Thesis (doctoral)--Universität Kiel, 1998. / Vita. Includes bibliographical references (p. 134-155).

Thesis (Ph. D.)--University of Washington, 1985. / Vita. Bibliography: leaves [113]-116.

The gastrointestinal tract forms the body’s largest interface with the external environment and is exposed to a vast amount of foreign material, including pathogenic and commensal bacteria, as well as food antigens. The gastrointestinal tract has multiple functions that are performed through complex interactions by its different components. It must be able to degrade food, absorb nutrients and eliminate waste, while at the same time maintain a balance between immune tolerance and protection against pathogenic and antigenic material. This concept of mucosally-induced tolerance is a key feature of the gut immune system, whereby a state of local and systemic unresponsiveness to food protein or systemic ignorance of commensal bacteria is maintained under homeostatic conditions through interactions between the host, dietary factors, and the intestinal microbiota. Dysfunctional interactions can lead to a breakdown in tolerance to otherwise innocuous antigens. One of the best characterized food sensitivities is celiac disease (CD). CD is a chronic immune-mediated disease triggered by the ingestion of gluten, the water insoluble protein fraction in wheat, rye and barley, in patients who are HLA/DQ2 or DQ8 positive. Celiac patients can experience a loss of oral tolerance to gluten any time throughout life. The clinical presentation of CD is variable and is often associated with extra-intestinal autoimmune diseases, such as type 1 diabetes (T1D). The increasing incidence of CD and the observation that only a small proportion of genetically susceptible individuals go on to develop active inflammation suggest a role for additional environmental factors in disease pathogenesis. The current treatment for CD is a strict, life-long adherence to a gluten-free diet (GFD), which is very demanding. Frequent gluten contamination can lead to persistent mucosal damage and symptoms, which have a negative effect on quality of life. Understanding the environmental and host factors that contribute to gluten tolerance is critical for the development of adjuvant therapies to the GFD. Therefore, the overall aim of my thesis is to characterize a humanized mouse model of gluten sensitivity in order to study factors that influence host-responses to gluten and to investigate potential therapeutic strategies. In chapter 3 of this thesis I characterized host responses to gluten using transgenic non-obese diabetic (NOD)/DQ8 mice. I found that gluten sensitization in NOD/DQ8 mice induced barrier dysfunction with a moderate degree of enteropathy and the development of anti-gliadin and anti-tissue-transglutaminase antibodies. I also explored the potential role of gluten in the development of T1D and found that gluten-induced barrier dysfunction was not sufficient to induce insulitis; a partial depletion of regulatory T cells (Tregs) plus gluten sensitization was required. In chapter 4, I utilized this model to demonstrate that the microbiota can modulate host responses to gluten. I found that both the presence and absence of a microbiota, as well as the composition of the microbiota influenced host responses to gluten in NOD/DQ8 mice. Finally, Chapters 5 and 6 of this thesis utilized transgenic DQ8 mice to explore two different adjuvant therapies for CD. In chapter 5, I showed that administration of a gluten binding polymer, P(HEMA-co-SS, to gluten-sensitive HLA/DQ8 mice reduced short-term and long-term gluten-induced barrier dysfunction and inflammation. In chapter 6, I discovered that elafin, a human anti-protease, was decreased in patients with active CD and in vitro, it inhibited the deamidation of gliadin peptides, a key step in the pathogenesis of CD. I showed that administration of elafin prevented gluten-induced barrier dysfunction and intraepithelial lymphocytosis. Together these results, (a) provide an in depth characterization of a humanized animal model for studying gluten-induced intestinal and extra-intestinal immune responses, (b) demonstrate the role of the microbiota as an environmental modulator of gluten-induced immune responses, (c) support the preclinical potential of two novel adjuvant therapies to the GFD. These findings emphasize the translational value of using relevant animal models to study the complex interactions between environmental and host factors that contribute to intestinal health and disease. / Thesis / Doctor of Philosophy (Medical Science)

No description available.

Celiac disease is a small intestinal immune-mediated enteropathy precipitated by exposure to gluten, a protein complex in the cereals wheat, barley and rye, in genetically susceptible people. Once considered an uncommon disorder restricted to children of European descent, it is now known to be one of the most common chronic diseases encountered in the Western world, with a serological prevalence of 1% that can be diagnosed at any age. Since it is so common much co-morbidity comprising malignant and non-malignant conditions will occur in association. Malignant complications particularly lymphoma were first described over 50 years ago but the natural history and how commonly these occurred were unknown until relatively recently. Similarly, many non-malignant conditions were known to occur but initially the risks were unclear. It was not until the frequency of coeliac disease could be determined accurately in the community and population-based studies of morbidity and mortality in coeliac disease patients carried out in defined cohorts that these questions could be answered. My research into these aspects of coeliac disease began in 1971 and a body of 35 of my publications spanning the years 1974 to 2018 on the morbidity and mortality of the disorder are presented in this thesis. I have introduced my research findings at many international and national meetings and these data have been influential in shaping the research agenda of other workers. One of my papers (Publication 9) published in Gut in 1989, was the most cited of all papers which appeared in the journal for that year. To date it has been cited 1122 times. Information exists for 24 papers presented here and for these the total number of citations stands at 3,887. This excludes references to book chapters. Anecdotal evidence indicates frequent mentions in lectures and clinical practice.

