Use of peptide mimetics of proteins for characterization of immune response in different pathological conditions

Proteins and peptides play a key role in almost all biological processes. All these functions are regulated through specific interactions between proteins and their ligands (e.g. peptides or other small molecules or ions) or other proteins; dysregulations of these mechanisms commonly lead to pathological conditions. An exhaustive comprehension of these interactions is fundamental in order to clarify their involvement in the onset of several diseases and to develop novel therapeutic strategies. Moreover, proteins and peptides are the most common and important antigenic target in the major part of pathologies. Protein fragments and peptides represent portions which interact with antibodies: these portions are known as active sites or epitopes. In order to correctly reproduce the aforementioned portions, the synthesis of mimetic molecules is considered a powerful approach. Mimetic peptides represent only the epitope or the active site of the respective protein, but they are much easier to synthetize, to handle and to eventually chemically modify, besides they are generally more proteolytically stable. The principal aim of this PhD project is to highlight how powerful and versatile the use of modified and non-modified peptide and protein antigenic probes as mimetics of specific target proteins can be for the study of many different pathological conditions and, furthermore, of several aspects of these pathologies which were never or poorly investigated before. In this PhD thesis the advantages and the high versatility of use of the aforementioned antigenic probes will be show on different types of diseases, from autoimmune to immuno-mediated and only genetic-related ones, considering both B and T immune responses, besides several kind of environmental triggers, such as viral or bacterial infections but also side effects of drugs. Following the so called Chemical Reverse Approach, specific peptide and protein probes were used as mimetics of putative epitope fractions to reveal the presence of specific B- or T-cell responses which can clarify several aspects of the pathology, such as the role of environmental factors or post-translational modifications in its onset. Some aspects of five different pathological conditions have been studied to demonstrate the highly versatile role of synthetic modified and non-modified peptide and protein fragments as antigenic probes for both B and T immune response characterization. The most important aspect this work wanted to investigate was the possible correlation between the pathogenesis of these diseases and several environmental factors, such as viral or bacterial infection and adverse reactions related to reactive small molecules. Using synthetic modified and non-modified peptide and protein fragments as antigenic probes, the possible role of viral and bacterial infections as triggers for different kind of pathologies was investigated on well-known autoimmune diseases, such as Type 1 diabetes (T1D), Latent Autoimmune Diabetes in Adults (LADA), psoriasis (PsO) and psoriatic arthritis (PsA), and supposed totally genetic-related diseases, such as Rett syndrome. Furthermore, the adverse B immune response highlighted after therapeutic treatments was also studied on immune-mediated diseases such as Fabry Disease (FD). Finally, a specific T cell response against modified endogenous protein characteristic of allergic reactions to antibiotics was also investigated.