Abstract
BackgroundConventional approaches to understand mechanisms underlying the development of pathological manifestations in ulcerative colitis (UC) mostly rely on identification of certain cell types and cytokines followed by verification of their roles in vitro and in vivo. In light of the highly dynamic processes in UC, requiring the cross talk of immune cells, epithelial-, endothelial-, muscle cells and fibrocytes, this approach might neglect temporal and spatial connectivity of individually differing inflammatory responses.MethodsWe undertook a more holistic approach whereby we designed a flow cytometric analysis- and ELISA panel and determined the immunological profiles of UC patients in comparison to Non UC donors. This panel consisted of B-cells, T-cells, macrophages, monocytes, NK- and NK T-cells and subtypes thereof, the cytokines TGFß1 and HGF, the chemokine TARC and periostin. Blood was collected from 41 UC patients and 30 non-UC donors. Isolated PBMC were subjected to flow cytometric analysis and sera were analyzed by ELISA. Data were analysed by cluster- and correlation analysis. To corroborate that the identified cells reflected the inflammatory condition in the colon of UC patients, leucocytes were isolated from colons of UC patients and subjected to the same flow cytometric analysis.ResultsImmunological profiling followed by cluster- and correlation analysis led to the identification of two inflammatory conditions: An ‘acute’ condition characterized by adaptive immune cells as plasma cells, TSLPR expressing CD11b+ macrophages, CD64 and CCR2 expressing CD14+ monocytes, HGF and TARC and a ‘remodeling’ condition signified by NK T-cells and TLSPR expressing CD14+ monocytes, TGFß1 and periostin. ROC analysis identified TARC and TGFß1 as biological markers with high potential to discriminate between these two conditions (Δ = −6687.72 ng/ml; p = 1E−04; AUC = 0.87). In addition, CD1a+ CD11b+ macrophages (Δ = 17.73% CD1a+ CD11b+; p = 5E−04; AUC = 0.86) and CD1a+ CD14+ monocytes (Δ = 20.35; p = 0.02, AUC = 0.75) were identified as markers with high potential to discriminate between UC and Non UC donors. CD1a+ CD11b+ macrophages and NK T-cells were found to be significantly increased in inflamed colons of UC patients as compared to non-UC control samples (p = 0.02).ConclusionsImmunological profiling of UC patients might improve our understanding of the pathology underlying individual manifestations and phases of the disease. This might lead to the development of novel diagnostics and therapeutic interventions adapted to individual needs and different phases of the disease. In addition, it might result in stratification of patients for clinical trials.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-016-1048-9) contains supplementary material, which is available to authorized users.
Highlights
Conventional approaches to understand mechanisms underlying the development of pathological manifestations in ulcerative colitis (UC) mostly rely on identification of certain cell types and cytokines followed by verification of their roles in vitro and in vivo
In this model an active role is assigned to epithelial cells as they release damage associated molecular pattern molecules (DAMP) such as TSLP to direct immune cells towards a Th2 characterized immune response resulting in increased mucus production, epithelial cell hyperplasia and fibrosis
Unswitched memory B-cell Switched memory B-cell Plasma cell Activated CD4+ T, regulatory T cells, Th2 cells MC MC, mature MC, tissue penetrating, inflammatory MC, expressing TSLP receptor (TSLPR) M1MC M2 MC, scavenging cells MC CD1a expressing cDC1 cDC1, mature cDC1 CD1a expressing cDC1 TSLPR expressing NK T-cell NK cell ILC2
Summary
Conventional approaches to understand mechanisms underlying the development of pathological manifestations in ulcerative colitis (UC) mostly rely on identification of certain cell types and cytokines followed by verification of their roles in vitro and in vivo. We have recently taken a slightly different view which is based on the assumption that the inflammatory response partially resembles an uncontrolled wound healing process caused by epithelial damage [2]. In this model an active role is assigned to epithelial cells as they release damage associated molecular pattern molecules (DAMP) such as TSLP (thymic stromal lymphopoietin) to direct immune cells towards a Th2 characterized immune response resulting in increased mucus production, epithelial cell hyperplasia and fibrosis. The crucial role of macrophages in UC is supported by the efficacy of infliximab an anti-tumor necrosis factor (TNFα) monoclonal human antibody with IgG1 effector function which is thought to be deleterious to macrophages expressing TNFα on their surfaces [10]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
