Abstract
In our previous study, we observed a severe reduction in the Src homology 2-containing-inositol-phosphatase-1 (SHIP1) protein in a subpopulation of subjects from a small adult Crohn’s Disease (CD) cohort. This pilot study had been undertaken since we had previously demonstrated that engineered deficiency of SHIP1 in mice results in a spontaneous and severe CD-like ileitis. Here, we extend our analysis of SHIP1 expression in peripheral blood mononuclear cells in a second much larger adult Inflammatory Bowel Disease (IBD) cohort, comprised of both CD and Ulcerative Colitis patients, to assess contribution of SHIP1 to the pathogenesis of human IBD. SHIP1 protein and mRNA levels were evaluated from blood samples obtained from IBD subjects seen at UCSF/SFVA, and compared to healthy control samples. Western blot analyses revealed that ~15% of the IBD subjects are severely SHIP1-deficient, with less than 10% of normal SHIP1 protein present in PBMC. Further analyses by flow cytometry and sequencing were performed on secondary samples obtained from the same subjects. Pan-hematolymphoid SHIP1 deficiency was a stable phenotype and was not due to coding changes in the INPP5D gene. A very strong association between SHIP1 deficiency and the presence of a novel SHIP1:ATG16L1 fusion transcript was seen. Similar to SHIP1-deficient mice, SHIP1-deficient subjects had reduced numbers of circulating CD4+ T cell numbers. Finally, SHIP1-deficient subjects with CD had a history of severe disease requiring multiple surgeries. These studies reveal that the SHIP1 protein is crucial for normal T cell homeostasis in both humans and mice, and that it is also a potential therapeutic and/or diagnostic target in human IBD.
Highlights
The global prevalence of inflammatory bowel disease (IBD) has been rising for the last several decades and is projected to continue doing so [1]
After normalization of the Src homology 2-containing-inositol-phosphatase-1 (SHIP1) levels to the housekeeping gene beta-actin, we defined a threshold for SHIP1 deficiency to be less than 10% of the SHIP1 protein level found in the pooled HX (C0) sample (Figure 1A)
SHIP1 deficiency was identified in some subjects in complete remission without IBD medications
Summary
The global prevalence of inflammatory bowel disease (IBD) has been rising for the last several decades and is projected to continue doing so [1]. While much progress has been made in understanding this heterogeneous disease, the causes of Crohn’s disease (CD) and ulcerative colitis (UC) are not fully known. Significant insights into the etiology of human IBD have come from a consortia of Genome-Wide Association Studies, which have identified more than 100 different inherited mutations that influence the risk of IBD in affected families [2]. Only 8–12% of IBD cases in adults can be attributed directly to any of these risk alleles. The risk factors for approximately 90% of IBD patients have yet to be defined, and the exact cause for IBD remains unknown in most adult cases. Even in subjects with known mutations, the mechanisms by which they promote IBD are incompletely understood, and these genetic studies have not yet resulted in the development of new treatments for IBD
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