Dr. Ron’s Research Review – May 25, 2011

This week’s research review focuses on recent research on celiac disease.

Gluten sensitivity, albeit gluten-induced, is different from celiac disease. Both are triggered by the ingestion of wheat gliadin. CD, but not GS, is associated with and possibly mediated by an autoimmune process.  (Sapone, Lammers et al. 2010)

Gluten-sensitive individuals (GS) cannot tolerate gluten and may develop gastrointestinal symptoms similar to those in CD, but the overall clinical picture is generally less severe and is not accompanied by the concurrence of tissue transglutaminase autoantibodies or autoimmune comorbidities. (Sapone, Lammers et al. 2011)

It is essential that patients with Type 1 diabetes mellitus, regardless of presence or absence of symptoms, should be investigated for celiac disease and autoimmune thyroid disorders. (Ergur, Ocal et al. 2011)

The prevalence of celiac disease was high in elderly people, but the symptoms were subtle. (Vilppula, Kaukinen et al. 2009)

Improved Xenobiotic Metabolism and Reduced Susceptibility to Cancer in Gluten-Sensitive Macaques upon Introduction of a Gluten-Free Diet (Sestak, Conroy et al. 2011)

Dr. Ron


Articles

Differential mucosal IL-17 expression in two gliadin-induced disorders: gluten sensitivity and the autoimmune enteropathy celiac disease

            (Sapone, Lammers et al. 2010) Download

BACKGROUND: The immune-mediated enteropathy, celiac disease (CD), and gluten sensitivity (GS) are two distinct clinical conditions that are both triggered by the ingestion of wheat gliadin. CD, but not GS, is associated with and possibly mediated by an autoimmune process. Recent studies show that gliadin may induce the activation of IL-17-producing T cells and that IL-17 expression in the CD mucosa correlates with gluten intake. METHODS: The small-intestinal mucosa of patients with CD and GS and dyspeptic controls was analyzed for expression of IL-17A mRNA by quantitative RT-PCR. The number of CD3+ and TCR-gammadelta lymphocytes and the proportion of CD3+ cells coexpressing the Th17 marker CCR6 were examined by in situ small-intestinal immunohistochemistry. RESULTS: Mucosal expression of IL-17A was significantly increased in CD but not in GS patients, compared to controls. This difference was due to enhanced IL-17A levels in >50% of CD patients, with the remainder expressing levels similar to GS patients or controls, and was paralleled by a trend toward increased proportions of CD3+CCR6+ cells in intestinal mucosal specimens from these subjects. CONCLUSION: We conclude that GS, albeit gluten-induced, is different from CD not only with respect to the genetic makeup and clinical and functional parameters, but also with respect to the nature of the immune response. Our findings also suggest that two subgroups of CD, IL-17-dependent and IL-17-independent, may be identified based on differential mucosal expression of this cytokine.

Divergence of gut permeability and mucosal immune gene expression in two gluten-associated conditions: celiac disease and gluten sensitivity

            (Sapone, Lammers et al. 2011) Download

BACKGROUND: Celiac disease (CD) is an autoimmune enteropathy triggered by the ingestion of gluten. Gluten-sensitive individuals (GS) cannot tolerate gluten and may develop gastrointestinal symptoms similar to those in CD, but the overall clinical picture is generally less severe and is not accompanied by the concurrence of tissue transglutaminase autoantibodies or autoimmune comorbidities. By studying and comparing mucosal expression of genes associated with intestinal barrier function, as well as innate and adaptive immunity in CD compared with GS, we sought to better understand the similarities and differences between these two gluten-associated disorders. METHODS: CD, GS and healthy, gluten-tolerant individuals were enrolled in this study. Intestinal permeability was evaluated using a lactulose and mannitol probe, and mucosal biopsy specimens were collected to study the expression of genes involved in barrier function and immunity. RESULTS: Unlike CD, GS is not associated with increased intestinal permeability. In fact, this was significantly reduced in GS compared with controls (P = 0.0308), paralleled by significantly increased expression of claudin (CLDN) 4 (P = 0.0286). Relative to controls, adaptive immunity markers interleukin (IL)-6 (P = 0.0124) and IL-21 (P = 0.0572) were expressed at higher levels in CD but not in GS, while expression of the innate immunity marker Toll-like receptor (TLR) 2 was increased in GS but not in CD (P = 0.0295). Finally, expression of the T-regulatory cell marker FOXP3 was significantly reduced in GS relative to controls (P = 0.0325) and CD patients (P = 0.0293). CONCLUSIONS: This study shows that the two gluten-associated disorders, CD and GS, are different clinical entities, and it contributes to the characterization of GS as a condition associated with prevalent gluten-induced activation of innate, rather than adaptive, immune responses in the absence of detectable changes in mucosal barrier function.

