MEVALONAT KİNAZ EKSİKLİĞİ (MKE) HASTALARINDA PYRİN VE NLRP3 İNFLAMAZOMLARININ PRENİLASYON ÜZERİNE ETKİLERİNİN ARAŞTIRILMASI

Abstract

Autoinflammatory diseases are rare and hereditary disorders characterized by excessive activation of the immune system as a result of pathological alterations in innate immunity, leading to recurrent inflammatory responses and periodic fever independent of infection. Familial Mediterranean Fever (FMF) is the most common autoinflammatory disease in Türkiye and arises from mutations in the MEFV gene encoding the pyrin protein. Another autoinflammatory disease, Mevalonate Kinase Deficiency (MKD), is an ultra-rare disorder caused by mutations in the MVK gene, which encodes the mevalonate kinase enzyme involved in the mevalonate pathway. It is thought that the autoinflammatory response observed in MKD patients results from a deficiency in prenylation. Prenylation is a post-translational modification observed in all eukaryotes and has been associated not only with autoinflammatory diseases but also with conditions such as cancer, Alzheimer’s disease, and progeria. This modification enables proteins to localize to and associate with cellular membranes and is believed to play a role in the suppression of the pyrin inflammasome through this function. Although previous studies have demonstrated that a deficiency in prenylation leads to inflammation, the effect of inflammation on prenylation itself has not yet been investigated. Within the scope of this thesis, pyrin and NLRP3 inflammasomes were stimulated in dermal fibroblast cells obtained from MKD patients, FMF patients, and healthy controls; in monocytes differentiated from induced pluripotent stem cells (iPSCs) derived from dermal fibroblasts of an FMF patient; and in primary monocytes isolated from the blood of MKD and FMF patients, in order to identify the predominant inflammasomes involved in these diseases. Subsequently, prenylation assays were performed in primary monocytes to examine the effects of the induced inflammatory response on prenylation. As a result of these experiments, it was observed that inflammation exacerbates prenylation deficiency in patients with MKD and FMF.