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Published on: January 19, 2017
Single-Cell Analysis of Refractory Celiac Disease Demonstrates Inter- and Intra-Patient Aberrant Cell Heterogeneity
Tessa Dieckman1, Mette Schreurs2, Ahmed Mahfouz3
1Department of Immunology, Leiden University Medical Center, Leiden, The Netherlands; Department of Gastroenterology and Hepatology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, The Netherlands.
Insights
Refractory celiac disease type II (RCDII) exhibits significant immune cell heterogeneity. Understanding this complexity is key to developing personalized therapies for RCDII patients.
Area of Science:
- Immunology
- Gastroenterology
- Oncology
Background:
- Refractory celiac disease type II (RCDII) is a rare small intestinal indolent lymphoma.
- Its pathogenesis involving aberrant immune cells remains poorly understood.
Purpose of the Study:
- To perform single-cell characterization of the immune system in RCDII.
- To investigate the heterogeneity of aberrant cells in RCDII.
Main Methods:
- Single-cell mass cytometry on paired intestinal and blood samples from RCDII patients and controls.
- Single-cell RNA sequencing of duodenal samples.
- Imaging mass cytometry for evaluating cell-cell interactions.
Main Results:
- Demonstrated significant intertumoral and intratumoral heterogeneity in aberrant RCDII cells.
- Observed phenotypic discrepancies between peripheral and duodenal aberrant cells.
- Identified proliferation of aberrant cells and their co-localization with antigen-presenting cells.
Conclusions:
- High-dimensional single-cell analyses reveal substantial heterogeneity in RCDII aberrant cells.
- This heterogeneity may explain variable disease status and treatment responses.
- Highlights the need for personalized RCDII therapy based on immune profiles.
Background & Aims:
Refractory celiac disease type II (RCDII) is a rare indolent lymphoma in the small intestine characterized by a clonally expanded intraepithelial intracellular CD3+surfaceCD3-CD7+CD56- aberrant cell population. However, RCDII pathogenesis is ill-defined. Here, we aimed at single-cell characterization of the innate and adaptive immune system in RCDII.
Methods:
Paired small intestinal and blood samples from 12 RCDII patients and 6 healthy controls were assessed by single-cell mass cytometry with a 39-cell surface marker antibody panel, designed to capture heterogeneity of the innate and adaptive immune system. A second single-cell mass cytometry panel that included transcription factors and immune checkpoints was used for analysis of paired samples from 5 RCDII patients. Single-cell RNA sequencing analysis was performed on duodenal samples from 2 RCDII patients. Finally, we developed a 40-marker imaging mass cytometry antibody panel to evaluate cell-cell interactions in duodenal biopsy specimens of RCDII patients.
Results:
We provide evidence for intertumoral and intratumoral cell heterogeneity within the duodenal and peripheral aberrant cell population present in RCDII. Phenotypic discrepancy was observed between peripheral and duodenal aberrant cells. In addition, we observed that part of the aberrant cell population proliferated and observed co-localization of aberrant cells with CD163+ antigen-presenting cells (APCs) in situ. In addition, we observed phenotypic discrepancy between peripheral and duodenal aberrant cells.
Conclusions:
Novel high-dimensional single-cell technologies show substantial intertumoral and intratumoral heterogeneity in the aberrant cell population in RCDII. This may underlie variability in refractory disease status between patients and responsiveness to therapy, pointing to the need for personalized therapy in RCDII based on patient-specific immune profiles.
