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Page: Pathophysiology
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Genetics
The vast majority of coeliac patients have one of two types of HLA DQ, a gene that is part of the MHC class II antigen-presenting receptor (also called the human leukocyte antigen) system and distinguishes cells between self and non-self for the purposes of the immune system. There are 7 HLA DQ variants (DQ2 and D4 through 9). Two of these variants—DQ2 and DQ8—are associated with coeliac disease. Every person inherits two copies, one from each parent. The gene is located on the short arm of the sixth chromosome, and as a result of the linkage this locus has been labeled CELIAC1.
Coeliac disease shows incomplete penetrance, as the gene alleles associated with the disease appear in most patients, but are neither present in all cases nor sufficient by themselves cause the disease. Over 95% of coeliac patients have an isoform of DQ2 (DQA1*0501:DQB1*0201 haplotype or more simply DQ2.5) and DQ8 (DQA1*0301:DQB1*0302), which is inherited in families. The reason these genes produce an increase in 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 is more likely to activate T lymphocytes and initiate the autoimmune process.
Every person carries two HLA-DQ genes, one inherited from their mother and one from their father. About 20–30% of people carry HLA-DQ2 but most of them do not have coeliac disease, suggesting additional factors are needed for coeliac disease to develop. Furthermore, about 5% of those people who do develop coeliac disease do not have the DQ2 gene. The frequency of these genes vary greatly; DQ2.5 is highly frequent in people originating from Sardinia, Basque Country, Ireland,and Scandinavia. DQ8 is more prevalent in those originating from South and Central America (up to 90% phenotype frequency), and also those from Sweden.
Pediatric celiac disease in India is associated with multiple DR3-DQ2 haplotypes
As the MHC class II antigen-presenting receptor functions as a dimer containing two protein subunits, these receptors can be made from the products of two different DQ alleles. Consequently, any one person with alleles A and B can produce 4 different receptor dimers, 2 in the cis-haplotype homodimer pairing (AA and BB) and 2 in the heterodimer pairing (AB and BA). DQ2.5 (haplotype product is DQ ?5-?2) and DQ8 (DQ ?3-?302) produce susceptibility in their cis-haplotype pair. However, trans-pairing of some receptor subunits can also produce disease. This is seen with a third pairing of haplotypes, DQA1*0201:DQB1*0202(DQ2.2) / DQA1*0505:DQB1*0301 (DQ7.55) that, when both are found in a single patient, can produce susceptibility to coeliac disease through trans-pairing of the DQA1*0505-DQB1*0202 subunits (producing the DQ ?5-?2 heterodimer). Other MHC class II genes may alter the risk produced by the main disease genes. For example, the genotype DQ2.2/DQ2.5 shows increased susceptibility. However, without the presence of DQ7.55 and DQ2.5, DQ2.2 is not usually associated with coeliac disease.
In addition to the HLA locus on chromosome 6q21.3, several other regions have been linked (especially 19p13.3 and 4p14).[39] Mendelian Inheritance in Man designates five regions as CELIAC1-5 (6q21.3, 5q31-q33, 2q33, 19p13.1, 15q11-q13). For CELIAC3, the CTLA4 gene was found to be linked, and CELIAC4 the gene coding for myosin IXB. CELIAC2 and CELIAC5 have no suspected gene association.
Prolamins
The proteins in food responsible for the immune reaction in coeliac disease are the prolamins. These are storage proteins rich in proline (prol-) and glutamine- (-amin) that dissolve in alcohols and are resistant to pepsin and chymotrypsin, the two main digestive proteases in the gut. Gliadin in wheat is the best-understood member of this family, but other prolamins exist and hordein (from barley), and secalin (from rye) may contribute to coeliac disease. However, not all prolaminins will cause this immune reaction and there is ongoing controversy on the ability of avenin (the prolamin found in oats) to induce this response in coeliac disease.
Tissue transglutaminase
Antibodies to the enzyme tissue transglutaminase (tTG) are found in an overwhelming majority of cases, and cross-react to gluten. Tissue transglutaminase modifies gluten peptides into a form that may stimulate the immune system more effectively.
Stored biopsies from suspected coeliac patients has revealed that autoantibody deposits in the subclinical coeliacs are detected prior to clinical disease. These deposits are also found in patients who present with other autoimmune diseases, anemia or malabsorption phenomena at a much increased rate over the normal population. Endomysial component of antibodies (EMA) to tTG are believed to be directed toward cell surface transglutaminase, and these antibodies are still used in confirming a coeliac disease diagnosis. However, a 2006 study showed that EMA-negative coeliac patients tend to be older males with more severe abdominal symptoms and a lower frequency of "atypical" symptoms including autoimmune disease. In this study the anti-tTG antibody deposits did not correlate with the severity of villous destruction. These findings, coupled with recent work showing that gliadin has an innate response component, suggests that gliadin may be more responsible for the primary manifestations of coeliac disease whereas as tTG is a bigger factor in secondary effects such as allegic responses and secondary autoimmune diseases. In a large percentage of coeliac patients, the anti-tTG antibodies also recognize a rotavirus protein called VP7. These antibodies stimulate monocytes 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-crossreactive anti-VP7 production. Antibodies to VP7 may also slow healing until the gliadin mediated tTG presentation provides a second source of crossreactive antibodies.
[edit] Villous atrophy and malabsorption
The inflammatory process, mediated by T cells, leads to disruption of the structure and function of the small bowel's mucous lining, and causes malabsorption as it impairs the body's ability to absorb nutrients, minerals and fat-soluble vitamins A, D, E and K from food). Lactose intolerance may be present due to the decreased bowel surface and reduced production of lactase, but typically resolves once the condition is treated.
Alternative causes of this tissue damage have been proposed and involve release of interleukin 15 and activation of the innate immune system by a shorter gluten peptide (p31-43/49). This would trigger killing of enterocytes by lymphocytes in the epithelium. The villous atrophy seen on biopsy may also be due to unrelated causes, such as tropical sprue, giardiasis and radiation enteritis. While positive serology and typical biopsy are highly suggestive of coeliac disease, lack of response to diet may require these alternative diagnoses to be considered.
Risk modifiers
There are various theories as to what determines whether a genetically susceptible individual will go on to develop coeliac disease. Major theories include infection by rotavirus or human intestinal adenovirus Some research has suggested that smoking is protective against adult onset coeliac disease.
A 2005 prospective and observational study found that timing of the exposure to gluten in childhood was important risk modifier. Early exposure to wheat, barley, or rye before the gut barrier has developed fully over the first three months after birth. People exposed during this period had five times the risk of developing coeliac disease over those exposed at 4 to 6 months. Those exposed later had a slightly increased risk relative to those exposed at 4-6 months.[49] However a 2006 study with similar numbers, found just the reverse, that early introduction of grains was protective.[50] Breastfeeding may also reduce risk. A meta-analysis indicates that prolonging breastfeeding until the introduction of gluten-containing grains into the diet was associated with a 52% reduced risk of developing coeliac disease in infancy; whether this persists into adulthood is not clear.
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