|Year : 2021 | Volume
| Issue : 1 | Page : 2-5
Coeliac disease etiology and pathogenesis
Ali Khalifa A. Elmdaah
Department of Internal Medicine, Norfolk and Norwich University Hospital, Norwich; MSc Gastroenterology, Queen Marry University of London, London, England
|Date of Submission||26-Sep-2020|
|Date of Acceptance||22-Dec-2020|
|Date of Web Publication||10-Apr-2021|
Dr. Ali Khalifa A. Elmdaah
Norfolk and Norwich University Hospital, Coleny Lane, Norwich NR4 7UY
Source of Support: None, Conflict of Interest: None
Coeliac disease is a chronic inflammatory autoimmune enteropathy that affects around 1% of people worldwide. It is caused by ingestion of gluten products in people who are genetically predisposed. The pathogenesis involves multifactorial factors of genetic, gluten exposure, and environmental triggers. HLA-DQ2 and HLA-DQ8 are the main responsible genes that contribute to the development of coeliac disease. Both innate and adaptive immune plays role in the pathogenesis. In this article, we will review the causes and pathogenesis of coeliac disease development.
Keywords: Coeliac disease, glute, innate and adaptive immune response
|How to cite this article:|
A. Elmdaah AK. Coeliac disease etiology and pathogenesis. Libyan J Med Sci 2021;5:2-5
| Introduction|| |
Coeliac disease is a chronic immune-mediated enteropathy involving both an innate and adaptive immune response that occurs in genetically predisposing people who are exposed to dietary gluten in addition to other environmental factors.,, the clinical symptoms of coeliac disease are varied of both intestinal and extraintestinal manifestations, for example, diarrhea which is the most common symptoms, abdominal pain, anemia, osteoporosis, dermatitis herpetiform, and failure to thrive. There is a high risk of developing non-Hodgkin's lymphoma in celiac patients, and approximately 30-fold raised the risk of developing adenocarcinoma in the small intestine.
| Etiology and Pathogenesis|| |
There are three principal etiological factors of developing the coeliac disease (genes, gluten, and environmental factors), and interaction of these triad leads to the pathogenesis of coeliac disease [Figure 1].
First, human leukocyte antigen (HLA) genes are the main genetic factors which contribute to the development of coeliac disease, namely, Class II HLA-DQ2 and HLA-DQ8 genes. These immune function genes are located on chromosome 6. HLA Class II is glycosylated transmembrane heterodimers located on the cell surface of antigen-presenting cells and composed of α/β chains. Around 30%–40% of general population are carrier of at least one of these alleles genes. Nowadays, almost 40 regions (loci) including HLA have been known as genetic predisposing for coeliac disease and they are mostly known immune genes.
Second, gluten is the primary trigger for coeliac disease and it is the main component of wheat. Furthermore, barley and rye contain similar toxic proteins. Gluten is composed of gliadins and glutenins which are rich in proline and glutamine peptides. These proteins resist the degradation by enteropeptidases and enter the intestinal mucosa due to increased mucosal permeability. Intestinal epithelial cells contain an enzyme called tissue transglutaminase TTG, which acts on gliadin and leads to its deamidation. The deamidated gliadin is recognized by antigen-presenting cells such as dendritic cells, B-cells, and macrophages and presents it to specific CD4+ TH1 which drives the adaptive immune response.
Third, although HLA-DQ2 and HLA-DQ8 are essential for the development of the disease, only about 1% of these people who expose to gluten develop coeliac disease. This suggests that the environmental factors have a role in the pathogenesis of coeliac disease. For example, breastfeeding, intestinal infections, and changes in intestinal microbiota, especially at the early stage of life are considered as risk factors for the later occurrence of coeliac disease. The role of breastfeeding in coeliac disease is a controversial issue. Some studies reported that breastfeeding, especially during the time of introducing food which contains gluten has a protective effect of the development of coeliac, whereas other studies have suggested that there is no protective effect of breastfeeding.
