Annotated Bibliography – Celiac Disease

  • Barratt, Stephen M., John S. Leeds, and David S. Sanders. “Factors Influencing the Type, Timing and Severity of Symptomatic Responses to Dietary Gluten in Patients with Biopsy-Proven Coeliac Disease.” Journal of gastrointestinal and liver diseases: JGLD4 (2013): 391–396. Print. Link Here

This study attempts to correlate the severity, timing and type of symptomatic responses that occur in patients with Celiac disease as a result of varying factors related to the disease. The authors questioned 224 individuals that conclusively had Celiac disease as determined through biopsy and found that patients adhering to a strict gluten free diet reported more severe reactions to gluten intake and were more likely to experience this severe reaction less than sixty minutes after the gluten intake as opposed to individuals who partially adhere to a gluten free diet. Other factors such as IBS and anxiety and depression also influenced the results of the study.

  • Casadio, Rita et al. “The Structural Basis for the Regulation of Tissue Transglutaminase by Calcium Ions.” European Journal of Biochemistry3 (1999): 672–679. Wiley Online Library. Web. 10 Mar. 2015. DOI:

In this article, the authors attempted to elucidate the mechanism and structure of tissue transglutaminase using homology modeling, molecular simulations, and SANS and SAXS techniques to confirm their model analysis. Using Clustal alignments as grounds for the homology model, the authors were able to construct a protein model for transglutaminase and identify a catalytic triad of Cys277, His335, and Asp358. The authors also determined using the model that tissue transglutaminase undergoes significant conformational change in the presence of Ca2+ ions but not in the presence of GTP, which they confirmed by SANS and SAXS analysis.

  • Caminero, Alberto et al. “Chapter 13 – Gluten Metabolism in Humans: Involvement of the Gut Microbiota.” Wheat and Rice in Disease Prevention and Health. Ed. Ronald Ross WatsonVictor R. PreedySherma Zibadi. San Diego: Academic Press, 2014. 157–170. ScienceDirect. Web. 2 May 2015. Link Here

This article discusses the metabolism of gliadin in individuals without Celiac disease, as well as the altered pathology involved in Celiac disease patients.

  • Di Sabatino, Antonio et al. “The Function of Tissue Transglutaminase in Celiac Disease.” Autoimmunity Reviews10 (2012): 746–753. ScienceDirect. Web. 10 Mar. 2015. DOI: 10.1016/j.autrev.2012.01.007

This paper is a review that discusses the underlying mechanism behind the toxicity of gliadin in patients with Celiac disease. The authors first discuss the traditional role of Tissue transglutaminase (tTG) in a non celiac patient, then transitioned to discussing the role to tTG as an autoantigen in patients with Celiac disease and the production of tTG-antibodies by preferential presentation of tTG deaminated gliain products by LA-DQ2 and HLA-DQ8 cells. The article finishes by discussing the inflammatory effects that result from this autoimmune response and proposing further research avenues.

  • Fasano, Alessio. “Zonulin and Its Regulation of Intestinal Barrier Function: The Biological Door to Inflammation, Autoimmunity, and Cancer.” Physiological Reviews1 (2011): 151–175. physrev.physiology.org. Web. 2 May 2015. DOI 10.1152/physrev.00003.2008

This article focuses on articulating the role of zonulin, its activation by luminally applied gliadin, and its role in Celiac disease pathogenesis.

  • Fasano, Alessio, and Carlo Catassi. “Celiac Disease.” New England Journal of Medicine25 (2012): 2419–2426. Taylor and Francis+NEJM. Web. 11 Mar. 2015. DOI 10.1056/NEJMcp1113994

This article offers diagnostic strategies for determining if a patient has Celiac disease, including serological tests, endoscopy, and small intestine biopsies.

  • Garrote, José Antonio et al. “Celiac Disease Pathogenesis: The Proinflammatory Cytokine Network:” Journal of Pediatric Gastroenterology and NutritionSuppl 1 (2008): S27–S32. CrossRef. Web. 20 Feb. 2015. DOI: 10.1097/MPG.0b013e3181818fb9

This review discuses the role of the pro-inflammatory response in celiac patients and the possible effects of the inability to control the inflammatory response. The authors discuss that multiple interleukins and IFN-gamma play an important role in initiating and maintaining the pro-inflammatory response triggered by gliadin peptides, and that the maintenance and inability to control this response may play a significant role in the pathogenesis of Celiac disease.

