A commanding role for lymphnodes in granulomatous inflammation

Abstract

Granuloma formation is the key pathophysiologic process in diseases such as tuberculosis (TB)and sarcoidosis. To improve patient outcomes, a deeper understanding of the biology and regulation of granulomas is an urgent human health need. Heightened inflammation within lymph nodes modulates systemic immunity, which has been shown to have a significant impact on the natural history of a range of immune-based diseases. However, the impacts of lymph node activities in granulomatous diseases, which have a distinct trophism for nodal tissue, are unknown. With the hypothesis that granulomas may shape lymphatic responses in clinically relevant ways, I measured the effect of granulomas on lymph node structure, systemic immunity, and clinical parameters through a series of studies of TB and sarcoidosis samples. Using digital pathology tools, I observed widespread obliteration of normal nodal structures by granulomatous inflammation in TB, with alteration of the vasculature including emergence of capillary-like lymphatics observed in regions typically void of such structures. In an exploratory machine learning study, well-formed granulomas and necrotic cores were reliably recognized with iterative training, suggesting that digitisation of histopathology slides with computer assisted interpretation can aid pathology triage in clinical practice. In sarcoidosis, lymph node involvement was associated with increased markers of systemic inflammation and reduced regulatory T cell potency. Recurrently active sarcoidosis, as measured by serial PET scanning with tagged glucose, occurred largely at nodal stations with previously demonstrated disease, suggesting the persistence of antigen and preservation of the granuloma apparatus in spite of clinically successful treatment courses. Taken together, these works position lymph nodes in granulomatous disease as critical effectors of the pathobiology and as potential therapeutic targets for long-term disease control. In addition, the scalability and high-performance of digital pathology tools support their implementation into global research and clinical care efforts, while imaging techniques which non-invasively survey metabolic signatures indicate local immune activities, shedding insight into the real-time clinical status of patients.

Date of Award	Mar 2024
Original language	English
Awarding Institution	University of Brighton
Supervisor	Simon Waddell (Supervisor) & Dr Max Gutierrez (Supervisor)