People with Crohn’s disease exhibit a dysregulated lymphocyte response to corticosteroids: Implications to stress-induced disease aggravation and failure of therapy

Karny Ilan ¹ Anna Nemirovsky ¹ Yehezqel Elyahu ¹ Ekaterina Vinogradov ¹ Shmuel Odes ² Doron Schwartz ² Alon Monsonego ¹

¹The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences; Zlotowski Center for Neuroscience; Regenerative Medicine and Stem Cell Research Center; and the National Institute of Biotechnology in the Negev; Ben-Gu, Ben Gurion University, Israel
²Gastroenterology, Soroka Medical Center, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel. *On Behalf of Israeli Ibd Research Nucleus (Iirn), Ben Gurion University, Israel

Background

Crohn’s disease (CD) is a chronic inflammatory bowel disease engendering both psychological and physiological stresses. Our previous studies in animal models of multiple sclerosis demonstrated that prolonged stress and chronic inflammation cause dysregulation of glucocorticoid (GC) signaling in different immune subsets, with consequent reduced sensitivity to GCs, so-called steroid resistance, and a shift towards a more aggressive immune response. The present study aims to identify and characterize patterns of steroid resistance in adult CD patients.

Methods

We analyzed leukocyte subset distribution, functionality and responsiveness to GCs using peripheral blood mononuclear cells (PBMCs) isolated from CD patients and from age- and sex-matched healthy controls. PBMCs underwent stimulation without or with methylprednisolone followed by measuring IL-2, TNFa, IL-10, IFN-g and IL-17A with ELISA or flow cytometry.

Results

MP in increasing doses caused a lesser reduction of PBMC cytokine production in people with CD (n=22) than in controls (n=22). Notably, MP in increasing doses caused a progressive reduction of TNFα-producing CD8 T cells in controls (n=18) and to a significantly lesser extent in people with CD (n=22). Non-activated PBMCs analyzed for lymphocyte subsets did not demonstrate major differences in a limited number of patients and controls (n=8).

Conclusions

Immune cell subsets in certain people with CD exhibit a loss of steroid sensitivity. This may be indicative of a dysregulated hypothalamus-pituitary-adrenal (HPA) axis, a phenomenon which may not only augur an inadequate response to corticosteroid therapy, but also may contribute to CD pathogenicity along with symptoms of anxiety and depression.