Improved Xenobiotic Metabolism and Reduced Susceptibility to Cancer in Gluten-Sensitive Macaques upon Introduction of a Gluten-Free Diet

            (Sestak, Conroy et al. 2011) Download

BACKGROUND: A non-human primate (NHP) model of gluten sensitivity was employed to study the gene perturbations associated with dietary gluten changes in small intestinal tissues from gluten-sensitive rhesus macaques (Macaca mulatta). METHODOLOGY: Stages of remission and relapse were accomplished in gluten-sensitive animals by administration of gluten-free (GFD) and gluten-containing (GD) diets, as described previously. Pin-head-sized biopsies, obtained non-invasively by pediatric endoscope from duodenum while on GFD or GD, were used for preparation of total RNA and gene profiling, using the commercial Rhesus Macaque Microarray (Agilent Technologies),targeting expression of over 20,000 genes. PRINCIPAL FINDINGS: When compared with normal healthy control, gluten-sensitive macaques showed differential gene expressions induced by GD. While observed gene perturbations were classified into one of 12 overlapping categories - cancer, metabolism, digestive tract function, immune response, cell growth, signal transduction, autoimmunity, detoxification of xenobiotics, apoptosis, actin-collagen deposition, neuronal and unknown function - this study focused on cancer-related gene networks such as cytochrome P450 family (detoxification function) and actin-collagen-matrix metalloproteinases (MMP) genes. CONCLUSIONS/SIGNIFICANCE: A loss of detoxification function paralleled with necessity to metabolize carcinogens was revealed in gluten-sensitive animals while on GD. An increase in cancer-promoting factors and a simultaneous decrease in cancer-preventing factors associated with altered expression of actin-collagen-MMP gene network were noted. In addition, gluten-sensitive macaques showed reduced number of differentially expressed genes including the cancer-associated ones upon withdrawal of dietary gluten. Taken together, these findings indicate potentially expanded utility of gluten-sensitive rhesus macaques in cancer research.

Celiac Disease and Autoimmune Thyroid Disease in Children with Type 1 Diabetes Mellitus: Clinical and HLA-Genotyping Results

            (Ergur, Ocal et al. 2011) Download

Objective: Increased prevalence of celiac disease (CD) and autoimmune thyroid disorders (ATD) in patients with Type 1 diabetes mellitus (T1D) has been widely reported. Such an association may lead to adverse effects on the growth, bone metabolism and fertility, and response to therapy may become difficult. The aim of this study was to evaluate the clinical findings and HLA typing results in patients with T1D associated with CD or ATD.Methods: The association of CD and ATD was evaluated in 38 children with T1D aged 1.5-16.8 years who had been followed for 48.3+/-28 months. Diagnosis of CD was based on positivity for serum endomysial IgA antibody and histopathological findings of intestinal biopsy specimens. Thyroid autoimmunity was assessed by antithyroglobulin and antithyroid peroxidase antibodies and with diagnostic ultrasonographic findings.Results: ATD was detected in 31.5%, and CD-in 7.8% of T1D patients. Subjects with CD showed either no symptoms or suggestive problems such as short stature, hepatosteatosis, pubertal delay and difficulties in the control of diabetes. Patients with ATD had no clinical symptoms. DQ8 was the most prominent finding in CD.Conclusions: It is essential that patients with T1D, regardless of presence or absence of symptoms, should be investigated for CD and ATD.Conflict of interest:None declared.

Celiac disease: how complicated can it get?

