MD Alessio Fasano - Gluten is like a bacteria

Описание: MD ALESSIO FASANO:
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GLUTEN UNDIGESTED:
Ordinarily, the small intestinal brush-border membrane enzymes rapidly break down the products of gastric and pancreatic digestion into single amino acids, dipeptides or tripeptides. However, their action on the relatively long, proline-rich products of peptic/pancreatic digestion of gluten is at best sluggish (Shan 2005).

Our analysis revealed that long, proteolytically resistant fragments were widespread within the α-gliadin, γ-gliadin, glutenin, hordein and secalin protein families of wheat, rye and barley. In contrast, analogous investigations on sequences of avenins (from oats) and a range of proteins present in bovine myoglobin, chicken ovalbumin, bovine casein and lactoglobulin (from meat, eggs or milk) showed no peptide products longer than 10 amino acids. Their susceptibility to proteolysis corresponds to their low proline content (an average of 6% in avenins, 2% in myoglobin, 3% in ovalbumin, 12% in casein and 4% in lactoglobulin). Only avenin and casein proteins produced digestion fragments of 8–10 residues. Notably, these avenin fragments contain T cell epitopes recognized by intestinal T cells of oats-intolerant Celiac Sprue patients (Shan 2005).

GLUTEN AND TRANSGLUTAMINASE
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Preliminary studies on the ability of the gliadin to act as a substrate for tissue transglutaminase (TG2) were carried out a decade ago. These studies carried out on TG2 and gliadin showed that gliadin and its proteolytic fragments were capable of acting in vitro as substrates for guinea pig liver TG2. This enzyme was able to use gliadin and its proteolytic fragments for cross-linking reactions between Gln endoresidues and either Lys endoresidues or free polyamines. It is worth noting that gliadin possesses a very large number of Gln residues (up to 36%), and that these residues are responsible for both Gln-Lys isodipeptide or polyamine-derivative formation (Martin 2012).

Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) analyses, followed by autoradiography detection, showed that gliadin and other food proteins, known to be responsible for CD and other food intolerances, were able to form large molecular weight aggregates in the presence of labelled polyamines and calcium-activated TG2. The ability of TG2 to catalyze the formation of large molecular weight aggregates with polyglutamine peptides and polyglutamine rich proteins has also been reported as a possible mechanism of neurodegenerative diseases (Martin 2012).

Neurodegenerative disorders are characterized by progressive neuronal loss and the aggregation of disease specific pathogenic proteins in hallmark neuropathologic lesions. Many of these proteins, including amyloid Αβ, tau, α-synuclein and huntingtin, are cross-linked by the enzymatic activity of transglutaminase 2 (TG2) (Grosso 2012).

Gliadins are preferred substrates for tissue transglutaminase (TG2). Gliadins are glutamine rich proteins and excellent glutamyl donor substrates for TG2. They give rise to crosslinks of gliadin with certain matrix proteins, such as collagens I, III and VI [DIeterich et al., unpublished data], and even to covalent incorporation of TG2 itself into high molecular weight complexes. The crosslinking of gliadins increases both immunogenicity and availability of gluten epitopes in the coeliac mucosa (Schuppan 2003).
In this line, IgA antibodies of coeliac patients are not only directed to gliadins, glutens and TG2, but also to crosslinked and deamidated neoepitopes and their titer may ocasionally exceed that of IgA anti-TG2 antibodies (Schuppan 2003).
Tissue transglutaminase is a ubiquitous intracellular enzyme which is released from fibroblasts, endothelial, and inflammatory cells during mechanical irritation or inflammation. Once secreted, tissue transglutaminase can crosslink glutamine-rich proteins, in particular gluten proteins from wheat (in which glutamine represents 30–50% of the aminoacids), with lysine groups of other proteins (Schuppan 2003).

It can be speculated that , under conditions where undigested gliadin peptides have access to the circulation due to a barrier disturbance, these peptides can potentially be cross -linked to proteins in organs where TG2 is available for the reaction. In this way, gliadin peptides may also be an initiating factor for other autoimmune diseases (Skovbjerg 2004).