Vriezinga et al. reported that there is no protective effect of introducing gluten in the early stage of life (at 16 weeks), and this did not drop the risk of developing coeliac at 3 years of age in children who are genetically predisposed to coeliac.
A study has examined the impact of introducing a Bifidobacterium species among celiac patients who are on a gluten-free diet. This study reported a drop in both Bacteroides species and level of IgA in stool which supported the evidence of the role of certain bacteria in the pathogenesis of coeliac disease.
Mårild et al. found that there is increased the risk of developing coeliac among babies who are delivered by elective cesarean section. They reflect this to the fact that baby during cesarean does not enter the birth canal. This could have an impact on the bacterial flora of the gut and could initiate coeliac disease.
Finally, there are some drugs such as antibiotics and proton pump inhibitors (PPIs), which have been correlated to the development of coeliac disease. The correlation between the use of antibiotics and the development of coeliac disease suggested the influence of intestinal dysbiosis in the pathogenesis of coeliac disease. Increase gastric pH to level above 4 due to PPIs inhibits the action of pepsin which allows the gluten to reach the small intestine in undigested form. Moreover, PPIs initiate immune reaction by increasing the gastric permeability to food antigens.
| Immunopathology of Coeliac Disease|| |
It is evident that both innate and adaptive (cell-mediated and humoral mediated) immune responses to gliadin involving in the pathogenesis of coeliac disease.
| The Role of Innate Immunity in Pathogenesis of Coeliac Disease|| |
There is a cardinal role of innate immunity in the immune dysregulation process in coeliac. This occurs in response to gliadin in the epithelial cells of the intestinal mucosa by increasing the production of inflammatory cytokines such as interleukin-15 (IL-15) and interferon-α (IFN) from enterocytes, dendritic cells, and macrophages. This role can be clearly described through the loss of tolerance to gluten and polarization of intraepithelial lymphocytes allowing them to destroy the intestinal epithelial cells. Moreover, zonulin is an intestinal protein controls the integrity of paracellular tight junctions. In coeliac disease, gliadin binding to chemokine receptor CXCR3 on intestinal epithelial cells which mediated release of zonulin through a MyD88-dependent that increase the intestinal permeability by acting on proteinase activating receptor 2 and epidermal growth factor., This change in intestinal permeability and loss of integrity of paracellular tight junction allow entering of more gliadin to lamina propria.
Oral tolerance is defined as maintenance of tolerogenic T-cells to antigen and this oral tolerance is preserved in the presence of retinoic acid and TGF-b cytokines that responsible for the development of T regulatory suppressor cells. However, in coeliac disease, the immune response occurs in response to gluten which promoted by IL15 rather than oral tolerance.
IL-15 has two important roles in the innate immune response of coeliac disease, and these roles are depending on its site of production either in intraepithelial cells or lamina propria. The upregulation of IL15 in intraepithelial cells leads to polarization of dendritic cells that initiate the loss of tolerance to gluten which is identified by increasing the number of gluten-specific CD4+ TH1 lymphocytes. However, upregulation of IL-15 in lamina propria affects the function of T-cell receptor (TCR) αβ intraepithelial lymphocytes, and this resulted in differentiation of these cells into cytotoxic CD8+ T cells which have the characteristic receptors of natural killer cells NK-G2D. Not only is that IL-15 upregulation responsible for differentiation of intraepithelial cells, but it is also responsible for upregulation of epithelial cells ligand for NK-2GD. This is leading to the destruction of the intestinal epithelium, which appears as villous atrophy and crypt hyperplasia, the histological features of coeliac disease [Figure 2].
|Figure 2: Schematic representation illustrates the role of T cells in immune cell response in coeliac disease pathogenesis done using Biorender|
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It is evident that IFN has a role in the loss of tolerance to gluten in coeliac disease through activation of tissue transglutaminase TG2 or effects on dendritic cells. Studies have demonstrated that hepatitis C patients who are treated with IFN develop coeliac disease.
