Nasal Associated Lymphoid Tissue in health, infection and autoimmunity

Abstract

The immune system exists in three core components - epithelial surface barrier immunity to prevent entry of foreign antigens from the environment; innate immunity to provide an immediate but non-specific cellular immune defence response to foreign antigens; and an adaptive immune response providing a long term memory recall immune response to foreign antigens through the action of antigen specific T lymphocytes and antibody producing B lymphocytes. Whilst the barrier and innate immune response to a foreign antigen at an epithelial surface occurs in the epithelium itself, the generation of long-term high affinity antigen specific B cells takes place in specialised lymphoid tissues. Much of what we know about this process is inferred from mouse models and studies of human peripheral blood. Both approaches have limitations, through either the inter-species variations of mouse models, or the local tissue immune variations in humans. In particular, human peripheral blood lacks specialised, location specific, cell types, such as epithelial cells and macrophages at barrier sites, and follicular CD4 T and B cells in lymphoid organs. Whilst lymphoid tissues are typically in anatomically challenging areas to sample, they can also exist in specialised niches within epithelial mucosa, where they are known as mucosal associated lymphoid tissues. One such epithelial surface is the respiratory tract, which contains the nasal associated lymphoid tissue (NALT). In this thesis, I develop a practical, safe and well-tolerated methodology for sampling the NALT in adult human subjects without the need for general anaesthesia, sedation or dedicated inpatient recovery facilites. Using this office-based biopsy technique, I use single cell transcriptomics, flow cytometry and confocal microscopy to use NALT tissue as a model for examining the development of human immune responses. In chapter three I show that NALT can be sampled in adult subjects thoughout their lifespan. Comparing this with paediatric data, I provide a development trajectory of NALT, which expands throughout the nasal cavity after birth, regresses later in childhood, but remains functional in the postnasal space in older age groups. Next, I chart the development of the response to immune challenge with SARS-CoV-2 viral infection. By following the viral infection over two timepoints, I show the early and later stages in the orchestration and development of local and systemic immune memory in the NALT to a specific immune challenge stimulus. Finally, I use an autoimmune disease with a strong nasal component, ANCA associated vasculitis (AAV), to explore how defects in the development and retention of local tissue memory immune cells can trigger an autoimmune phenotype. In this section I focus on mapping the tissue immune phenotype of two AAV subtypes - Granulomatosis with Polyangiitis (GPA) and Eosinophilic Granulomatosis with Polyangiitis (EGPA). I then use this data to contextualize paired pre- and post- treatment samples to assess the impact of interleukin-5 blockade treatment on disease-associated signals and cell types in EGPA.