The immune system is an intricate network of cellular and molecular interactions playing out through our bodies. Immune cells serve as sentinels against pathogens and the immune response represents a coordinated action to eliminate these threats. Nonetheless, immune cells may act against other tissues, a defining feature of autoimmunity. Autoimmune conditions can appear in various tissues, having a devastating impact in the quality of life of patients, and limited therapeutic options. These are complex diseases, involving a plethora of immune cell types and states interacting with tissue-specific stromal and epithelial cells. Understanding them requires technologies capable of unraveling cells and their phenotypes with high resolution. Single-cell RNA-sequencing (scRNA-seq) is a technology whose accuracy, scale, and use has exponentially grown in the last decade. scRNA-seq extracts gene expression information from individual cells, revealing cell types and states, gene regulation and intercellular communication in the context of a tissue, in health and disease. Single-cell sequencing technologies have also grown in complexity and scale. This has allowed researchers to profile more cells and more data modalities from individual cells, such as open chromatin regions or surface proteins. Furthermore, gene expression distribution in tissues can also be spatially assessed using spatial transcriptomics approaches.
This project aims to understand the regulation of immune cell infiltration and subsequent formation of Tertiary Lymphoid Structures in various tissues affected by autoimmune diseases, by combining bioinformatics and machine learning approaches with methods to probe the immune system in vivo and in vitro to validate its key interactions. By identifying and functionally characterising the ligands and receptors modulating TLS formation and development across tissues using scRNA-seq, Spatial Transcriptomics (ST), and multiomics, the project can provide a detailed picture of the cell types in tissues affected by autoimmune disease, and unravel their cell-cell interactions. These will be further characterised in the context of TLS morphology and development, and the immune function and underlying regulation of the key signalling molecules will be further unravelled with in vitro studies, ultimately setting a path from discovery to functional validation. This is further expected to serve as a springboard to clinical research by investigating the key targets revealed in the project.
