Aberrant plasmacytoid dendritic cell distribution and function in patients with Crohn's disease and ulcerative colitis

Abstract

SummaryDendritic cell (DC) function is believed to be of critical importance for the pathogenesis of inflammatory bowel disease (IBD). To date, most research in animal models and the few human data available is restricted to myeloid DC, while plasmacytoid DC (pDC) capable of controlling both innate and adaptive immune responses have not yet been investigated systematically in human Crohn's disease (CD) or ulcerative colitis (UC). CD11c-, CD303 + / CD304 + and CD123 + pDC from peripheral blood (n = 90), mucosal tissue (n = 28) or mesenteric lymph nodes (n = 40) (MLNs) of patients with UC and CD or controls were purified and cultured. Thereafter, pDC were enumerated, phenotyped and cytokine secretion measured by flow cytometry (FACS), immunohistochemistry and/or cytometric bead array, respectively. Interferon (IFN)-a secretion following cytosine phosphatidyl guanine (CpG) A oligodeoxynucleotide (ODN) 2216 (5Ј-GGGGGACGATCGTCGGGGGG-3Ј) stimulation was assessed by enzyme-linked immunosorbent assay (ELISA). We found a significantly higher frequency of pDC in the inflamed colonic mucosa and MLN of IBD patients. Moreover, the fraction of CD40 and CD86 expressing cultured peripheral blood pDC was significantly higher in flaring UC and CD patients and their secretion of tumour necrosis factor (TNF)-a, interleukin (IL)-6 and IL-8 were increased significantly compared with controls. In contrast, the IFN-a secretion of peripheral blood pDC isolated from flaring IBD, particularly in UC patients, was reduced significantly compared with controls. Our data suggest an aberrant distribution and function of pDC in IBD, contrary to their generally implicated role as inducers of tolerance. We speculate that the impaired IFN-a secretion may relate to the hypothesized defect in innate immunity in IBD and could also impact upon the generation of regulatory T cells (Treg).

TH17 cells promote microbial killing and innate immune sensing of DNA via interleukin 26

“…These diseases are characterized by high numbers of pDCs and high IFN-α expression in tissues 30,44,45 , which suggests that IL-26 overexpression drives uncontrolled inflammatory responses via exaggerated IFN-α induction. As a consequence of this process, IL-26 may further enhance tissue injury by releasing self-DNA, leading to a self-sustaining inflammatory cycle that unleashes autoimmunity.…”

Protein Tyrosine Phosphatase PTPRS Is an Inhibitory Receptor on Human and Murine Plasmacytoid Dendritic Cells

“…Although the colitis in Ptprs-deficient mice (Muise et al, 2007) or in compound Ptprs/Ptprf mice (this study) might have complex origins and involve the function of LAR phosphatases in other cell types, the pDC-intrinsic function of Ptprs appears essential. Notably, pDC hyperactivation has been documented in inflammatory bowel disease (Baumgart et al, 2011) and in colitis associated with the Wiskott-Aldrich syndrome (Prete et al, 2013). Consistent with the emerging key role of DCs as regulators of intestinal inflammation (Bar-On et al, 2011; Bogunovic et al, 2012), our results suggest that a primary pDC hyperactivation might be linked to disrupted immune homeostasis in the intestine.…”

S1PR1-mediated IFNAR1 degradation modulates plasmacytoid dendritic cell interferon-α autoamplification

“…We further postulate that other G protein-coupled receptors may use similar mechanisms to regulate IFN-I amplification and possibly other diverse biological responses. Because pDCs are causal effectors in the pathogenesis of autoimmune disorders, including lupus and psoriasis (24), and have been linked to disease progression in animal models of multiple sclerosis and ulcerative colitis (25,26), our study indicates that the efficacy of S1PR1 therapies in these disease states may manifest through attenuation of an IFNAR1 cytokine amplification loop. The role of this pathway in therapeutic efficacy and as a biomarker for patient subsets that might benefit from S1PR1 agonist therapies warrants exploration.…”