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Gluten enteropathy, namely Celiac disease (CD), is a hereditary predisposed disease, accompanied by the atrophy of the small intestine mucosa, associated malabsorption syndrome, and the development of various deficiency conditions. Celiac disease is caused by food containing gluten—the proteins of cereals that are the diet of the majority of the world population. Some immunogenic peptides of gluten proteins formed during digestion, mainly gliadins from wheat, rye, and barley, are resistant to proteolysis by human digestive peptidases and cause CD in predisposed people.
Celiac disease or gluten-sensitive enteropathy is a classic autoimmune disease, because it is characterized by tissue immunogenic inflammation and occurs in individuals with a specific set of HLA genes, namely those people whose genome contains certain alleles of the T-cell-specific immune response genes—HLA-DQ2 and HLA-DQ8, which are part of the HLA-DR3 genotype. HLA-DQ2 and HLA-DQ8 molecules have a high affinity for deamidated gliadin peptides, and in complex with tissue transglutaminase (TG2), present them to immune cells. TG2 deamidates gliadin peptides to form negatively charged deamidated peptides, leading to enhanced binding to HLA-DQ2 or HLA-DQ8 and subsequent presentation to the immune system, resulting in strong immunogenic inflammation in the intestinal wall. The T-cell-specific immune response is to gliadins, their deamidated fragments (peptides), TG2, and connective tissue proteins that are part of the endomysium and reticulin. Manifestations of autoimmune reaction are the destruction of the small intestinal mucosa and malabsorption of nutrients .
Proline- and glutamine-rich peptides derived from α-gliadins (a low-molecular-weight variety of gliadins) and γ-gliadins (cysteine-rich gliadins stabilized by disulfide bonds) containing more than nine amino acid residues are toxic to predisposed people . For example, the 33-mer α-2 gliadin peptide LQLQPFPQPQLPYPQPQLPYPQPQLPYPQPQPF is a substrate for a TG2 enzyme that modifies glutamine residues to promote pathogenesis. Another 26-mer peptide, FLQPQQPFPQQPQQPYPQQPQQPFPQ, is formed from γ-5 gliadin. Shorter immunogenic proline- and glutamine-rich peptides containing 10–20 amino acid residues ( Table 1 ) often are used for model studies . However, it is the 33- and 26-mer peptides, derived from α- and γ-gliadins, respectively, that are particularly strong activators of T-cells and therefore strongly correlate with the onset and development of CD .
|Size||Peptide Sequence||Origin||Position||Composition (Pro, Gln), %|
|33-mer||LQLQPFPQPQLPYPQPQLPYPQPQLPYPQPQPF||α-2 gliadin||56–88||Pro 40, Gln 30|
|26-mer||FLQPQQPFPQQPQQPYPQQPQQPFPQ||γ-5 gliadin||26–51||Pro 35, Gln 46|
|20-mer||LQPQQPFPQQPQQPYPQQPQ||γ-5 gliadin||60–79||Pro 35, Gln 50|
|20-mer||QQQQPPFSQQQQSPFSQQQQ||glutenin||Pro 15, Gln 60|
|19-mer||LGQQQPFPPQQPYPQPQPF||α-gliadin||31–49||Pro 37, Gln 37|
|17-mer||QLQPFPQPELPYPQPQS||α-gliadin||57–73||Pro 35, Gln 29|
|15-mer||VQGQGIIQPQQPAQL||γ-gliadin||Pro 13, Gln 40|
|15-mer||QQPPFSQQQQQPLPQ||glutenin||Pro 27, Gln 53|
|14-mer||PQPQLPYPQPQLPY||α-2 gliadin||62–75||Pro 43, Gln 29|
|13-mer||LGQQQPFPPQQPY||α-gliadin||31–43||Pro 31, Gln 38|
|12-mer||FSQPQQQFPQPQ||γ-5 gliadin||102–113||Pro 25, Gln 50|
|12-mer||QLQPFPQPQLPY||α-9 gliadin||57–68||Pro 33, Gln 33|
|10-mer||QPQQSFPQQQ||γ-gliadin||Pro 20, Gln 60|
The intensity of the inflammatory process in CD varies from an increased content of intraepithelial lymphocytes in the epithelium of the villi of the small intestine to atrophy of the mucous membrane. Due to the complexity of the diagnosis, which was previously based on the results of a biopsy, CD was considered a rare disease that was mostly found in Europeans and manifested during the first years of life. Later, sensitive and specific serological tests permitted estimates of the actual number of patients . Screening studies have shown that this disease is not age-related, can occur at any time, and is much more common than previously thought, namely 1% of the world’s population. In most patients, CD occurs with mild symptoms or has atypical clinical manifestations. A persistent epidemiological pattern is the steady increase in gluten intolerance in humans . The reasons for this can be the following factors: the increase in gluten consumption worldwide; early introduction of complementary foods containing cereals in children of the first year of life against the background of a decrease in the duration of breastfeeding; the emergence of new varieties of wheat with a high content of gluten; and accelerated methods in the production of bakery products (reducing the fermentation period) that increase the content of toxic gluten peptides . Malabsorption is the classic manifestation of CD. At the same time, the following symptoms are observed: chronic diarrhea, flatulence, weight loss, and vitamin and microelement deficiencies. Over time, there is a high risk of developing cancer and other autoimmune diseases, as well as nervous disorders .
