For almost 30 years, Dr. Aksentijevich has used genetic and genomic approaches to understand human inflammatory diseases and to advance the molecular diagnosis of these conditions. Dr. Aksentijevich began her research career by making major contributions to the linkage mapping and positional cloning of the gene mutated in familial Mediterranean fever (FMF). She went on to discover mutations in the p55 tumor necrosis factor receptor that cause a dominantly-inherited periodic fever syndrome now known as TRAPS (the TNF receptor-associated periodic syndrome). The manuscript reporting this discovery also proposed the now widely accepted concept of autoinflammatory disease to denote a group of disorders mediated by cells of the innate immune system.
Dr. Aksentijevich subsequently discovered the genetic basis of two disorders in which interleukin 1b plays an important role. First, she found de novo gain-of-function missense mutations in NLRP3, a PYRIN domain-containing activator of IL-1b, that cause neonatal-onset multisystem inflammatory disease (NOMID), an autoinflammatory disease characterized by fevers, urticaria-like rash, bony overgrowth, and chronic aseptic meningitis. Later, she discovered loss-of-function mutations in the endogenous IL-1 receptor antagonist that cause neonatal pustulosis and multifocal osteomyelitis. This recessively-inherited disorder is now termed DIRA, the deficiency of the IL-1 receptor antagonist.
More recently, Dr. Aksentijvich and her colleagues have described two disorders, denoted PLAID and APLAID, that are caused by dominantly inherited mutations in phospholipase Cγ2 (PLCγ2), leading to cold urticaria, immunodeficiency, and systemic inflammation. She also led a team that discovered recessive loss-of-function mutations in the gene encoding adenosine deaminase 2 (ADA2) in patients with early-onset stroke, vasculopathy, and fever. The underlying condition is now known as DADA2 (deficiency of ADA2), and is an important cause of polyarteritis nodosa as well as bone marrow failure.
Dr. Aksentijevich has also made important contributions to our understanding of non-Mendelian forms of autoinflammation. She and her team discovered a postnatal myeloid-restricted somatic mutation in NLRP3 in a patient with adult-onset Muckle-Wells syndrome (MWS), raising the possibility that other patients with adult-onset recurrent fevers might also have somatic mosaicism. She also demonstrated digenic inheritance in patients with CANDLE (chronic atypical neutrophilic dermatitis with lipodystrophy and elevated temperature) syndrome, implicating 3 genes (PSMA3, PSMB4, and PSMB9) in addition to the already known PSMB8. This was the first documented example of digenic inheritance in autoinflammatory disease.
During the last 3 years Dr. Aksentijevich has discovered several new autoinflammatory conditions caused by mutations in enzymes involved in the control of ubiquitination in immune cells. This includes the identification of dominant loss-of-function mutations in TNFAIP3 in patients with early-onset Behçet's-like disease, denoted haploinsufficiency of A20 (HA20), and the discovery of recessive loss-of-function mutations in the linear deubiquitinase OTULIN causing a neonatal-onset form of panniculitis denoted otulipenia. Dr. Aksentijevich also discovered recessive hypomorphic mutations in TRNT1, encoding an enzyme that adds CCA to the 3' ends of all tRNAs, as the cause of an infantile-onset syndrome with sideroblastic anemia, B cell immunodeficiency, recurrent fever, and developmental delay (SIFD).
Dr. Aksentijevich has published numerous additional studies on the genetics and pathogenesis of autoinflammatory diseases. She is Board-Certified in Clinical Molecular Genetics and she runs a CLIA certified molecular diagnostic laboratory for patients with autoinflammatory diseases. She is a Past President of the International Society for Systemic Autoinflammatory Diseases (ISSAID).
Posted: July 16, 2018