By Ciara Coleman PhD
Coeliac Disease (CD) is defined as a common, chronic inflammatory disease of the small intestine that occurs in genetically predisposed individuals and is triggered by exposure to the storage protein of wheat – gluten – and similar proteins in related grains (Schuppan et al., 2009). The word coeliac, meaning “hollow” in Greek, was first described by the Greek physician Aretaeus in the first century AD (Thomas, 1945). Although the first real description of Coeliac Disease came in 1888 by Samuel Gee (Gee, 1888), the link between Coeliac Disease and diet wasn’t established until the 1950s by Willem Dicke. Dicke a Dutch paediatrician, highlighted the role wheat played in the onset of CD and how its exclusion from the diet led to dramatic improvements in patients symptoms (Dicke, 1950). The link between gluten and Coeliac Disease was made in 1952 by Anderson et al (1952).
The histological classification of Coeliac Disease was not formalised until 1992 when Marsh (Marsh, 1992) established a grading system for the intestinal damage seen in the coeliac lesion. It consisted of 3 stages ranging from lymphocyte infiltration and crypt hyperplasia to total villous atrophy. Coeliac Disease was thought of as primarily a paediatric disease for a very long time. It is now clear that the onset of Coeliac Disease (CD) can occur at any age, from early infancy to late adulthood.
Symptoms of Coeliac Disease
Coeliac Disease (CD) symptoms vary between infants, adolescents and adults. Young children generally present with “classical” CD symptoms such as diarrhoea, failure to thrive and abdominal distension (Vivas et al., 2008). Older children and adolescents often show atypical gastrointestinal symptoms such as pain, vomiting or constipation. They also present with extraintestinal symptoms such as arthritis, anaemia and neurological symptoms. Adults normally present with diarrhoea, anaemia, osteoporosis, IBS, bloating, chronic fatigue and signs of villous atrophy among 3 others (Tengah et al., 2002) (Rampertab et al., 2006).
Currently the only effective therapy for the treatment of Coeliac Disease (CD) is a gluten free diet (GFD). If left untreated, CD has been associated with increased morbidity and mortality (Corrao et al., 2001).
The European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) guidelines for the diagnosis of CD was first published in 1990. Diagnosis requires both accurate histological and serological testing (Walker-Smith et al., 1990). Thus, the requirement of both histological and serological testing has been the gold standard for diagnosing CD for over 20 years.
Gluten is the protein fraction of wheat, barley and rye, which is responsible for the induction of Coeliac Disease (CD). The gluten protein itself can be divided into ethanol-soluble prolamins (gliadin) and ethanol-insoluble glutenins. The storage proteins (prolamins) of wheat are enriched in glutamine (>30%) and proline (>15%) (Schuppan, 2000). Similar storage proteins are present in barley (hordeins) and rye (secalines).
Several of the gluten epitopes are immune-stimulatory, however some are more vigorous than others. An immune-dominant peptide of α-gliadin has been identified that is composed of 33 amino acids (residues 57-89). Theses are resistant to degradation by human intestinal, gastric and pancreatic proteases (Shan et al., 2002;Di Sabatino and Corazza., 2009). An inflammatory response is generated against derivatives of this peptide primarily in the upper small intestine in patients with CD. This reaction is mediated by the innate and adaptive immune systems. It is characterized by the infiltration of intraepithelial lymphocytes (IELs) and lamina propria lymphocytes (LPLs) to the small intestine alongside villous atrophy.
Coeliac Disease Pathogenesis and HLA molecules
A large body of evidence supports a genetic contribution to Coeliac Disease Pathogenesis. There is a high degree of familial aggregation with about 5-15% of first-degree relatives being affected. A much larger concordance rate, 83-86% among monozygotic twins compared with 11% in dizygotic twins (Greco et al., 2002).
