AUTHOR=Sudan Raki , Fernandes Sandra , Srivastava Neetu , Pedicone Chiara , Meyer Shea T. , Chisholm John D. , Engelman Robert W. , Kerr William G. 

TITLE=LRBA Deficiency Can Lead to Lethal Colitis That Is Diminished by SHIP1 Agonism

JOURNAL=Frontiers in Immunology

VOLUME=Volume 13 - 2022

YEAR=2022

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.830961

DOI=10.3389/fimmu.2022.830961

ISSN=1664-3224

ABSTRACT=Humans homozygous for inactivating LRBA mutations exhibit a spectrum of immune-related pathologies including Inflammatory bowel disease (IBD).  The cause of this pathology remains undefined. Here we show that disruption of the colon epithelial barrier in LRBA-/- mice by DSS consumption leads to severe and uniformly lethal colitis.  Analysis of BM chimeras showed that susceptibility to lethal colitis is due to LRBA-deficiency in the immune compartment and not the gut epithelium. Further dissection of the immune defect in LRBA-deficient hosts showed that LRBA is essential for expression of CTLA4 by Treg cells and for IL22 and IL17 expression by ILC3 cells in the large intestine when the gut epithelium is compromised by DSS. We further show that SHIP1 agonism partially abrogates the severity and lethality of DSS-mediated colitis. Our findings indicate that enteropathy induced by LRBA-deficiency has multiple causes and that SHIP1 agonism can partially abrogate the inflammatory milieu in the gut of LRBA-/- hosts.