Identification of key immunogenic post-translational modifications in Trichohyalin: a potential major autoantigen in Alopecia Areata
Alopecia UK
University College Dublin
This project is aimed at discovery of HF-associated autoantigens in AA. Strong evidence for TCHH as a major AA autoantigen in humans as well as in several other mammals is intriguing. Given that TCHH is a substrate for immunogenic PTMs citrullination and deamidation, we speculate that there might be an abnormal immune response against normal antigens that becomes immunogenic at a certain stage of their maturation i.e., during early stages of anagen. We hypothesize that in the initial stages of TCHH maturation, either before or during loss of immune-privilege (IP), key PTMs in TCHH may prompt an active immune response against anagen HF in AA. The presentation of modified TCHH peptides on MHC molecules locally could be an initial activation event of the (auto)immune response in AA. To evaluate this hypothesis, we aim to address the following key questions in this proposal. 1. Which amino acid residues undergoes citrullination and deamidation modifications in TCHH during its maturation in the IRS during anagen? 2. Which post-translational modifications in THH could be potentially immunogenic? 3. Will theimmunogenic peptides identified(in 2 above)be able to induce cellular and antibody immunoreactivity in AA?
1.1 Normal biological development and functioning