Defective Immune Homeostasis Mechanisms in Celiac Disease, in Its Progression to Refractory Celiac Disease and Transformation to Enteropathy-Associated T-Cell Lymphoma
Joaquim Carreras Esteban, Yara Yukie Kikuti, Tomoki Kikuchi, Sakura Hayashi, Johbu Itoh, Giovanna Roncador, Rifat Hamoudi, William J Howat, Noriko M Tsuji, Naoya Nakamura. Tokai University, School of Medicine, Isehara, Kanagawa, Japan; National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Ibaraki, Japan; University of Cambridge, Cambridge, Cambridgeshire, United Kingdom; UCL-Cancer Institute, London, United Kingdom; CRUK CRI, Cambridge, Cambridgeshire, United Kingdom; CNIO, Madrid, Spain
Background: CD is a multifactorial and polygenic (complex) disorder with a postulated defect in the mucosal immuno tolerance and homeostasis mechanisms.
Design: CD-RCD-EATL sequence was studied for FOXP3+Tregs, ITGAX+DCs, BTLA+cells, PDCD1+TFH, CD69+IELs and AICDA protein IHC expression with network analysis in 69 cases including 50 CD (20 conventional-CD, 18 RCD1 and 10 RCD2) and 19 EATL. 2D/3D digital quantification compartmentalized LP, ILFs and tumoral lymphoid areas.
Results: In comparison to physiological conditions, CD was characterized by higher numbers of FOXP3+Tregs (5.3±2.2 vs. 1.3) and ITGAX+DCs (4.9±4.3 vs. 3.3), but lower BTLA+cells (12.8±13.2 vs. 24.7) and PDCD1+TFH (2.9±3.9 vs. 21.0) cells. AICDA was rarely found, only positive at ILFs with GC reaction. Progression from CD to RCD1, RCD2 and EATL transformation was characterized by a decreasing trends of FOXP3+Tregs (5.0±2.2 vs. 6.6±3.7 vs. 3.4±2.0 vs. 1.2±1.6; P<0.05; cubic fit method R2=0.416) and BTLA+cells (8.8±10.4 vs. 18.6±15.6 vs. 10.8±11.4 vs. 0.4±0.6;P<0.05,R2=0.318). ITGAX+DCs had decreasing trend from CD to RCD but EATL transformation switched to increase (3.4±2.3 vs. 7.6±4.9 vs. 1.8±1.6 vs. 15.7±14.5;P<0.05). ILFs tended to correlate with LP findings. PDCD1+TFH cells showed a continuous increasing trend (0.5±0.6 vs. 2.6±4.0 vs. 5.3±4.7 vs. 21.4±5.5;P<0.05,R2=0.826). AICDA was mainly negative but its presence increased in GCs in EATL. FOXP3+IELs were occasionally identified. Progression to RCD and EATL is characterized by 3D morphological changes of IELs. Network analysis confirmed the importance of both immune regulation and B-cell response in CD.
Conclusions: CD has high FOXP3+Tregs and ITGAX+DCs but lower BTLA+cells and PDCD1+TFH cells. RCD progression and EATL transformation stages show a defect in inhibitory pathways of FOXP3 and BTLA while modulatory ITGAX and inhibitory PDCD1 are increased. AICDA increases in cancer transformation. Immune homeostasis appears to be dysfunctional in CD pathogenesis.
Funded by CRUK A8329, JSPS, MEXT and Tokai UNV.
Tuesday, March 5, 2013 1:15 PM
Proffered Papers: Section G, Tuesday Afternoon