Part three Pathogenesis

Background: Refractory Coeliac Disease (RCD) is characterized by persisting mucosal pathology in spite of a strict gluten free diet (GFD). In RCD type II phenotypically aberrant (CD7+CD3-CD4/8-cytoplasmicCD3+) T-lymphocytes are present within the Intraepitelial Lymphocyte (IEL) population in the small intestine, and 50-60% of these patients develops an Enteropathy Associated T-cell lymphoma (EATL). Aim: To investigate whether aberrant T-lymphocytes in RCD II can be detected in other parts of the small intestinal mucosa besides the intraepithelial compartment. Additionally, the presence of aberrant T-lymphocytes was analyzed in two RCD II patients that developed atypical skin lesions. Methods: Multiparameter flow cytometric immunophenotyping was performed on both IEL and lamina propria lymphocyte (LPL) cell suspensions, isolated from small bowel biopsy specimens of RCD II patients (n=14), and on cutaneous lymphocytes isolated from skin-lesion biopsy specimens of RCD II patients (n=2). In addition, immunofluorescence analysis of frozen RCD II derived small intestinal biopsies was performed. Results: Our results clearly show that aberrant T-lymphocytes may be present in both the IEL and the LPL compartments of RCD II derived small intestinal biopsies. Although the highest percentages are always present in the IEL compartment, aberrant LPL can exceed 20% of total LPL in half the RCD II patients. Interestingly, cutaneous lymphocytes isolated from atypical skin lesions that developed in some RCD II patients showed a similar aberrant immunophenotype as found in the intestinal mucosa. Conclusions: In RCD II the aberrant T-lymphocytes may also reside in the subepithelial layer of the small intestinal mucosa, in the lamina propria, and even in extraintestinal localizations including the skin. Whether this phenomenon represents a passive overflow from the intestinal epithelium or active trafficing towards other anatomical localizations remains to be elucidated. RCD II appears to be a disseminated disease, which may impose the risk of EATL development outside the intestine.