Molecular characterization of tumor necrosis factor-associated pathologic inflammation in autoimmune disease and viral infection

Abstract

Inflammation is a defense system to protect hosts from microbes and tissue injury. However, inflammation may also provoke autoimmune disease and aggravate pathologic reaction of viral infection. Although tumor necrosis factor (TNF) inhibitor is the most widely used biologic agent in spondyloarthritis (SpA) - one of the autoimmune disease, sufficient therapeutic response is not achieved in a certain group of SpA patients. Here, I investigated transcriptomic characteristics and immune phenotype of peripheral blood immune cells of SpA patients with insufficient response. I found that increased gene expression and serum level of allograft inflammatory factor 1 (AIF-1) were associated with insufficient response to TNF inhibitor. $CD4^+$ T cells from SpA patients who had higher serum level of AIF-1 than a certain level and AIF-1-stimulated $CD4^+$ T cells showed enhanced key feature of SpA pathogenesis - Th17 response, after TNF inhibition. In second part of this study, I investigated single-cell transcriptome of peripheral blood immune cells from COVID-19 patients. I compared severe influenza, and mild/severe COVID-19 to identify factors driving severe progression of COVID-19. COVID-19 exhibited unique hyper-inflammatory signatures across all types of immune cells, particularly upregulation of the TNF/IL-$1\beta$ response compared to severe influenza. Notably, IFN response co-existed with the TNF/IL-$1\beta$ response and exacerbated hyper-inflammation in monocytes from severe COVID-19. In summary, TNF-associated inflammation contributes to immunopathology of autoimmune disease and viral infection.