Bioinformatics and systems biology approaches in the study of giant cell arteritis

Abstract

Giant Cell Arteritis (GCA) is a complex autoimmune vasculitis that affects large arteries mainly in the elderly population and can lead to severe complications. This work explores and describes the pathophysiological mechanisms of GCA, studies the side effects of prednisone and the mechanism of action of Tocilizumab using quantitative analysis and in-silico system biology method, and lastly, presents and evaluates MMPred, a Bioinformatics tool that incorporates alignment and HLA-II epitope prediction algorithm to predicted autoantigens that could be responsible to post-infection autoimmunity. This work identified relevant associations between the use of prednisone and known and/or potential side effects in Real World Data and also investigated further those associations providing in-silico evidence of proteins that could be involved in the insurgence of these side effects. Data mining is applied to gene expression data of PBMCs (Peripheral Blood Mononuclear Cells) revealing a key role for STAT3 and MYC as predictors of response to Tocilizumab treatment. At last, the bioinformatics tool MMPred (Molecular Mimicry Predictor) is described, tested, and applied to two relevant test cases in which a relation between viral infection and the insurgence of autoimmune diseases is known. While a statistical evaluation of the tool is limited by data availability, the analysis suggests the capability of the tool to identify biologically relevant autoantigens that could trigger the autoimmune response in the context of SARS-CoV-2 and Varicella Zoster Virus infections. In the first case, an interesting similarity between the human Helicase MOV10 and the NSP13 protein from SARS-CoV-2 is identified and described. In the second instead, the VZV protein 66 shows a high degree of similarity with many human proteins, among which KIT and SYK which are predicted to have strong functional relation with the early stage of inflammation and the dysfunction of immune checkpoints in Giant Cell Arteritis, and the proteins MAPK3 and MAPK1 which are known to related to the process of vascular occlusion in Giant Cell Arteritis.

Date of Award	20 Feb 2025
Original language	English
Supervisor	Xavier Daura Ribera (Director) & Judith Farrés Marisch (Director)