Significance of intraepithelial lymphocytosis in small bowel biopsy samples with normal mucosal architecture

Current diagnostic criteria of celiac disease require small bowel villous atrophy, although the damage develops gradually. We therefore searched for evidence of disease in 10 adults suspected to have celiac disease, but evincing only minor mucosal inflammation and increase in gammadelta+ cells without villous atrophy. Twenty untreated celiac and 27 nonceliac patients served as biopsy controls. CD3+, alphabeta+, and gammadelta+ cells were increased in patients with only minor mucosal lesions, but less than in celiac patients. The inflammation resolved on gluten-free diet, and abdominal symptoms were alleviated. Eight of 10 had positive endomysial, seven gliadin, and nine tissue transglutaminase antibodies; all normalized on diet. Eight patients had osteopenia; HLA DQ2 was found in all. Minor mucosal lesions with an increase in gammadelta+ intraepithelial lymphocytes were suggestive of celiac disease. Our patients showed a clinical, histological, and serological recovery on diet; risk of osteopenia speaks in favor of dietary treatment.

Celiac disease without villous atrophy: revision of criteria called for.

Intraepithelial lymphocytes (IELs) bearing the γδ TCR are more abundant in the small intestinal mucosa of patients with celiac disease (CD) compared with healthy individuals. However, their role in disease pathogenesis is not well understood. Here, we investigated the functional attributes of TCRγδ+ IELs isolated from intestinal biopsies of patients with either active celiac disease (ACD) or those on a gluten-free diet (GFD). We found that compared with individuals with ACD, individuals on GFD have a higher frequency of CD8+TCRγδ+ IELs that express the inhibitory NK receptor NKG2A and intracellular TGF-β1. TCR triggering as well as cross-linking of NKG2A increased both TGF-β1 intracellular expression and secretion in vitro. Coculture of sorted TCRγδ+NKG2A+ IELs, IL-15–stimulated TCRαβ+ IELs, and HLA-E+ enterocytes resulted in a decreased percentage of cytotoxic CD8+TCRαβ+ IELs expressing intracellular IFN-γ and granzyme-B and surface NKG2D. This inhibition was partially abrogated by blocking either TGF-β alone or both NKG2A and HLA-E. Thus, our data indicate that suppression was at least partially mediated by TGF-β secretion as a result of engagement of NKG2A with its ligand, HLA-E, on enterocytes and/or TCRαβ+ IELs. These findings demonstrate that human small intestinal CD8+TCRγδ+ IELs may have regulatory potential in celiac disease.

/pdf/small-intestinal-cd8-tcrgd-nkg2a-intraepithelial-lymphocytes-rtz1sj09ot.pdf

Small intestinal CD8 + TCRγδ + NKG2A + intraepithelial lymphocytes have attributes of regulatory cells in patients with celiac disease

Mouse and human intestinal immunity: same ballpark, different players; different rules, same score

Intraepithelial lymphocytes in celiac disease.

Gamma/delta T cells are increased in the gut epithelium of patients with coeliac disease compared with normal controls. The aim of this study was to determine whether the increase in gamma delta intraepithelial lymphocytes (IEL) is specific for coeliac disease, in which case it could be of diagnostic importance. Biopsies were obtained from children with no intestinal disease, coeliac disease, cow-milk-sensitive enteropathy/post-enteritis syndrome (CMSE PES) and miscellaneous other enteropathies (n = 67). Intraepithelial CD3+ and gamma delta T cells were identified in frozen sections using peroxidase immunohistochemistry. In normal biopsies there were 0-7 gamma delta IEL/100 cells in the epithelium. In untreated coeliac patients this increased to 9-22 gamma delta IEL/100 cells in the epithelium (P = 0.000004). Of 27 patients with morphologic intestinal damage which was not due to coeliac disease, four with CMSE/PES had gamma delta IEL/100 cells in the epithelium in the same range as the patients with coeliac disease. Of these, two had high densities of CD3+ IEL in the epithelium and were indistinguishable from patients with untreated coeliac disease. The other two could be excluded as possible coeliacs because their CD3+ IEL/100 epithelial cells were in the normal range. Thus an increase in gamma delta IEL is not specific for coeliac disease. However, enumeration of both of gamma delta IEL and CD3+ IEL densities will be useful in the exclusion of coeliac disease as a diagnosis in some children.

Gamma/delta T cells and the diagnosis of coeliac disease

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Gamma/delta T cells and the diagnosis of coeliac disease