Final Report Summary - IAI (Intracellular antibody Immunity) Antibodies are sufficient to confer immune protection against viral infection. They are the principle correlate of protection upon vaccination and the most important therapeutic molecule in modern medicine. Historically, antibodies were thought to function purely extracellularly and that when pathogens entered cells antibodies became redundant. The most significant discovery of this project is the discover that there is an intracellular humoral immune system, in addition to the extracellular mechanisms that have been known about for over a century. My lab has discovered a highly conserved mammalian antibody receptor (TRIM21) that is distinct from all previously described receptors, not least because it is expressed cytosolically. We have shown that it is the highest affinity antibody receptor in humans. We have also discovered that complement, the other half of humoral immunity, also provides immune function inside the cell. We have discovered that intracellular humoral immunity potently neutralizes infection by a broad range of pathogens. We have shown that in addition to neutralization, intracellular humoral immunity activates the three main innate immune pathways – NFkB, AP-1 and IRF3/5/7 – to stimulate a broad range of pro-inflammatory cytokines including interferon. Uncovering the mechanism of this unusual dual sensor and effector response, we have found that this is achieved through a complex sequence of ubiquitination reactions mediated by multiple distinct E2 enzymes. Perhaps most importantly we have shown that TRIM21 is required for efficient immune protection in mammals. Specifically, we have shown that antibody protective immunity against viruses is compromised in organisms lacking TRIM21. Most recently we have found that TRIM21 is effective not only against viruses and bacteria but also protein-based pathogens such as prions. Our discovery that TRIM21 can prevent the spread of the neurodegenerative prion tau, a leading cause of Alzheimers, has far reaching consequences for future therapeutic development.
