1. Insights into the expanding intestinal phenotypic spectrum of SOCS1 haploinsufficiency and therapeutic options.
- Author
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Rodari, Marco M., Cazals-Hatem, Dominique, Uzzan, Mathieu, Martin Silva, Nicolas, Khiat, Anis, Ta, Minh Chau, Lhermitte, Ludovic, Touzart, Aurore, Hanein, Sylvain, Rouillon, Cléa, Joly, Francisca, Elmorjani, Adrienne, Steffann, Julie, Cerf-Bensussan, Nadine, Parlato, Marianna, and Charbit-Henrion, Fabienne
- Subjects
REGULATORY T cells ,INTESTINES ,KILLER cells ,T cells ,GENETIC testing ,ADRENAL insufficiency - Abstract
Purpose: 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. Methods: 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. Results: 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
bright :CD16lo :CD16hi NK subtype ratios were not modified by ruxolitinib. Conclusion: 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. [ABSTRACT FROM AUTHOR]- Published
- 2023
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