  • Garner, Chad et al. “Genome-Wide Association Study of Celiac Disease in North America Confirms FRMD4B as New Celiac Locus.” PLoS ONE7 (2014): n. pag. PubMed Central. Web. 10 Mar. 2015. DOI: 10.1371/journal.pone.0101428

This study focuses on identifying new and confirming suspected SNP’s that correlate to the presence of Celiac disease. The article addresses the fact that 35% of the disease risk comes as a result of having the HLA-DQ2 genotype (which is part of the major histocompatibility complex), but that there are also at least 40 other loci that are responsible for some of the disease risk. In order to identify new loci in which SNP’s are correlated with the disease, the authors performed a genome wide association study of 1550 North American celiac cases (3084 control cases) and determined 12 SNP’s across four regions were significantly correlated with the disease and that seven other SNP’s across four other regions were suggestive of correlation with the disease.

  • Henderson, Kate N. et al. “A Structural and Immunological Basis for the Role of Human Leukocyte Antigen DQ8 in Celiac Disease.” Immunity1 (2007): 23–34. ScienceDirect. Web. 10 Mar. 2015. DOI: 10.1016/j.immuni.2007.05.015

This paper provided a structure of HLA-DQ8 bound to a deamidated gliadine peptide. The authors demonstrated that the conformation of the peptide when bound to the protein allowed for sufficient solvent accessibility of the two glutamine residues on the substrate to bind to the T-cells which initiates the autoimmune response. They also demonstrated that substrates that lack these residues cannot bind the T cells

  • Iwańczak, Barbara, Krzysztof Matusiewicz, and Franciszek Iwańczak. “Clinical Picture of Classical, Atypical and Silent Celiac Disease in Children and Adolescents.” Advances in Clinical and Experimental Medicine: Official Organ Wroclaw Medical University5 (2013): 667–673. Print. Link Here

This article describes several common symptoms that are associated with Celiac disease including diarrhea, skin conditions, and general intestinal issues.

  • Kim, Chu-Young et al. “Structural Basis for HLA-DQ2-Mediated Presentation of Gluten Epitopes in Celiac Disease.” Proceedings of the National Academy of Sciences of the United States of America12 (2004): 4175–4179. PubMed Central. Web. 11 Mar. 2015. DOI: 10.1073/pnas.0306885101

In this paper, the authors solved the structure of HLA-DQ2 with an immunogenic epitope of gluten. The authors discerned that the glutimate residue present due to the deamidation of the gluten peptide plays a crucial role in binding HLA-DQ2. The authors also suggest that the ability of the HLA-DQ2 variant to more capably bind proteins high in proline concentration plays a significant role in its association with celiac disease.

  • Koning, Frits et al. “Pathomechanisms in Celiac Disease.” Best Practice & Research Clinical Gastroenterology3 (2005): 373–387. ScienceDirect. Web. 10 Mar. 2015. Coeliac Disease. DOI: 10.1016/j.bpg.2005.02.003

This review quite literally covers everything. It has sections on the genetic susceptibility, the role of tissue transglutaminase, the diagnosis of Celiac disease, the modification of gliadin by tissue transglutaminase, the role of specific gliadin peptides in the activation of the innate immunity response, tissue transglutaminase as an autoantigen, the gliadin specific B-lymphocyte response, and finally the role of IL-15 in the inflammatory pathway in Celiac patients.

  • Lammers, Karen M. et al. “Gliadin Induces an Increase in Intestinal Permeability and Zonulin Release by Binding to the Chemokine Receptor CXCR3.” Gastroenterology1 (2008): 194–204.e3. PubMed Central. Web. 1 May 2015. DOI 10.1053/j.gastro.2008.03.023

This article discusses the role of zonulin and its associated to gliadin binding. It mainly focuses on how gliadin binding to the CXCR3 receptor is significant in the pathogenesis of Celiac disease.

  • Liu, Edwin et al. “Risk of Pediatric Celiac Disease According to HLA Haplotype and Country.” The New England journal of medicine1 (2014): 42–49. PubMed Central. Web. 10 Mar. 2015. DOI: 10.1056/NEJMoa1313977

This study attempted to correlate the presence of the HLA-DQ2 or HLA-DQ8 haplotypes to having an increased risk of having celiac disease. The authors concluded that individuals with the HLA-DQ2 haploytpye, especially homozygotes, were much more likely to develop Celiac disease in early childhood. The authors found that 26% of homozygous for HLA-DQ2 developed Celiac disease and 11% of heterozygous for HLA-DQ2 and HLA-DQ4 developed the disease (other genotypes were also included), suggesting that HLA-DQ2 offers the most susceptibility to the disease.

