Resokine Pathway Hypothesis: A homeostatic pathway that controls the set point of key cells in the immune system to ensure appropriate control of immune responses, characterized by:
- A series of extracellular proteins derived from a single gene, the histidine aminoacyl tRNA synthetase (HARS)
- Balancing of the immune responses to prevent self-tissue damage and promote tissue or tumor homeostasis
Resokine: Extracellular Proteins Derived From HARS Gene
Cells, in a regulated fashion, secrete Resokine proteins. Disruptions or insufficiencies in the Resokine pathway leads to an increased immune response. We developed sensitive assays to detect Resokine proteins in circulation between 10pM and 1nM in humans and mammals.
aTyr discovered that these extracellular proteins act as a set point modulator of the immune system, regulating the threshold for T cell activation, and possibly other immune cells, to aid in tissue and cancer homeostasis. Evolutionarily, this fundamental pathway dates back over 400 million years, much longer than several other targets in immunology and immuno-oncology.
Human Evidence of Resokine Pathway in Patients: Resokine Knockout Increases T Cell Engagement
Evidence of the pathway’s importance in regulating T cells can be seen in a rare human autoimmune disease called Anti-Synthetase Syndrome. In this disease, patients break tolerance and develop auto-antibodies to Resokine proteins. This results in increased invasion of T cells into tissue, primarily muscle and lung. A similar phenotype can be replicated in animals. In both humans and in animals under these functional knockout conditions Resokine levels are very low and unable to brake the immune system.