Celiac disease pathophysiology
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The etiology of the celiac disease is known to be multifactorial, both in that multiple factors can lead to the disease and that multiple factors are necessary for the disease to manifest in a patient. Gluten triggers autoimmunity and results in the inflammation of the gastrointestinal mucosa. Gluten in wheat, rye, and barley may trigger the autoimmunity to develop celiac disease. Gluten peptides cross the epithelium into the lamina propria where they are deamidated by tissue transglutaminase. The peptides are then presented by DQ2+ or DQ8+ antigen-presenting cells to pathogenic CD4+ T cells. The CD4+ T cells trigger the T-helper-cell type 1 response which results in the infiltration of inflammatory cells into the lamina propria and epithelium. This inflammatory process ultimately leads to crypt hyperplasia and villous atrophy. It is suggested that the gliadin may be responsible for the primary manifestations of celiac disease whereas tTG is a bigger factor in secondary effects such as allergic responses and secondary autoimmune disease. Over 95% of celiac patients have an isoform of DQ2 (encoded by DQA1*05 and DQB1*02 genes) and DQ8 (encoded by the haplotype DQA1*03:DQB1*0302), which is inherited in families. The reason these genes produce an increased risk of celiac disease is that the receptors formed by these genes bind to gliadin peptides more tightly than other forms of the antigen-presenting receptor. Therefore, these forms of the receptor are more likely to activate T lymphocytes and initiate the autoimmune process. Celiac disease is associated with other autoimmune diseases such as type 1 diabetes mellitus, IgA deficiency, IgA nephropathy, insulin dependent diabetes mellitus (IDDM), Sjogren’s syndrome, juvenile idiopathic arthritis, juvenile rheumatoid arthritis, Hashimoto's thyroiditis, Graves Disease, and dermatitis herpetiformis.
The etiology of the celiac disease is known to be multifactorial, both in that more than one abnormal factor can lead to the disease and also more than one factor is necessary for the disease to manifest in a patient. Gluten triggers autoimmunity and results in the inflammation of the gastrointestinal mucosa.
- Prolamines are storage proteins with a similar amino acid composition to the gliadin fractions of wheat. Prolines have been identified in barley (hordeins) and rye (secalines), and are related closely to the properties of wheat cereal that affect people with celiac disease.
- Wheat varieties or sub-types containing gluten such as spelt and the rye/wheat hybrid triticale may also trigger the symptoms of celiac disease.
- Gluten is mainly found in wheat. Gluten consists of storage proteins that remain after starch is washed from wheat-flour dough.
- These storage proteins have different solubilities in alcohol–water solutions and are usually separated into two fractions:
- Gluten proteins are grouped into four main types (ω5-, ω1,2-, α/β-, γ-gliadins).
- Several gliadin epitopes are immunogenic and also have direct toxic effects.
Gluten in wheat, rye, and barley may trigger the autoimmunity to develop celiac disease. Gluten peptides cross the epithelium into the lamina propria where they are deamidated by tissue transglutaminase. The peptides are then presented by DQ2+ or DQ8+ antigen-presenting cells to pathogenic CD4+ T cells. The CD4+ T cells trigger the T-helper-cell type 1 response which results in the infiltration of inflammatory cells into the lamina propria and epithelium. This inflammatory process ultimately leads to crypt hyperplasia and villous atrophy.
Epithelial translocation of gluten peptides
The gluten peptides can be translocated through the gastric epithelium via these mechanisms:
Modification of gluten peptides
Antigenic presentation of gluten peptides
The glutamic acid molecules cross-linked with tTG are presented to CD4+ T cells.
The activation of CD4+ T cell produces several proinflammatory cytokines which may trigger the secretion of tissue-damaging matrix metalloproteinases and activation of lymphocytes against the enterocytes which result in enterocyte apoptosis and villous flattening.
- Alternative causes of this tissue damage have been proposed and involve the release of interleukin 15 and activation of the innate immune system by a shorter gluten peptide (p31–43/49). This triggers the killing of enterocytes by lymphocytes in the epithelium.
Anti-transglutaminase antibodies to the enzyme tissue transglutaminase (tTG) are found in an overwhelming majority of cases. Tissue transglutaminase modifies gluten peptides into a form that may stimulate the immune system more effectively.
- Endomysial component of antibodies (EMA) to tTG are believed to be directed towards cell surface transglutaminase.