| The Role of Adaptive Immunity in Pathogenesis of Coeliac Disease|| |
Antigen-presenting cells such as macrophages, dendritic cells, and B cells mediate adaptive immune response. These cells express HLA Class II DQ2 or DQ8 that present resistant gliadin peptides and interact with gliadin-specific CD4+ TH1 lymphocytes. HLA-DQ molecules have a different binding affinity to deamidated peptides. For instance, HLA-DQ2.5 and HLA-DQ2.2 bind deamidated gliadin, which has glutamic acid at position P4, P5, and sometimes P7, whereas HLA-DQ8 binds with peptides which have deamidation at position P1 or P9. It has been shown that HLA-DQ2.5 molecule is associated with high risk of developing coeliac disease, while HLA-DQ2.2 and HLA-DQ8 are associated with low risk of developing the disease.
Gliadin-specific CD4+ T lymphocytes react with undigested gliadin that presented by HLA-DQ molecules on antigen-presenting cells. These cells produce inflammatory cytokines IFNγ which induces expression of HLA-E in enterocytes. A large number of CD8+ T cytotoxic cells in intraepithelial lymphocytes ILEs which are natural killer-like cells express the ligand NKG2C for HLA-E. This activation leads to the destruction of epithelial cells and villous atrophy. This clear reprogramming of cytotoxic T lymphocytes could explain the refractory sprue feature in long-term complication of coeliac and the fact that these cytotoxic T-cells in long-term complication might experience malignant transformation and lymphoma. Furthermore, there is also role of other cytokines such as IL-21 which has an impact on T-regulatory lymphocytes and intraepithelial lymphocytes. IL-21 is produced by intraepithelial lymphocytes and lamina propria lymphocytes and IL-15 increases its production through Akt activation.
The reactive gliadin-specific T-cells activate B-cells in secondary lymphoid tissue and only selected high-affinity cells to antigen are differentiated into memory B cells and plasma cells. The mechanism of activation is unclear, but it has been reported that B-cell receptors of TG2 specific B-cells recognize both gluten peptides and TG2 and produce antibodies that develop the disease. In the lamina propria, plasma cells secrete autoantibodies called reticulin and endomysial antibodies. The endomysial antibodies are specific for tissue transglutaminase TG. The secretory IgA released into intestinal lumen bind to gluten and form SIgA-gluten complex, which bind to CD27 on the luminal surface of enterocytes leading to recycling of intact gluten peptides into the lamina propria [Figure 3].
|Figure 3: B cell response role in the pathogenesis. Illustration done using Biorender|
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Tissue transglutaminase enzyme tTG2 is a calcium-dependent enzyme that responsible for catalyzation of expressing proteins in all cell types. TG2 is normally located inside the cells in an inactive form but becomes active in the presence of calcium if it is transported extracellularly. Oxidation is responsible for the inactivation of TG2 in the normal physiological condition. However, the alternation in environments such as inflammation keeps TG2 active extracellularly.
B -cells are antigen-presenting cells and can recognize gluten and present it to T-cells. This would not only activate B-cells, but it also activates more T-cells, resulting in amplification of the immune response.
Intraepithelial cells of both CD8+ T cell receptor TCR ab and TCR gd have a role in coeliac. These unconventional cells do not require MHC for antigen recognition and produce cytokines IL-21 that initiate the immune response.
| Conclusion|| |
Coeliac disease is a chronic immune enteropathy that occurs in people who are genetically predisposing to the disease after exposing to gluten. The incidence of disease in both adults and children is increasing among different ethnic groups. Gluten is the primary etiological and trigger factor for developing the disease, and interaction between gluten, genetic factors, and environmental factors is responsible for pathophysiology, histology, and clinical features of coeliac disease.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]