能会改善结果。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Clinical and experimental immunology 医学-免疫学

CiteScore

8.40

自引率

2.20%

发文量

101

审稿时长

3-8 weeks

期刊介绍： Clinical & Experimental Immunology (established in 1966) is an authoritative international journal publishing high-quality research studies in translational and clinical immunology that have the potential to transform our understanding of the immunopathology of human disease and/or change clinical practice. The journal is focused on translational and clinical immunology and is among the foremost journals in this field, attracting high-quality papers from across the world. Translation is viewed as a process of applying ideas, insights and discoveries generated through scientific studies to the treatment, prevention or diagnosis of human disease. Clinical immunology has evolved as a field to encompass the application of state-of-the-art technologies such as next-generation sequencing, metagenomics and high-dimensional phenotyping to understand mechanisms that govern the outcomes of clinical trials.