  • Nanayakkara, Merlin et al. “Enterocyte Proliferation and Signaling Are Constitutively Altered in Celiac Disease.” PloS One10 (2013): e76006. NCBI PubMed. Web. DOI: 10.1371/journal.pone.0076006

This article discusses the interaction between the gliadin peptide and epithelial growth factor receptor (EGFR) signaling which is responsible for enterocyte proliferation. The authors demonstrated that crypts enterocytes proliferation was up regulated in CD patients and that this increase in proliferation is dependent upon EGFR and IL-15 signaling. The authors also showed that patients both of and off a gluten free diet showed signs of increased crypts enterocyte proliferation, which suggested that something about the Celiac mucosal membrane leaves them susceptible to the proliferation in the presence of gliadin peptides.

  • Niewinski, Mary M. “Advances in Celiac Disease and Gluten-Free Diet.” Journal of the American Dietetic Association4 (2008): 661–672. ScienceDirect. Web. 10 Mar. 2015. DOI: 10.1016/j.jada.2008.01.011

This article discusses that currently the only treatment to celiac disease is a lifelong adherence to a gluten free diet. The authors also discuss the possibility of refractory celiac disease, in which an individual may not respond completely to a gluten free diet and still experience some of the symptoms.

  • Nisticò, L et al. “Concordance, Disease Progression, and Heritability of Coeliac Disease in Italian Twins.” Gut6 (2006): 803–808. PubMed Central. Web. 2 May 2015. DOI 10.1136/gut.2005.083964

This study focuses on determining the genetic heritability of Celiac disease by studying the concordance rate of Celiac disease in dizygotic and monozygotic twins.

  • Paolella, Gaetana et al. “Celiac Anti-Type 2 Transglutaminase Antibodies Induce Phosphoproteome Modification in Intestinal Epithelial Caco-2 Paolella, Gaetana et al. “Celiac Anti-Type 2 Transglutaminase Antibodies

This paper attempt to elucidate the mechanism behind which the intake of gliain in CD patients, which stimulates the otherwise silent type 2 transglutaminase (TG2) specific B-lymphocytes, is responsible for the pathogenic nature of the disease. The authors previously showed that these antibodies inhibit the ability of TG2 to repair mucosal membranes by reducing its catalytic activity and now hypothesize that the anti-TG2 antibodies result in Celiac symptoms due to their interaction with membrane bound TG2 and subsequent disruption of signaling pathways in which TG2 is involved (specifically the phosphorylation of various proteins). The authors treated Caco-2 cells with recombinant TG2 antibodies and used different analyses like 2D electrophoresis coupled with specific staining of phosphoproteins and subsequent MS to conclude that 9 proteins in the Caco-2 cells were hyper-phosphorylated and 3 proteins were hypo-phosphorylated, which suggested to them that the presence of TG2 antibodies disrupted cell homeostasis by acting as a signaling molecule

  • Papp, Maria et al. “Haptoglobin Polymorphism: A Novel Genetic Risk Factor for Celiac Disease Development and Its Clinical Manifestations.” Clinical Chemistry4 (2008): 697–704. www.clinchem.org. Web. 2 May 2015. DOI 10.1373/clinchem.2007.098780

This paper explores the evolution of a new polymorphism that is strongly associated with Celiac disease and has relevance as to the increased expression of zonulin in Celiac patients’ small intestines.

  • Paveley, W. F. “From Aretaeus to Crosby: A History of Coeliac Disease.” BMJ : British Medical Journal6664 (1988): 1646–1649. Print. Link Here

This paper simply offers a general history of Celiac disease, dating back to the second century AD, in which Aretaeus most likely gave the first report of the disease and gave it its title (the Coeliac Affection). The next report of Celiac disease was supposedly 1700 years later, in 1887, when Dr. Samuel Jones Gee recognized that the disease could be controlled by diet but really failed miserably to discern what the proper diet should consist of. The article then discusses a few early treatments and schools of thought on the cause (including a nervous problem and a diet excluding potatoes, cereal, bread, and crackers) before finally discussing that William-Karel Dicke uncovered the relationship between wheat and the disease in the late 1950’s.

