Abstract
Notwithstanding uncertain pathogenesis of inflammatory bowel disease (IBD), deregulation of adaptive immunity is paramount for the development of inflammation. Essential role in the resolution of inflammation is played by apoptosis, deregulated in lymphocytes isolated from inflamed intestine. Despite IBD being a systemic disease, little is known about apoptosis of peripheral lymphocytes. The concentrations of Bcl-2, cytochrome c, p53, and caspase-9 were determined (ELISA) in lymphocyte-enriched fractions of peripheral blood mononuclear cells (LE-PBMCs) from 64 individuals (42 with IBD) and related to IBD phenotype and activity, treatment, and inflammatory and hematological indices. The diagnostic potential of evaluated markers was determined as well. All evaluated molecules were significantly lower in IBD patients, of which cytochrome c and p53 were significantly lower exclusively in patients with Crohn's disease (CD) and cytochrome c differed significantly between CD and ulcerative colitis (UC). Caspase 9 was significantly lower in active IBD and Bcl-2 in active UC whereas cytochrome c was higher in active CD. Treatment with corticosteroids affected the concentrations of cytochrome c and p53. Both positively correlated with hsCRP and the concentrations of all markers were interrelated. As IBD markers, Bcl-2 and caspase-9 displayed good accuracy and, as a panel of markers with cytochrome c, their accuracy was excellent (92%). As CD markers Bcl-2, cytochrome c, and p53 displayed fair accuracy but combined determination of Bcl-2 and cytochrome c improved the accuracy to 85%. Taken together, our results imply diminished intrinsic apoptotic capacity of LE-PBMCs in IBD but an upregulation of proapoptotic features parallel to increasing severity of inflammation. Observed abnormalities in intrinsic pathway of apoptosis are more pronounced in CD. Upon positive validation on a larger set of patients, combined quantification of Bcl-2 and cytochrome c might be considered as an adjunct in differential diagnosis of UC and CD of colon and rectum.
Highlights
Inflammatory bowel disease (IBD) is chronic, incurable conditions of digestive tract decreasing patients’ quality of life and affecting currently more than five million people all over the world [1]
Our results show significant differences in the concentrations of key players of apoptosis in LE-Peripheral blood mononuclear cells (PBMCs) of IBD patients as compared to healthy individuals; they do not explicitly indicate the resistance to apoptosis
Lymphocytes T in lamina propria are more susceptible to apoptosis than circulating lymphocytes, a response to the environment rich in antigens
Summary
Inflammatory bowel disease (IBD) is chronic, incurable conditions of digestive tract decreasing patients’ quality of life and affecting currently more than five million people all over the world [1]. Compound background of the development of IBD involves interplay between immune system (the immunome) and the gut microbiota (the microbiome) in individuals with genetic predisposition (the genome) in presence of the environmental factors (the exposome) [2]. As a consequence there is no causative treatment available and administrated therapeutic strategies continue to depend mostly on systemic immunosuppression being just one link in the complicated chain of interactions. Introduction of biologic therapy directed against tumor necrosis factor (TNF)α over two decades ago improved clinical outcomes in IBD patients and paved the way for other immunotherapies [3]; still the effectiveness of IBD treatment does not exceed
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