Intraepithelial Lymphocytes and LAIR1 Expression in Celiac Disease

Background: Celiac disease (CD) is a gluten-sensitive immune-related enteropathy of the small intestine characterized by villus atrophy, crypt hyperplasia, and increased intraepithelial lymphocytes (IELs). Objectives: To characterize the phenotype of IELs and immune cells of the lamina propria of small intestine control using immuno-oncology and immune-phenotype markers and test the most relevant marker, an immune checkpoint co-inhibitory receptor, leukocyte associated immunoglobulin like receptor 1 (LAIR1) in CD. Methods: Immunohistochemical analysis of CD3, CD4, CD8, CD103 (ITGAE), Granzyme B, TCR beta (β), TCR delta (δ), CD56 (NCAM), CD16, LAIR1 (CD305), PD-L1, PD1 (CD279), BTLA (CD272), TOX2, HVEM (TNFRSF14), CD163, HLA-DP-DQ, IL4I1, and FOXP3 was performed using histological analysis. Gene expression analysis was performed using an independent dataset to expand and confirm the findings. Results: IELs exhibited a cytotoxic T-cell phenotype and were positive for CD3, CD8, CD103, TCRβ, and LAIR1. The lamina propria was abundant in CD163, HLA-DP-DQ, BTLA, PD-L1, CD103, CD56, and LAIR1-positive cells corresponding to macrophages and T- and B-lymphocytes. In CD, IELs and part of the inflammatory cells of the lamina propria cells were LAIR1-positive. CD was characterized by higher LAIR1-positive cell expression than the small intestine control (P = 0.004). Higher intestinal lesions evaluated by Marsh scoring were correlated with higher LAIR1 (P < 0.001). Gene expression analysis confirmed the overexpression of the LAIR1 pathway in CD and highlighted BTLA. At the protein level, BTLA overexpression was confirmed in CD. Finally, as a proof-of-concept AI analysis, a convolutional neural network classified LAIR1-stained image-patches between the 3 diagnoses of small intestine control, CD, and reactive tonsils with high accuracy (99.6%). Conclusions: IELs exhibit cytotoxic T-cell phenotype and are CD3, CD8, CD103, TCRβ, and LAIR1 positive in small intestine control. Increased numbers of LAIR1-positive IELs and lamina propria immune cells characterize CD.