  • Schuppan, Detlef. “Current Concepts of Celiac Disease Pathogenesis.” Gastroenterology1 (2000): 234–242. ScienceDirect. Web. 1 May 2015. DOI 10.1053/gast.2000.8521

This article gives a summary of the pathogenesis of Celiac disease, commenting mostly on the interaction gliadin peptides have with the intestinal mucosa and the subsequent immune response.

  • Schuppan, Detlef, Birgit Esslinger, and Walburga Dieterich. “Innate Immunity and Coeliac Disease.” The Lancet9377 (2003): 3–4. ScienceDirect. Web. 10 Mar. 2015. DOI: 10.1016/S0140-6736(03)13843-3

This article is a shorter review that discusses the relationship between innate immunity and Celiac disease. The article states that it is clear that certain gluten peptides elicit the innate immune response (only found in HLA-DQ2 positive patients) whereas other elicit the adaptive immune response. The article also suggests that in order to further elucidate the disease, the next step might be to identify loci involved in the innate immune response that are correlated with Celiac disease.

  • Sollid, Ludvig M., and Chaitan Khosla. “Future Therapeutic Options for Celiac Disease.” Nature Clinical Practice Gastroenterology & Hepatology 2.3 (2005): 140–147. www.nature.com. Web. 1 May 2015. DOI 10.1038/ncpgasthep0111

Many of the options this article discusses focus on the interaction between either gliadin and the tight junctions of the small intestine, or the preemptive digestion of gliadin by additional enzymes

  • Sollid, L. M., and C. Khosla. “Novel Therapies for Coeliac Disease.” Journal of Internal Medicine6 (2011): 604–613. Wiley Online Library. Web. 3 May 2015. DOI 10.1111/j.1365-2796.2011.02376.x

This article is essentially an updated version of the article above it.

  • Van Berge-Henegouwen, G P, and C J Mulder. “Pioneer in the Gluten Free Diet: Willem-Karel Dicke 1905-1962, over 50 Years of Gluten Free Diet.” Gut11 (1993): 1473–1475. Print. Link Here

This article also discusses William-Karel Dicke and his contribution to the development of the gluten free diet as a result of over 50 years of research. Dicke performed studies in which he maintained children on wheat free diets in hospitals and witnessed normalized growth and weight gain (once these children were sent home and the diet was not maintained, the weight gain and growth decreased again). Finally, Dicke concluded that wheat and rye starches were responsible for the anorexia and mal absorption seen in patients with celiac disease, and even went one step further to conclude (with the help of biochemists Van der Kamer and Weyers) that gliadin, the water insoluble portion of the gluten component of wheat, was the protein responsible for the symptoms seen in Celiac patients.

  • van der Windt DM et al. “Diagnostic Testing for Celiac Disease among Patients with Abdominal Symptoms: A Systematic Review.” JAMA17 (2010): 1738–1746. Silverchair. Web. 3 May 2015. Link Here

This article discusses the canonical diagnostic methods for determining if a patient has Celiac disease and comments on their efficacy.

  • Van Heel, David A. et al. “Genetics in Coeliac Disease.” Best Practice & Research Clinical Gastroenterology3 (2005): 323–339. ScienceDirect. Web. 10 Mar. 2015. Coeliac Disease. DOI: 10.1016/j.bpg.2005.01.001

This review discusses the importance of the HLA-DQ2 mutation in Celiac patients, however also works to identify other genetic factors that are significant in the development of Celiac disease. The authors discuss the identification of regions on chromosomes 5 and 19 that are strongly linked to Celiac disease, and discuss variant versions of the chromosome 2q CD28-CTLA4-ICOS region that are also weakly linked to the disease.

  • Vanga, Rohini R., and Ciaran P. Kelly. “Novel Therapeutic Approaches for Celiac Disease.” Discovery Medicine95 (2014): 285–293. Print. Link Here

This review discuses novel treatments for Celiac disease that differ from the traditional non-gluten diet. The authors discus the possibility of glutenase enzymes to detoxify gliadin, molcules that would reduce the access of gliadin to the antigen presenting cells, molecules that would inhibit tissue transglutaminase to disallow the modified gliadin molecules from binding to the HLA-DQ2 and HLA-DQ4, and modulation of the increased inflammatory response. These are in response to some patients who have shown incomplete response to a gluten free diet.

 

Jump to other pages of Celiac disease:

Title Page

History and Metabolic Context

Molecular Basis of the Disease State

Treatment and Disease Management

Conclusions and Proposals for Future Work