Dr. Tomas Mustelin’s research is focused on elucidating the molecular underpinnings of rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), ANCA-associated vasculitis (AAV), primary Sjögren’s syndrome (pSS), and other autoimmune conditions.
Protein citrullination in RA
Our model is that neutrophils are pivotal in the initiation and propagation of RA by driving a pathogenic intra- and extracellular citrullination reaction that both alters the function of several proteins and cell types in the joint, as well as provides abundant ‘neo’-autoantigens for which we do not have immunological tolerance. Indeed, neutrophils have been known for decades to be abundant in synovial fluid and their elimination by apheresis suppresses symptoms of RA. It follows that inhibition of citrullination could be highly therapeutic for patients. The lab will be studying the mechanisms by which pathological citrullination occur in RA patients, the impact of citrullination of interesting proteins, and the regulation of the citrullinating enzymes PAD2 and PAD4.
Involvement of retroelements in SLE pathogenesis
We are addressing the hypothesis that long interspersed nuclear elements (LINE1) are the core drivers of type I interferon production in SLE and related diseases like pSS. Transcriptional activation of LINE1 gives rise to a reverse transcriptase (RT), which produces DNA that can activate the cGAS – STING pathway, leading to IFNb production. The lab will verify that this pathway operates in SLE and pSS patients and will test if inhibition of the LINE1 RT will stop IFN production and would be therapeutically beneficial for patients.
How PTPN22 contributes to autoimmunity
Continuing from the original discovery of the PTPN22 polymorphism by our lab in 2004, we plan to study how PTPN22 variants affect disease-relevant pathways and cell types in RA, SLE, and AAV.
Development of novel therapeutics for our patients
The lab will be looking for opportunities to discover and develop new therapeutics for RA, SLE, pSS, and AAV, based on novel insights into disease pathogenesis.