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Updated: Feb 23, 2026
Intravital Imaging of Intraepithelial Lymphocytes in Murine Small Intestine
Published on: June 24, 2019
ROC-king onwards: intraepithelial lymphocyte counts, distribution & role in coeliac disease mucosal interpretation
Kamran Rostami1, Michael N Marsh2,3, Matt W Johnson2
1Department of Gastroenterology and Pathology, Milton Keynes University Hospital, Milton Keynes, UK.
Insights
A definitive normal range for intraepithelial lymphocytes (IEL) in coeliac disease (CD) diagnosis was established. A cut-off of 25 IEL/100 enterocytes optimizes discrimination between normal and CD duodenal biopsies.
Area of Science:
- Gastroenterology
- Histopathology
- Immunology
Background:
- Accurate diagnosis of coeliac disease (CD) relies on quantifying intraepithelial lymphocytes (IEL) in duodenal biopsies.
- A standardized normal range for IEL counts is currently lacking, hindering definitive histological diagnosis.
Purpose of the Study:
- To establish an optimal cut-off value for intraepithelial lymphocyte (IEL) counts to differentiate normal duodenal mucosa from Marsh III lesions indicative of coeliac disease (CD).
Main Methods:
- A multicentre study involving 19 centres analyzed over 400 duodenal biopsy specimens.
- Receiver operating characteristic (ROC) curve analysis was employed to determine the optimal IEL count threshold.
- IEL counts were standardized as IEL per 100 enterocytes.
Main Results:
- The mean IEL count was significantly higher in CD patients (54±18/100 enterocytes) compared to controls (13±8/100 enterocytes).
- ROC analysis identified an optimal cut-off of 25 IEL/100 enterocytes, achieving 99% sensitivity and 92% specificity.
- No significant differences in IEL counts were observed across Marsh III sublesions (a, b, c).
Conclusions:
- A threshold of 25 intraepithelial lymphocytes (IEL) per 100 enterocytes effectively discriminates between normal and coeliac disease (CD) duodenal biopsies with Marsh III lesions.
- The findings suggest a potential dose-response relationship between environmental antigenic influence (gluten) and IEL counts.
Objectives:
Counting intraepithelial lymphocytes (IEL) is central to the histological diagnosis of coeliac disease (CD), but no definitive 'normal' IEL range has ever been published. In this multicentre study, receiver operating characteristic (ROC) curve analysis was used to determine the optimal cut-off between normal and CD (Marsh III lesion) duodenal mucosa, based on IEL counts on >400 mucosal biopsy specimens.
Design:
The study was designed at the International Meeting on Digestive Pathology, Bucharest 2015. Investigators from 19 centres, eight countries of three continents, recruited 198 patients with Marsh III histology and 203 controls and used one agreed protocol to count IEL/100 enterocytes in well-oriented duodenal biopsies. Demographic and serological data were also collected.
Results:
The mean ages of CD and control groups were 45.5 (neonate to 82) and 38.3 (2-88) years. Mean IEL count was 54±18/100 enterocytes in CD and 13±8 in normal controls (p=0.0001). ROC analysis indicated an optimal cut-off point of 25 IEL/100 enterocytes, with 99% sensitivity, 92% specificity and 99.5% area under the curve. Other cut-offs between 20 and 40 IEL were less discriminatory. Additionally, there was a sufficiently high number of biopsies to explore IEL counts across the subclassification of the Marsh III lesion.
Conclusion:
Our ROC curve analyses demonstrate that for Marsh III lesions, a cut-off of 25 IEL/100 enterocytes optimises discrimination between normal control and CD biopsies. No differences in IEL counts were found between Marsh III a, b and c lesions. There was an indication of a continuously graded dose-response by IEL to environmental (gluten) antigenic influence.
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