Genetic linkage studies have shown that the disease is most strongly associated with HLA-DQ genes. 90% of Coeliac Disease (CD) patients carry a variant of the DQ2 (DQ2.5 – composed of DQA1*0501-DQB1*0201 chains or DQ2.2 – DQA1*0201-DQB1*0202) heterodimer. The majority of the remaining patients are carriers of the DQ8 (DQA1*0301-DQB1*0302) heterodimer (Gutierrez-Achury et al., 2011). The HLA-DQ2.5 variant can be encoded on several haplotypes. Both DQA1*0501 and DQB1*0201 are located on the same DR3-DQ2 haplotype and thus the HLA-DQ2.5 heterodimer is encoded in cis in this instance. Alternatively, the DQ2.5 variant is encoded in trans when these two genes (DQA and DQB) are located on different haplotypes. For example, DR5-DQ7 (DQA1*0505) and DR7-DQ2 (DQB1*0202). Both of these haplotypes produce a similar disease risk (Abadie et al., 2011).
Individuals that carry two copies of the DQB1*02 allele i.e. homozygous for the DR3-DQ2 haplotype or heterozygous for the DR3-DQ2/DR7-DQ2 haplotype have a particularly increased risk for CD (Sollid and Lie, 2005;Abadie et al., 2011). It is reported that approximately 41% of the genetic susceptibility of CD can be explained by the HLA molecules (Gutierrez-Achury et al., 2015). However, the HLA molecules alone are not sufficient to cause CD as approximately 40% of the general population carry either HLA-DQ2/DQ8, but only 1% actually develops CD. This shows that although these alleles are necessary, they are not sufficient to cause CD. Thus, supporting the role of environmental susceptibility factors as well as further genetic risk factors in CD pathogenesis.
Immunological role of the HLA risk variants
The ingestion of gluten in genetically susceptible individuals triggers a cascade of immunological processes leading to the development of Coeliac Disease (CD). In CD, the HLA class II DQ2 and DQ8 molecules expressed on the surface of antigen-presenting cells bind and present gluten peptides to CD4+ T-cells in the coeliac intestinal mucosa (Lundin et al., 1993). Peptides with negatively charged residues at key anchor positions (P4, P6, and P7) are favoured by the positively charged peptide-binding groove of HLA-DQ2 and HLA-DQ8 molecules (Kim et al., 2004). However, in their native state, gluten peptides lack the negatively charged amino acids preferred by the HLA-DQ2 and HLA-DQ8 heterodimers unless acted upon by tissue transglutaminase (tTG) (Dieterich et al., 1997).
tTG is a multifunctional enzyme with numerous physiological roles in vivo. During tissue injury it is released into the intestinal mucosa were it plays a role in matrix assembly and tissue repair (Upchurch et al., 1991). However, tTG also has high avidity for gluten peptides in patients with CD. It can deamidate glutamine, which has a neutral charge, into the negatively charged glutamic acid. tTG therefore allows gluten peptides to bind to the DQ2 and DQ8 molecules with greater affinity to be later recognized by CD4+ T-cells in individuals with CD (Kagnoff, 2005).
Immunological model of Coeliac Disease (CD) pathogenesis
Several types of immune cells are required to create the lesions associated with CD. One of these cell types is the gluten reactive CD4+ T-cell. CD4+ T-cells are found in the peripheral blood and gut mucosa of coeliac patients (Christophersen et al., 2014). They recognise deamidated gluten and initiate a cascade of immune processes that are required for CD pathogenesis. Therefore these cells are sometimes referred to as the gatekeepers/master regulators of the immune response, which lead to CD. These cells infiltrate the lamina propria (LP) of the active coeliac lesion. Initiating a Th1 type immunological response with the production of IFNγ and IL21 (Bodd et al., 2010).
IFNγ is considered to play a key role in the mucosal damage associated with CD. It can adjust the intestinal permeability and lead to the release and activation of matrix metalloproteinases (MMPs). Release of MMPs can damage the mucosa. Activated gluten reactive CD4+ T-cells also up-regulate the expression of IL15 produced by enterocytes, LP dendritic cells and macrophages, which plays a central role in influencing the activity of the cytotoxic CD8+ IELs. IL15 synergizes with IL21 produced by CD4+ T-cells leading to activation of IELs. IL15 also up-regulates the NKG2D and the NKG2C receptors on the surface of IELs. Up-regulation of whcih induces epithelial lesions via the interactions of these receptors with their respective ligands- MICA and HLA-E expressed on enterocytes (Sollid and Jabri, 2013).