Patients with active inflammatory bowel disease lack immature peripheral blood plasmacytoid and myeloid dendritic cells

Abstract

Background: Breakdown of tolerance against the commensal microflora is believed to be a major factor in the pathogenesis of inflammatory bowel disease (IBD). Dendritic cells (DC) have been implicated in this process in various animal models, but data on human DC in IBD are very limited. Aim: To characterise plasmacytoid DC (PDC) and myeloid DC (MDC) in patients with active versus inactive IBD and healthy controls. Patients and Methods: Peripheral blood was obtained from 106 patients (Crohn's disease (CD) n = 49, ulcerative colitis (UC) n = 57) and healthy controls (n = 19). Disease activity was scored using the modified Truelove Witts (MTWSI) for UC and the Harvey Bradshaw severity indices (HBSI) for CD. Four colour flow cytometric analysis was used to identify, enumerate, and phenotype DC. DC from patients with acute flare ups and healthy controls were cultured and stimulated with CpG ODN 2006 or lipopolysaccharide (LPS). Results: IBD patients in remission (PDC UC, 0.39%; CD, 0.35%; MDC-1 UC, 0.23%; CD, 0.22% of PBMC) have slightly lower numbers of circulating DC compared with healthy controls (PDC 0.41%, MDC-1 0.25% of PBMC). In acute flare ups IBD patients experience a significant drop of DC (PDC UC, 0.04%; CD, 0.11%; MDC-1 UC, 0.11%; CD, 0.14% of PBMC) that correlates with disease activity (correlation coefficients: PDC MTWSI, 0.93; HBSI, 0.79; MDC-1 MTWSI, 0.75; HBSI, 0.81). Moreover, both express a4b7 integrin and display an immature phenotype. Freshly isolated PDC and MDC-1 from untreated flaring IBD patients express higher baseline levels of CD86 which increases further in culture and upon stimulation compared with healthy controls. Conclusion: IBD patients lack immature blood DC during flare ups which possibly migrate to the gut. An aberrant response to microbial surrogate stimuli suggests a disturbed interaction with commensals.

A six‐color flow cytometric assay for the analysis of peripheral blood dendritic cells

“…The lower constitutive expression of the costimulatory molecules CD80, CD86, and CD40 on pDCs than mDCs clearly documented with our assay is in accordance with the tolerogenic function ascribed to pDCs (16). A few observations of lower expression of these markers on pDCs have been previously reported, but with methods that used isolated or cultured PBDCs, or compared data obtained from different tubes (17)(18)(19)(20). In this respect, the direct comparison between DC subsets made possible by our 6-color assay may be more reliable.…”

Crucial role of plasmacytoid dendritic cells in the development of acute colitis through the regulation of intestinal inflammation

“…[26][27][28] On the other hand, previous studies have shown the lack of peripheral blood pDCs in patients with active IBD, and instead their accumulation in the inflamed colonic mucosa and mesenteric lymph node (MLN) and dysfunction. 29,30 However, how pDCs contribute to the development of IBD remains unclear.…”

Crohn’s disease specific pancreatic antibodies: clinical and pathophysiological challenges

“…The current discourse in this context refers to an imbalance between tolerance to commensal microbiota or food-derived antigens and immune responses to pathogens [1]. Thus, mucosal inflammation observed in CrD is triggered by such dysregulation of the innate as well as adaptive immune responses [1,75]. A molecule like GP2 interacting with FimH positive microbes and facilitating the phagocytosis thereof could play a major role in triggering and perpetuating inflammatory processes in CrD.…”