Celiac disease in patients with type 1 diabetes: a condition with distinct changes in intestinal immunity?

Abstract

Two common chronic childhood diseases-celiac disease (CD) and type 1 diabetes (T1D)-result from complex pathological mechanisms where genetic susceptibility, environmental exposure, alterations in intestinal permeability and immune responses play central roles. In this study, we investigated whether these characteristics were universal for CD independently of T1D association. For this purpose, we studied 36 children with normal small-bowel mucosa and 26 children with active CD, including 12 patients with T1D. In samples from the small-bowel mucosa, we detected the lowest expression of tight junction protein 1 (TJP1) mRNA in CD patients with T1D, indicating an increase in intestinal permeability. Furthermore, these samples displayed the highest expression of forkhead box P3 (FoxP3) mRNA, a marker for regulatory T cells, as compared with other patient groups. At the same time, serum levels of IgA antibodies specific for the CD-related antigens deamidated gliadin and tissue transglutaminase (tTG) were the highest in CD patients with T1D. In contrast, no significant differences were found in IgA or IgG antibodies specific for bovine beta-lactoglobulin or Bifidobacterium adolescentis DSM 20083-derived proteins. There were also no differences in the transamidating activity of serum autoantibodies between patients and control individuals. Our results show that patients with T1D and newly detected CD exhibit severely altered intestinal permeability, strong local immune activation and increased immunoregulatory mechanisms in the small bowel. Further study is required to determine whether these extreme changes in this CD subgroup are due to some specific environmental factors (virus infections), unknown genetic effects or autoimmune reactions to antigenic targets in intracellular tight junctions. INTRODUCTIONWith an approximate prevalence of 1.0% in Western countries, celiac disease (CD) is one of the most common lifelong chronic disorders. 1 CD and type 1 diabetes (T1D) form a significant sector of childhood diseases with high rate of co-occurrence. 2 Both diseases are autoimmune in origin and develop as a result of complex pathological mechanisms, involving several common genetic, environmental and immunological factors. Among these, the common susceptibility loci of HLA and other immune system-related genes, 3 permeability changes in the small-bowel mucosa, 4 and association with wheat consumption 4,5 are prominent. Both diseases are increasing in most regions of the world, 6,7 as are several other autoimmune diseases, but the actual cause of the disease remains unknown. However, several recent studies have highlighted the role of environmental and social changes that have taken place over the last several decades. 8,9 The central event in the pathogenesis of CD is damage to the small intestinal mucosa that occurs after ingestion of gluten or related prolamins in genetically susceptible individuals. During this process, several morphological and immunological alterations have been demonstrated in the small-bowel mucos...

Children diagnosed with both Type 1 diabetes and Celiac disease - An Immunological challenge

“…Upregulated FoxP3 expression may counterbalance the loss of mucosal integrity by maintaining immune tolerance in the small intestine of patient with both celiac disease and T1D [137] . Contrary, a low expression of the tight junction protein 1 (TJP1) serving as a marker of intestinal mucosa integrity has been found in patients with both T1D and celiac disease [136,138] . Also gliadin and tTG IgA antibodies were the highest in these patients [138] .…”

“…Contrary, a low expression of the tight junction protein 1 (TJP1) serving as a marker of intestinal mucosa integrity has been found in patients with both T1D and celiac disease [136,138] . Also gliadin and tTG IgA antibodies were the highest in these patients [138] . These results may reveal that intestinal permeability is most severely impaired in patients with these two immunological diseases in combination [138] .…”

Autoimmune Disorders Associated to Type 1 Diabetes Mellitus in Children and Adolescents

“…Recently, in samples from the small bowel mucosa from patients with celiac disease and type 1 diabetes a low expression of tight junction protein 1 (TJP1) mRNA has been observed, indicating an increase in intestinal permeability that might represent a causative factor. Furthermore, the highest expression of Forkhead box P3 (FoxP3) mRNA, a marker of regulatory T cells was observed, suggesting an increased immunoregolatory mechanisms (Uibo et al, 2011). The mean prevalence of celiac disease in type 1 diabetes is about 8%, with an extremely variable range (from 1% up to 11%) (Kakleas et al, 2010), almost 10-20 fold higher than observed in general pediatric population (Maki et al, 2003).…”

Celiac disease and diabetes mellitus type 1.

“…An immature or damaged mucosa makes the mucous barrier more permeable, which can result in an allergic or autoimmune reaction in genetically predisposed individuals 9,10 . Uibo et al 11 detected the lowest expression of tight junction protein 1 (TJP1) mRNA in small bowel mucosa samples from celiac patients with diabetes mellitus type 1, indicating an increase in intestinal permeability. Furthermore, these samples displayed the highest expression of forkhead box P3 (FoxP3) mRNA, a marker of regulatory T cells, when compared with controls and celiac patients 11 .…”

“…Uibo et al 11 detected the lowest expression of tight junction protein 1 (TJP1) mRNA in small bowel mucosa samples from celiac patients with diabetes mellitus type 1, indicating an increase in intestinal permeability. Furthermore, these samples displayed the highest expression of forkhead box P3 (FoxP3) mRNA, a marker of regulatory T cells, when compared with controls and celiac patients 11 . Antigen presenting cells (APC), which present antigens to T cells of the intestinal mucosa, are vital to the immunological processes.…”