Insights into the expanding intestinal phenotypic spectrum of SOCS1 haploinsufficiency and therapeutic options

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:CD16^lo:CD16^hi 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.

Keywords: Autoimmune enteropathy; JAK inhibition; JAK-STAT; SOCS1 haploinsufficiency.

Fig. 1

Disease timeline and treatment strategies. A P1 was initially treated by infliximab (anti-TNF-α) and after relapse by ustekinumab (anti-IL-12/IL-23). B P2 was initially treated with systemic steroids. Ruxolitinib was introduced after SOCS1 diagnosis. A single asterisk (*) indicates a blood sampling before and after 1 year of treatment

Fig. 2

SOCS1 variants in patients with intestinal manifestations. A Pedigree showing segregation of heterozygous SOCS1 variants. Affected individuals are represented by a filled circle. B Domain structure of SOCS1. C SOCS1 expression in HEK293T cells overexpressing SOCS1-WT and mutant alleles. The pPURO-FLAG-HA-EGFP (6104bp) plasmid served as transfection control. D Schematic representation of JAK-STAT signaling. A single asterisk (*) indicates members encoded by genes previously associated with intestinal monogenic disorders. E p-STAT1 in EBV-LCLs from a healthy control and P1 stimulated with IFN-γ (10³ IU/ml for 20 min) with or without 200 μM ruxolitinib. Data are representative of 2 independent experiments

Fig. 3

Resolution of P2’s CIPO by ruxolitinib treatment. A Image CT scan, histology of lymphocytic intestinal leiomyositis in surgical specimens HES staining (scale bar= 900 μm or 100 μm) and immunohistochemistry staining of CD3⁺, CD8⁺, GzB⁺ lymphocytes before and after 3 months of ruxolitinib (R) (scale bar=100 μm). B Quantitative PCR analysis of indicated cytokines in P2’s duodenum before (pre-R) and after 3 months ruxolitinib (post-R). C Heatmap of plasma inflammatory cytokines in P2 before (pre-R) and after 1 year ruxolitinib (post-R)