Janus kinases (JAKs) are intracellular proteins that mediate the messages of dozens of extracellular messaging molecules — hormones, growth factors, and cytokines — inside cells. JAKs activate signal transducer and activator of transcription (STAT) proteins that regulate gene expression in the nucleus. The JAK-STAT pathway regulates several vital biological functions, such as the immune response, metabolism, and development.
Mutations in JAKs, STATs, or proteins that regulate their function can cause an erroneous JAK-STAT signaling response, which can lead to serious diseases. In inflammatory diseases, such as rheumatoid arthritis, overactivation due to excessive stimulation of the JAK-STAT pathway is also seen.
The dissertation describes a novel mutation in the IRF2BP2 gene that was found in two patients with unique clinical features. The patients had inflammatory symptoms combined with lymphopenia. The study found that certain JAK-STAT pathways were overactive in immune cells of the patients. In addition, the study showed that the damaged protein produced by the gene mutation could not regulate JAK-STAT signaling responses similarly to the normally produced protein.
— Even though such a small cohort of patients does not allow very far-reaching conclusions about the new disease we are describing, it is important to also report case studies, Palmroth says.
— Our understanding of immune system disorders is built piece by piece, and the goal of long-term research is to ease the diagnosis and treatment of diseases caused by even rare gene mutations in the future.
Several medicines belonging to the class of JAK inhibitors are currently available for the suppression of overactive JAK-STAT pathways, and the number of JAK inhibitors under development is also significant. Currently approved indications are found in autoimmune diseases and in hematological cancers.
Although available JAK inhibitors have been shown to be effective and well tolerated in clinical trials, their exact mechanisms of action in patients are not well known. In addition, biochemical comparative studies including several JAK inhibitors in the same study are also needed to understand the differences between JAK inhibitors.
In this doctoral study, JAK inhibitor tofacitinib was shown to inhibit several JAK-STAT pathways in immune cells of patients with rheumatoid arthritis, but the strength of the inhibition depended on the JAK-STAT pathway and the cell type studied. The study also found that the activity of certain STAT proteins before treatment with tofacitinib associated with the treatment response.
A comparative study of JAK inhibitors, on the other hand, showed differences in the properties of 20 different JAK inhibitors and showed that understanding of the significance of these differences requires a combination of several different research methods.
— Examining the properties of JAK inhibitors helps us understand how they elicit the desired response and what mechanisms underlie the unwanted side effects, says Palmroth.
Maaria Palmroth was born in Jämsä and graduated with a master's degree from Tampere University in 2015. The dissertation research was conducted at Molecular Immunology research group lead by Professor Olli Silvennoinen at Tampere University. Palmroth currently works as a consultant for Pfizer Oy through MedEngine Oy.
The doctoral dissertation of MSc Maaria Palmroth in the field of molecular immunology titled JAK-STAT Signaling and Inhibition in Immunological Diseases will be publicly examined on the Faculty of Medicine and Health Technology of Tampere University on June 3rd 2022 in Arvo building auditorium F114, address: Arvo Ylpön katu 34. The opponent will be Professor Mathias Müller from University of Veterinary Medicine Vienna, Austria. Professor Olli Silvennoinen from the Faculty of Medicine and Health Technology Tampere University will act as custos.
The event can be followed also via remote connection
The dissertation is available online at
https://urn.fi/URN:ISBN:978-952-03-2397-4
Photo: Aleksi Palmroth