Université Paris-Cité, Institut Imagine, Laboratory of Intestinal Immunity, INSERM U1163, Paris, France.
Department of Pathology, Beaujon Hospital, Assistance Publique-Hôpitaux de Paris, Clichy, France.
J Clin Immunol. 2023 Aug;43(6):1403-1413. doi: 10.1007/s10875-023-01495-7. Epub 2023 May 9.
Hyper activation of the JAK-STAT signaling underlies the pathophysiology of many human immune-mediated diseases. Herein, the study of 2 adult patients with SOCS1 haploinsufficiency illustrates the severe and pleomorphic consequences of its impaired regulation in the intestinal tract.
Two unrelated adult patients presented with gastrointestinal manifestations, one with Crohn's disease-like ileo-colic inflammation refractory to anti-TNF and the other with lymphocytic leiomyositis causing severe chronic intestinal pseudo-occlusion. Next-generation sequencing was used to identify the underlying monogenic defect. One patient received anti-IL-12/IL-23 treatment while the other received the JAK1 inhibitor, ruxolitinib. Peripheral blood, intestinal tissues, and serum samples were analyzed before-and-after JAK1 inhibitor therapy using mass cytometry, histology, transcriptomic, and Olink assay.
Novel germline loss-of-function variants in SOCS1 were identified in both patients. The patient with Crohn-like disease achieved clinical remission with anti-IL-12/IL-23 treatment. In the second patient with lymphocytic leiomyositis, ruxolitinib induced rapid resolution of the obstructive symptoms, significant decrease of the CD8+ T lymphocyte muscular infiltrate, and normalization of serum and intestinal cytokines. Decreased frequencies of circulating Treg cells, MAIT cells, and NK cells, with altered CD56:CD16:CD16 NK subtype ratios were not modified by ruxolitinib.
SOCS1 haploinsufficiency can result in a broad spectrum of intestinal manifestations and need to be considered as differential diagnosis in cases of severe treatment-refractory enteropathies, including the rare condition of lymphocytic leiomyositis. This provides the rationale for genetic screening and considering JAK inhibitors in such cases.
JAK-STAT 信号的过度激活是许多人类免疫介导疾病的病理生理学基础。本文通过研究 2 例 SOCS1 杂合功能缺失的成年患者，阐明了其在肠道调节受损时所导致的严重和多形性后果。
2 例无关联的成年患者均以胃肠道表现为首发症状，其中 1 例表现为克罗恩病样回结肠炎症，对 TNF 拮抗剂治疗无效，另 1 例表现为淋巴细胞性平滑肌瘤导致严重慢性肠道假性梗阻。采用下一代测序技术鉴定潜在的单基因缺陷。1 例患者接受抗 IL-12/IL-23 治疗，另 1 例患者接受 JAK1 抑制剂鲁索利替尼治疗。在接受 JAK1 抑制剂治疗前后，通过质谱流式细胞术、组织学、转录组学和 Olink 检测分析患者外周血、肠道组织和血清样本。
在这 2 例患者中均发现了 SOCS1 的新型种系失功能变异。患有类克罗恩病的患者接受抗 IL-12/IL-23 治疗后达到临床缓解。在另 1 例患有淋巴细胞性平滑肌瘤的患者中，鲁索利替尼迅速缓解了梗阻症状，显著减少了 CD8+T 淋巴细胞的肌内浸润，并使血清和肠道细胞因子恢复正常。鲁索利替尼未能改变循环 Treg 细胞、MAIT 细胞和 NK 细胞的频率，以及改变 CD56:CD16:CD16 NK 亚型的比例。
SOCS1 杂合功能缺失可导致广泛的肠道表现，在严重治疗抵抗性肠病，包括罕见的淋巴细胞性平滑肌瘤的情况下，需要考虑作为鉴别诊断。这为在这种情况下进行基因筛查和考虑 JAK 抑制剂提供了依据。