Currently, there is no cure for CD. A strict gluten-free diet (GFD) is the only effective way to maintain the health of CD patients. In most patients with gluten sensitivity, the introduction of GFD leads to at least partial healing of the duodenal mucosa, improvement of most symptoms associated with gluten consumption, and a decrease in the titers of specific antibodies in gluten disease. However, in many patients, even with long-term strict adherence to GFD, symptoms may persist, including inflammatory and architectural changes in the small intestine mucosa and positive antibody levels . A number of factors may contribute to an incomplete response to a GFD. It is difficult to avoid cross-contamination during food production because gluten is widely used in the food industry. Food labeling may be inaccurate, misleading, or incorrect. In a double-blind clinical trial, patients with CD in remission who were given 50 mg of gluten daily experienced a 20% reduction in villus height/crypt depth compared to a daily placebo or 10 mg of gluten . This indicates that even traces of gluten can cause chronic mucosal damage. The acceptable (safe) limit of gluten may vary from patient to patient and may correspond to 10–100 mg per day, even though a slice of wheat bread contains approximately 3–4 g of gluten . Sticking to such a strict diet is difficult; generally, it is more expensive, less accessible, severely restricts food choice, may result in products with off-taste, and may lead to asocialized individuals (especially in adolescents) and depressive states . Moreover, there is a lack of vitamins and minerals, as well as a tendency to anemia and osteoporosis, in patients on GFDs. In most cases, unintended gluten exposure can occur in patients as a result of the consumption of 10–1000 mg of “hidden” gluten contained in common food ingredients such as sauces, salad dressings, food starches, malt extract thickeners, and other flavors, and sometimes simply as a result of cross-contamination during cooking. Thus, the complete elimination of gluten is, at best, a difficult task. Despite attempts to adhere to GFD, long-term treatment of patients with gluten disease often results in severe atrophy of the villi . It is possible that many patients are inadvertently consuming hundreds of milligrams (or more) of gluten per day. Therefore, there is a need to develop a non-dietary (pharmacological) therapy that would either supplement or replace GFD and neutralize up to 1 g of gluten while the food is still in the stomach.
Various therapeutic strategies are being developed to combat CD. Enzyme therapy is especially promising, as a supplement to food in the form of a peptidase preparation that efficiently degrades prolamins peptides . This approach is based on a direct effect on the pathogenic substance, namely, uncleaved peptides with a large number of proline and glutamine residues that are not digested by typical stomach enzymes.
2. Peptidases that Effectively Hydrolyze Prolamins and Their Immunogenic (Toxic) Peptides
|Number||Peptidase Class||Enzymes||Substrates 1|
|1||Serine peptidases||Prolyloligopeptidase (POP),
fibroblast activation protein
|(Xaa)n-Xbb-Pro↓Xbb-(Xaa)n, n = 1–13 (the length of the peptide is approximately 30 amino acid residues)|
|2||Dipeptidylpeptidases (DPP) 2,
DPP 4, DPP 8, DPP 9, FAP
|Xbb-Pro↓Xbb-(Xaa)n, n = 2–12|
|3||Prolylcarboxypeptidase (PRCP)||(Xaa)n-Xbb-Pro↓Xbb, n—any number|
|4||Metallopeptidases||Aminopeptidases P (APP) 1,
|Xbb↓Pro(Xaa)n, n = 1–9|
This entry is adapted from 10.3390/pharmaceutics13101603
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