# Microbial Peptides: Key Players in Reducing Gluten Immunogenicity Through Peptide Degradation
## 2 Gluten, Gliadin, and Immunogenic Peptides: Characteristics  
Gluten is a composite protein predominantly found in cereals such as wheat, barley, and rye, comprising two main fractions: gliadins and glutenins. These proteins are fundamental to the baking industry due to their unique physicochemical properties. Gliadins confer the dough's viscosity and extensibility, while glutenins provide elasticity and strength, together creating the dough's characteristic viscoelastic network [31]. Although these properties are essential for bread quality and texture, they pose significant challenges for individuals suffering from gluten-related disorders, including celiac disease CeD and NCGS [32].  
Among gluten proteins, gliadin is regarded as playing a key role in immunogenicity [33]. This protein is composed of complex amino acid sequences, particularly those rich in proline (Pro) and glutamine (Gln). These amino acids are considered the main factors responsible for the immunogenicity of gluten-derived fragments, as their structure enables the peptides to reach the small intestine intact and bind to immune receptor [34]. This composition renders gliadin difficult to digest, as proline in particular hinders the activity of human digestive enzymes. Due to this resistance to digestion, partially undigested gliadin predisposed individual to developing an immune response [35]. Once in the intestinal lamina propria, these gliadin-derived peptides undergo posttranslational modification by tissue transglutaminase 2 (TG2), which deamidates specific glutamine residues into glutamic acid. This modification increases the peptides' affinity for the major histocompatibility complex (MHC) class II molecules, namely HLA-DQ2.5, HLA-DQ8, or HLA-DQ2.2, which are strongly associated with CeD susceptibility [36] The 33-mer peptide fragment derived from \(\alpha\)-gliadin is one of the most extensively studied immunogenic peptides. It contains multiple proline and glutamine-rich sequences, rendering it highly resistant to enzymatic digestion and particularly effective at eliciting a CD4+ T-cell mediated immune response [36; 37] (Figure 1).  
The immune activation initiated by these peptides leads to the recruitment and activation of various immune cells, including CD4+ T cells, B cells, and antigen-presenting cells (APCs). The B-cell response targets both the deamidated gluten peptides (DGP) and the autoanti TG2, resulting in the production of disease-specific autoantibodies, against gliadin, DGP and TG2 [36]. This immune cascade causes chronic inflammation, epithelial cell damage, and disruption of the intestinal barrier, ultimately leading to villous atrophy and impaired nutrient absorption, characteristic hallmarks of celiac disease [38; 39].  
Although gliadin is the most extensively studied fraction for its immunogenicity, glutenins also contribute to the generation of immunogenic peptides. Glutenins, despite being larger and structurally more complex than gliadins, contain similarly proline and glutamine-rich sequences that resist digestion and contribute to immune activation in CeD [18]. Together, peptides derived from both gliadin and glutenin fractions initiate and perpetuate the immune response in susceptible individuals.  
The resistance of these peptides to enzymatic digestion and their central role in CeD pathogenesis have made them a prime target for therapeutic intervention. Enzymatic therapies have been developed to degrade these immunogenic peptides before they can activate the immune system. Proyloligopeptidase (POP) and proylendopeptidase (PEP) are two classes of enzymes capable of cleaving the proline-rich peptide bonds within gluten fragments, significantly reducing their immunogenic potential [41]. These enzymes have potential applications both in the food industry for the production of safer gluten-free products and as therapeutic supplements for affected individuals.