Thesis (MSD) --Boston University, Henry M. Goldman School of Dental Medicine, 2015 (Department of Molecular and Cell Biology). / Includes bibliography: leaves 46-50. / Celiac disease (CD) is an autoimmune disorder characterized by enteropathy caused by ingested gluten. Human transglutaminase 2 (TG 2) localized in the lamina propria of the small intestine modifies gluten by deamidating glutamine residues, which enhances gluten binding to T-cell receptors and downstream inflammatory immune responses. Many other human TGs and microbial transglutaminases (MTGs) share a similar catalytic activity with TG2. This study aimed to investigate the presence and activities of oral TGs from both human and microbial origins in whole saliva (WS) and dental plaque of healthy individuals. It also aimed to establish a method and positive control to detect MTG activity from oral bacteria. [TRUNCATED]

Thesis (M.S.)--California Polytechnic State University, 2009. / Mode of access: Internet. Title from PDF title page; viewed on September 23, 2009. Major professor: Michael Black, Ph.D. "Presented to the faculty of California Polytechnic State University, San Luis Obispo." "In partial fulfillment of the requirements for the degree [of] Master of Science in Biological Sciences." "May 2009." Includes bibliographical references (p. 82-85).

Thesis (Ph.D.)--University of Nebraska-Lincoln, 2009. / Title from title screen (site viewed September 08, 2009). PDF text: vii, 85 p. ; 645 K. UMI publication number: AAT 3352597. Includes bibliographical references. Also available in microfilm and microfiche formats.

INTRODUCTION: Celiac disease (CD), an inflammatory condition of the small bowel, is now recognized as the most common of the autoimmune disorders (Kenrick & Day, 2014). Unfortunately, due to poor awareness among primary care providers (PCPs) this disease remains highly underdiagnosed despite its increasing prevalence (Catassi & Fasano, 2008). Aims of this quality improvement project were to examine current knowledge and practices of nurse practitioners in the primary care setting that influence the screening and diagnosis of CD. METHODS: A 32-item survey was sent out to nurse practitioner primary care providers (NP- PCPs) in the Dallas-Fort Worth Metroplex over a four-week period. The survey assessed demographic characteristics, knowledge and clinical practices of nurse practitioners as it relates to CD diagnosis. Data was analyzed using SPSS and descriptive statistics. RESULTS: Eighteen valid responses were received for analysis. The majority of respondents reported having no familiarity with the American College of Gastroenterology (ACG) and National Institute for Health and Care Excellence (NICE) guidelines. Two thirds of the respondents reported their education did not properly prepare them to accurately diagnose celiac disease. The vast majority also reported they do not test patients, pediatric or adult, using any celiac related blood test. The same results were true for patients being sent for intestinal biopsy. Although able to list typical symptoms of CD, many respondents were unaware of atypical symptoms. Most also omitted family history as important when considering celiac related testing. CONCLUSIONS: Overall NP-PCPs are not aware of and therefore do not follow clinical guidelines related celiac disease. It is clear that NP-PCPs need to be made aware of the prevalence of this disease and should be directed to follow evidence-based practice guidelines in their primary care practices. One step for doing this includes providing better education for NP- PCP students. Educators should include lectures or discussions about CD in their curriculum and provide students with resources such as the NICE and ACG guidelines. For practicing NPs, free continuing education can be offered. Lastly, clinicians who are aware of the high rates of underdiagnosis can present CD related information at conferences and meetings.

The gluten-free diet is the only treatment available for gluten-related disorders, such as celiac disease, an autoimmune reaction to gluten, or non-celiac gluten or wheat sensitivity, a symptomatic reaction to wheat or gluten. However, gluten may not be the only culprit, and patients on a gluten-free diet have been suggested to symptomatically improve through the placebo effect, alterations in immune activity, and alterations in gut microbiota composition. It is unclear which of these mechanisms underlie symptoms in gluten-related disorders and well-designed clinical studies are needed to better understand them. This thesis aims to understand the mechanisms and symptomatic responses by which wheat and gluten affect individuals with gluten-related disorders. I hypothesize that patients with gluten-related disorders have increased psychological symptoms and immune reactivity which may be modulated by the gut microbiota. To test this, I conducted a clinical crossover trial to investigate whether whole wheat or gluten triggered symptoms versus gluten-free control, or nocebo, in irritable bowel syndrome patients adopting a gluten-free diet. Participants reacted similarly to each intervention, suggesting a strong 'nocebo effect' to be the main trigger of their symptoms. However, several participants did not comply to the protocol, muddying the results. Subsequent follow-up visits after disclosing personalized study results found no changes in participant beliefs, behaviours, and symptoms, and most remained on a gluten-free diet. Next, a systematic review of 65 observational studies found an elevated risk of IBD in celiac disease and vice versa. Finally, a systematic review of 6 RCTs found limited evidence that probiotics are safe and possibly therapeutic for ameliorating symptoms in celiac disease. Overall, the work presented in this thesis critically assesses the mechanisms by which gluten and wheat trigger symptoms in gluten-related disorders and highlights the importance of rigorous clinical trial design to control for psychological factors and patient compliance. / Thesis / Doctor of Philosophy (PhD) / Gluten, a wheat protein, is commonly associated with the autoimmune condition celiac disease, symptomatic worsening from gluten or wheat in non-celiac gluten/wheat sensitivity, and irritable bowel syndrome. This thesis strove to understand how gluten and other wheat proteins impact symptoms via psychological, immune, and/or bacteria-mediated pathways in gluten-related disorders. A clinical trial tested the effects of whole wheat, gluten, and gluten-free control on symptoms in irritable bowel syndrome patients on a gluten-free diet. We found no differences between interventions but discovered widespread diet non-compliance and that patient fears triggered symptoms. Informing patients of whether wheat, gluten, or gluten-free control triggered their symptoms did not change their dietary beliefs or behaviours. Additionally, two systematic reviews found a relationship between celiac disease and inflammatory bowel disease, and a possible therapeutic effect of probiotics in celiac patients. Our findings provided insights into the content and quality of the clinical evidence for gluten-related disorders.