Increased density of jejunal gammadelta+ T cells in patients having normal mucosa--marker of operative autoimmune mechanisms?

Both from a clinical and a biological point of view, coeliac disease can be classified among the autoimmune diseases, or one could suspect autoimmune mechanisms to be operative in the disease. The aim of the present study was to find evidence for mucosal markers of coeliac disease latency in patients clinically suspected but on routine biopsy excluded for the disease. Monoclonal antibodies were used to stain jejunal intraepithelial lymphocytes and mucosal HLA-DR. Serum IgA-class reticulin autoantibodies were measured by an indirect immunofluorescence and gliadin antibodies by an enzyme-linked immunosorbent assay method. The DQA1*0501 and DQB1*0201 alleles were determined. Twenty-seven of 107 consecutive patients had coeliac disease. Altogether 39 of 79 (49%) children with normal jejunal mucosa had an increased density of intraepithelial gammadelta+ T cells (> or = 4.4 cells/mm). IgA-class reticulin autoantibodies were positive in 18 (23%) of the children excluded for coeliac disease. The antibody positivity was mostly seen in patients carrying the DQAI 0501 and DQB1*0201 alleles. Also, reticulin autoantibody-positive children having normal jejunal mucosal morphology had significantly higher densities of intraepithelial gammadelta+ T cells than antibody negative ones. On 1.5-4.5 year follow-up four out of 18 (22%) children primarily excluded for coeliac disease showed mucosal deterioration and coeliac disease. Many patients clinically suspected of coeliac disease but having normal jejunal mucosa show markers of coeliac disease latency which may be gluten-induced indicating autoimmune mechanisms to be operative in the gut.

Changing jejunal gamma delta T cell receptor (TCR)-bearing intraepithelial lymphocyte density in coeliac disease.

The function of jejunal intraepithelial gamma delta+ T cells is obscure, but they are commonly implicated as playing a role in inflammatory and autoimmune conditions. In coeliac disease (CoD), there are controversial reports as to gluten dependency of these cells. We have now studied the small bowel mucosal intraepithelial T cell densities, and the ratios of gamma delta+ to CD3+ T cells and gamma delta+ to alpha beta+ T cells during early disease development and on a gluten-free diet. Nine children initially excluded for CoD were followed up and rebiopsy after 0.8-4.5 years showed mucosal deterioration. Further, 21 biopsy specimens from newly diagnosed CoD patients were studied, together with 20 specimens taken from children on a gluten-free diet. During CoD development the density of gamma delta+ and alpha beta+ T cells as well as the ratios of gamma delta+ to CD3+ T cells and gamma delta+ to alpha beta+ T cells increased. In the latent stage of CoD when the small bowel mucosal architecture was still normal, two children had clearly normal densities of gamma delta+ (< 2.5 cells/100 epithelial cells) and alpha beta+ (< 25.0 cells/100 epithelial cells) T cells, and low ratios as well. In patients with newly diagnosed CoD the densities decreased significantly on a long-term gluten-free diet. We conclude that the density of intraepithelial gamma delta+ T cells as well as alphabeta+ T cells in CoD is gluten-dependent. CoD can develop in a child ingesting normal amounts of gluten and having normal jejunal mucosal morphology on biopsy and a normal density of gamma delta+ T cells.

Celiac disease and markers of celiac disease latency in patients with primary Sjögren's syndrome.

OBJECTIVE: Many autoimmune diseases occur concomitantly with celiac disease. We investigated prospectively the occurrence of celiac disease and small-bowel mucosal inflammation in patients with primary Sjögren's syndrome. METHODS: A total of 34 patients with primary Sjögren's syndrome and 28 controls underwent small bowel biopsy. Villous morphology, jejunal intraepithelial lymphocytes, and mucosal HLA-DR were evaluated and DQA and DQB alleles, serum antiendomysial, and antigliadin antibodies were examined. RESULTS: Five (14.7%) of 34 Sjögren's syndrome patients were found to have celiac disease. The density of jejunal intraepithelial gammadelta+ T cells was increased in all celiac and in four nonceliac patients. All celiac patients, 69% of nonceliac Sjögren's syndrome patients, and 11% of control subjects showed enhanced HLA-DR expression (p < 0.001). HLA DQ2 was present in 19 (56%) patients with Sjögren's syndrome, including all five with celiac disease. CONCLUSIONS: The findings show a close association between Sjögren's syndrome and celiac disease. Even among nonceliac patients with primary Sjögren's syndrome, an ongoing inflammation is often present in the small bowel mucosa.

Expression of HSP-65 in jejunal epithelial cells in patients clinically suspected of coeliac disease.

BACKGROUND: Coeliac disease (CD) can be classified both clinically and biologically an autoimmune disease. A close relationship obtains between heat shock proteins (HSPs) and numerous autoimmune diseases. HSPs are overexpressed when protecting the host against environmental insult. We sought here to establish whether dietary gluten is such a stress stimulus in patients clinically suspected of CD, and whether the expression of HSP-65 associates with densities of intraepithelial gammadelta+ T cells and/or with expression of mucosal HLA-DR. METHODS: Seventy-eight children with clinical suspicion of CD underwent a jejunal biopsy. Monoclonal antibodies were used to stain jejunal epithelial HSP-65, intraepithelial lymphocytes and mucosal HLA-DR. Serum IgA-class endomysial autoantibodies (EMA) were measured by an indirect immunofluorescence method. CD susceptibility HLA DQA1*0501 and DQB1*0201 alleles (HLA DQ2) were determined. RESULTS: Enhanced expression of epithelial cell mitochondrial HSP-65 was found in 80% (16/20) of coeliacs and in 24% (14/58) of children excluded for the disease, but in only 7% (2/28) of control subjects (p < 0.001, p = 0.049, respectively). Children with enhanced expression of HSP-65 had significantly higher gammadelta+ T cell densities than those with normal HSP-65 expression. A clear association between HSP-65 and serum IgA-class EMA were also ascertained in patients with normal jejunal mucosal morphology. HLA DQ2 positivity did not correlate with the HSP-65 expression. CONCLUSIONS: Gluten might be an environmental insult not only in CD patients but also in some patients excluded for the disease on biopsy. Enhanced expression of epithelial cell stress proteins might be an indicator of such an insult.