- It is suggested that the gliadin may be responsible for the primary manifestations of celiac disease whereas tTG is a bigger factor in secondary effects such as allergic responses and secondary autoimmune diseases.
- Stored biopsies from suspected celiac patients have revealed that autoantibody deposits in the subclinical gastrointestinal mucosal lining of celiacs are detected prior to clinical disease. These deposits are also found in patients who present with other autoimmune diseases, anemia or malabsorption phenomena at an increased rate compared to the normal population.
- In a large percentage of celiac patients, the anti-tTG antibodies also recognize a rotavirus protein called VP7. These antibodies stimulate monocyte proliferation and rotavirus infection might explain some early steps in the cascade of immune cell proliferation. Indeed, earlier studies of rotavirus damage in the gut showed this causes a villous atrophy.
- This suggests that viral proteins may take part in the initial flattening and stimulate self-reactive anti-VP7 production. Antibodies to VP7 may also slow healing until the gliadin mediated tTG presentation provides a second source of self-reactive antibodies.
- HLA genes are a part of the MHC class II antigen-presenting receptor (also called the human leukocyte antigen) system and distinguish between self and non-self antigens for the immune system. There are 7 HLA DQ variants (DQ2 and DQ4 through 9).
- DQ2 and DQ8 are associated with celiac disease. The gene is located on the short arm of the sixth chromosome, and as a result of the linkage, this locus has been labeled as CELIAC1.
- Over 95% of celiac patients have an isoform of DQ2 (encoded by DQA1*05 and DQB1*02 genes) and DQ8 (encoded by the haplotype DQA1*03:DQB1*0302), which is inherited in families. The reason these genes produce an increased risk of celiac disease is that the receptors formed by these genes bind to gliadin peptides more tightly than other forms of the antigen-presenting receptor. Therefore, these forms of the receptor are more likely to activate T lymphocytes and initiate the autoimmune process.
- Most celiac patients bear a two-gene HLA-DQ haplotype referred to as DQ2.5 haplotype. This haplotype is composed of 2 adjacent gene alleles, DQA1*0501 and DQB1*0201, which encode the two subunits, DQ α5 and DQ β2. In most individuals, the DQ2.5 isoform is encoded by one of two chromosomes 6 inherited from parents. Most celiacs inherit only one copy of the DQ2.5 haplotype, while some inherit it from both parents; the latter are especially at risk of celiac disease, as well as being more susceptible to severe complications.
- Some individuals inherit DQ2.5 from one parent and portions of the haplotype (DQB1*02 or DQA1*05) from the other parent, increasing risk. Less commonly, some individuals inherit the DQA1*05 allele from one parent and the DQB1*02 from the other parent, called a trans-haplotype association, and these individuals are at similar risk for the development of celiac disease as those with a single DQ2.5 bearing chromosome 6, but in this case, the disease tends to be non-familial.
- In addition to the CELIAC1 locus, CELIAC2 (5q31-q33 - IBD5 locus), CELIAC3 (2q33 -CTLA4 locus), CELIAC4 (19p13.1 - MYOIXB locus), have been linked to coeliac disease. The CTLA4 and myosin IXB and gene have been found to be linked to celiac disease and other autoimmune diseases. Two additional loci on chromosome 4, 4q27 (IL2 or IL21 locus) and 4q14, have been found to be linked to coeliac disease.
- Type 1 diabetes mellitus
- IgA deficiency
- IgA nephropathy
- Insulin dependent diabetes mellitus (IDDM)
- Sjogren’s syndrome
- Juvenile idiopathic arthritis
- Juvenile rheumatoid arthritis
- Hashimoto's thyroiditis
- Graves Disease
- Dermatitis herpetiformis
- Primary sclerosing cholangitis
- Autoimmune hepatitis
- Irritable bowel syndrome
- Down's syndrome
- Turner syndrome
On gross pathology, duodenum usually shows:
- Scalloping of duodenal folds
- Mosaic mucosal pattern
- Mucosal atrophy
- Marsh stage 0: normal mucosa
- Marsh stage 1: increased number of intraepithelial lymphocytes, usually exceeding 20 per 100 enterocytes
- Marsh stage 2: proliferation of the crypts of Lieberkuhn
- Marsh stage 3: partial or complete villous atrophy
- Marsh stage 4: hypoplasia of the small bowel architecture
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