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Aethiopathology of coeliac Disease
Medicine (A100)
Queen Mary University of London
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MSc Gastroenterology 2009 / 10 Assignment for Professor Parveen Kumar Aethiopathology of coeliac Disease Words count: 1,358 Dr. Eltagi A. Yousef Abbreviations used in this assignment APCs - Antigen Presenting Cells CD - Coeliac Disease CS - Coelicac Sprue CTLs - Cytotoxic T lymphocytes HLA - Human leukocyte antigen IELs - Intraepithelial Lymphocytes IFN-a – Interferon Alfa IL-2 – Interleukin 2 LP - Lamina Propria MHC - Major Histocompatibilty Complex NaCl – Sodium Chloride NK – Nature Killer SI - small intestine TNF-a – Tumour Necrosis Factor Alfa tTG or TG2 - Tissue Transglutaminase Aethiopathogenesis The interaction of the water-insoluble protein fragment (gluten) of particular cereals (wheat, rye, barley and oats) with the mucosa of the upper SI in susceptible individuals, play the key role in the pathogenesis of CD As mentioned early the CD is considered to be an immune disorder that is triggered by environmental agent (gliadin) in genetically predisposed persons. The wide spectrum of clinical picture of CD is the result of a complex intervention of varying environmental, genetic and immune factors. Environmental Factors These include: The age of introduction of the first gluten containing diet to the infant and breast-feeding, rotavirus infection and adenovirus-12 which has structural similarity with α-gliadin. According to solubility properties, identified several wheat proteins as being responsible for the grain toxicity in CD. Wheat proteins are prolamins (soluble in ethanol), glutenins (soluble in dilute acid or alkali solution), globulins (soluble in 10% NaCl) and little albumins (soluble in water). Gluten is the cohesive mass remaining after washing dough. It is encompasses the prolamins and the glutenins. The prolamins of wheat are referred to as gliadins. Prolamins from other cereals named according to their source – secalins from rye, hordeins from barley, avenins from oats and zeins from corn. Rice, corn and sorghum are grains that do not activate the CD. There are four subset of gliadin – alfa, beta, gamma and omega, and all of them are toxic to patients with CD, but, among of those fractions the α-gliadin is the most damaging one to the mucosa of upper SI. The hypothesis of progression of CD is thought to be result from multistep process of intermolecular and intramolecular antigen spreading. With disease progression there an increase in intracellular tissue transglutaminase (tTG or TG2), which is activated by high extracellular Ca+2 ions and may lead to progressive deamination of glutens and enhancement of gliadin-specific CD4+ T cells response. α-gliadin induces lesion of upper IS mucosa by recruitment of IELs. Gianfran and colleagues reported that α-gliadin-derived peptide is recognized by CD8+ T lymphocytes and is associated with cytotoxic activity in patients with CD. The tTG plays a key role in pathogenesis of CD. It is induces formation of aggregates of gluten and dendritic cells endocytose these readily. Also TG2 deaminidates glutamine residues on gluten that make the peptides fit better into HLA DQ2 and DQ8 antigen pockets and that makes it “taster” to T cells and improves their activation. Rotavirus and its antigen can break mucosal protective barrier directly or indirectly by the local production of anti-rotavirus antibody. Due to cross-reactivity between rotavirus protein and a-gliadin, the anti-rotavirus antibodies bind to gliadin and form immune complexes with it. The combination of infection antibody cross-reactivity with gliadin and others stressors can severely lead to impairment of mucosal integrity and entry of gliadin peptides, tight junction proteins and other antigens into submucosa, regional lymph nodes and blood stream. All these antigens will be endocytosed and presented by dendritic cells with HLA-DQ2 or HLA-DQ8 to CD4+ T lymphocyte. Subsequently CD4+ T cells activate T H1 which produces proinflammatory cytokines (IFN-a) leading to mucosal damage. Also CD4+ T cells activate TH2 which in turn lead to activation B cell resulting in production of antibodies participating in more mucosal damage. Genetic factors Observation by Howell and Coworkers reveals that the CD was associated with specific HLA-DQ2 haplotypes. The HLA-D (human leukocyte antigen) is the MHC class II (major histocompatibilty complex) molecules involved in antigen presenting to CD4+ T cells The HLA-DQ2 is found in 95% of patients (compared with 30% of controls) and HLADQ8 is found in most of the remaining patients with CD. After gluten is absorbed an antigen presenting cells (APCs) of lamina propria probably dendritic cells, that express HLA-DQ2 or HAL-DQ8 present gliadin peptide on their antigen presenting grooves to CD4+ T lymphocytes. These lymphocytes then activate TH1 to secrete cytokine mainly, IFN-, TNF- IL-2, and IL-6 which lead to enterocytes damage and induce expression of aberrant HLA class II on luminal surface of enterocytes which facilitates direct antigen presentation to CD4+ T lymphocytes. In turn activation of TH2 leads to activation of B cells resulting in producing a lot of anybodies (IgA, IgG and IgM) against gluten, tTG, tight junction proteins and other tissue proteins. Non-HLA genes involved in progression of CD are molecules affecting the ‘immunological synapse’:CD247 (T cell receptor-zeta), CD28, and CD80. Cytokines and chemokines: IL2/IL21, IL12A, CCR4, CCR gene cluster. T cell development in the thymus: THEMIS, RUNX3, ETS1, TNFSFR14 and innate immune detection of viral RNA: TLR8. Conclusion Coeliac disease is a chronic multifactorial (environmental, genetic and immune) condition, triggers by gluten intolerance leading to upper small intestine mucosal damage. There is a significant role played by CD4+ T cells, APCs and IELs. But whatever causative factor, the treatment is one – gluten-free diet. Coeliac Disease 9 months gluten-free diet References 1. Kumar & Clark’s (2009). Clinical Medicine. 7th ed. London: Elsevier Limited. 2. Sleisenger and Fordtran’s (2006). Gastrointestinal and Liver Disease. 8th ed. Philadelphia: Saunders Elsver. 3. Mark Peakham and Diego Vergani (1997). Basic and Clinical Immunology. 1th ed. London: Pearson Professional Limited 4. Jue Underwood (2000). Pathology, General and Systemic. 3rd ed. London: Harcourt Publishers Limited. 5. Wikimedia foundation, San Francisco, USA [Internet] Available from <wikimediafoundation>. [Accessed many times] 6. Dr. Vince McDonald’s, Lecture material for MSc gastroenterology QMUL and others 2009/10 7. Sollid LM 2002. Coeliac disease: dissecting a complex inflammatory disorder. Nature Reviews Immunology 2: 647-655. 8. Meresse B et al. 2006. Reprogramming of CTLs into natural killer –like cells in celiac disease. J Exp Med 203: 1343-1355 9. Di Sabatino A et al. 2006. Epithelium derived interleukin 15 regulates intraepithelial lymphocyte Th1 cytokine production, cytotoxicity and survival in coeliac disease. Gut 55: 469-477. 10 Sabatino A et al. 2007. Evidence for the role of interferon-alfa production by dendritci cells in the Th1 response in celiac disease. Gastroenterology 133: 11751187
Aethiopathology of coeliac Disease
Module: Medicine (A100)
University: Queen Mary University of London
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