            (Tjon, van Bergen et al. 2011) Download

In the small intestine of celiac disease patients, dietary wheat gluten and similar proteins in barley and rye trigger an inflammatory response. While strict adherence to a gluten-free diet induces full recovery in most patients, a small percentage of patients fail to recover. In a subset of these refractory celiac disease patients, an (aberrant) oligoclonal intraepithelial lymphocyte population develops into overt lymphoma. Celiac disease is strongly associated with HLA-DQ2 and/or HLA-DQ8, as both genotypes predispose for disease development. This association can be explained by the fact that gluten peptides can be presented in HLA-DQ2 and HLA-DQ8 molecules on antigen presenting cells. Gluten-specific CD4(+) T cells in the lamina propria respond to these peptides, and this likely enhances cytotoxicity of intraepithelial lymphocytes against the intestinal epithelium. We propose a threshold model for the development of celiac disease, in which the efficiency of gluten presentation to CD4(+) T cells determines the likelihood of developing celiac disease and its complications. Key factors that influence the efficiency of gluten presentation include: (1) the level of gluten intake, (2) the enzyme tissue transglutaminase 2 which modifies gluten into high affinity binding peptides for HLA-DQ2 and HLA-DQ8, (3) the HLA-DQ type, as HLA-DQ2 binds a wider range of gluten peptides than HLA-DQ8, (4) the gene dose of HLA-DQ2 and HLA-DQ8, and finally,(5) additional genetic polymorphisms that may influence T cell reactivity. This threshold model might also help to understand the development of refractory celiac disease and lymphoma.

Increasing prevalence and high incidence of celiac disease in elderly people: a population-based study

            (Vilppula, Kaukinen et al. 2009) Download

BACKGROUND: Celiac disease may emerge at any age, but little is known of its appearance in elderly people. We evaluated the prevalence of the condition in individuals over 55 years of age, and determined the incidence of biopsy-proven celiac disease (CDb) and celiac disease including seropositive subjects for anti-tissue transglutaminase antibodies (CDb+s). METHODS: The study based on prevalence figures in 2815 randomly selected subjects who had undergone a clinical examination and serologic screening for celiac disease in 2002. A second screening in the same population was carried out in 2005, comprising now 2216 individuals. Positive tissue transglutaminase antibodies were confirmed with small bowel biopsy. RESULTS: Within three years the prevalence of CDb increased from 2.13 to 2.34%, and that of CDb+s from 2.45 to 2.70%. Five new cases were found among patients previously seronegative; two had minor abdominal symptoms and three were asymptomatic. The incidence of celiac disease in 2002-2005 was 0.23%, giving an annual incidence of 0.08% in this population. CONCLUSION: The prevalence of celiac disease was high in elderly people, but the symptoms were subtle. Repeated screening detected five biopsy-proven cases in three years, indicating that the disorder may develop even in the elderly. Increased alertness to the disorder is therefore warranted.


References

Ergur, A. T., G. Ocal, et al. (2011). "Celiac Disease and Autoimmune Thyroid Disease in Children with Type 1 Diabetes Mellitus: Clinical and HLA-Genotyping Results." J Clin Res Pediatr Endocrinol 2(4): 151-4.

Sapone, A., K. M. Lammers, et al. (2011). "Divergence of gut permeability and mucosal immune gene expression in two gluten-associated conditions: celiac disease and gluten sensitivity." BMC Med 9: 23.

Sapone, A., K. M. Lammers, et al. (2010). "Differential mucosal IL-17 expression in two gliadin-induced disorders: gluten sensitivity and the autoimmune enteropathy celiac disease." Int Arch Allergy Immunol 152(1): 75-80.

Sestak, K., L. Conroy, et al. (2011). "Improved Xenobiotic Metabolism and Reduced Susceptibility to Cancer in Gluten-Sensitive Macaques upon Introduction of a Gluten-Free Diet." PLoS One 6(4): e18648.

Tjon, J. M., J. van Bergen, et al. (2011). "Celiac disease: how complicated can it get?" Immunogenetics 62(10): 641-51.

Vilppula, A., K. Kaukinen, et al. (2009). "Increasing prevalence and high incidence of celiac disease in elderly people: a population-based study." BMC Gastroenterol 9: 49.