Ivona Aksentijevich, M.D.
Metabolic, Cardiovascular and Inflammatory Disease Genomics Branch
Inflammatory Disease Section
M.D. University of Belgrade Medical School, Serbia
Dr. Ivona Aksentijevich obtained her medical degree from Belgrade University in the former Yugoslavia. In 1990 she joined Dr. Daniel Kastner in the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) to work as a post-doctoral fellow on the positional cloning of the gene mutated in patients with familial Mediterranean fever (FMF), and later stayed in the same group as a staff scientist. In 2010, she moved with Dr. Kastner to the National Human Genome Research Institute (NHGRI) and continues to study the genetics of monogenic autoinflammatory diseases. Dr. Aksentijevich is certified in clinical molecular genetics by the American Board of Medical Genetics, and supervises a CLIA-certified laboratory for autoinflammatory disease diagnostics in the IDS. Her scientific accomplishements are numerous, and include the identification of several genes underlying known autoinflammatory diseases as well as the discovery of multiple previously unknown conditions. She is a past president of the International Society on Systemic Autoinflammatory Diseases (ISSAID).
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).
Pras E, Aksentijevich I, Gruberg L, Balow JE Jr, Prosen L, Dean M, Steinberg AD, Pras M, Kastner DL. Mapping of a gene causing familial Mediterranean fever to the short arm of chromosome 16. N Engl J Med, 326:1509-11.1992. [PubMed]
Aksentijevich I, Pras E, Gruberg L, Shen Y, Holman K, Helling S, Prosen L, Sutherland GR, Richards RI et al. Refined mapping of the gene causing familial Mediterranean fever by linkage and homozygosity studies. Am J Hum Genet, 53:451-61.1993. [PubMed]
Aksentijevich I, Pras E, Gruberg L, Shen Y, Holman K, Helling S, Prosen L, Sutherland GR, Richards RI, Dean M, Pras M, Kastner DL. Familial Mediterranean fever in Moroccan Jews: demonstration of a founder effect by extended haplotype analysis. Am J Hum Genet,53:644-51.1993. [PubMed]
Pras E, Arber N, Aksentijevich I, Katz G, Schapiro JM, Prosen L, Gruberg L, Harel D, Liberman U, Weissenbach J, Pras M, Kastner DL. Localization of a gene causing cystinuria to chromosome 2p. Nature Genet, 6:415-19 1994. [PubMed]
International FMF Consortium (Ivona Aksentijevich, one of four first co-authors). Ancient missense mutations in a new member of the RoRetgene family are likely to cause familial Mediterranean fever. Cell, 90:797-807. 1997. [PubMed]
Aksentijevich I, Torosyan Y, Samuels J, Centola M, Pras E, Chae JJ, Oddoux C, Wood G, Azzaro MP, Palumbo G, Giustolisi R, Pras M, Ostrer H, Kastner DL. Mutation and haplotype studies in familial Mediterranean fever revealed new ancestral relationships and evidence for a high carrier frequency with reduced penetrance in the Ashkenazi Jewish population. Am J Hum Genet, 64:949-62. 1997. [PubMed]
McDermott M, Aksentijevich I, Galon J, McDermott E, Ogunkolade W, Centola M, Mansfield E, Gadina M, et al. Germline mutations in the extracellular domains of the 55kDa TNF receptor (TNFR1) define a family of dominantly inherited autoinflammatory syndromes.Cell,97:133-44. 1999. [PubMed]
Galon J, Aksentijevich I, McDermott M, O'Shea JJ, and Kastner DL. TNFRSF1A mutations and autoinflammatory syndromes. CurrOpinion in Immunology, 12(4):479-86. 2000. [PubMed]
Aksentijevich I, Galon J, Soares M, Mansfield E, Hull K, et al. The TNF receptor-associated periodic fever syndrome (TRAPS): new mutations in TNFRSF1A, ancestral origins, genotype-phenotype studies, and further genetic heterogeneity of periodic fevers. Am J Hum Gene,t 69:301-14. 2001. [PubMed]
Aksentijevich I, Nowak M, Mullah M, et al. De novo CIAS1 mutations, cytokine activation, and evidence for genetic heterogeneity in patients with neonatal onset multisystem inflammatory disease (NOMID): A new member of the expanding family of pyrin-associated autoinflammatory diseases. Arthritis Rheumatol, 46(12):3340-48. 2002. [PubMed]
McDermott M and Aksentijevich I. The autoinflammatory syndromes. Curr Opin Allergy Clin Immun, 2:511-16. 2002. [PubMed]
Aksentijevich I, Putnam CD, Remmers EF, Mueller JL, Le J, Kolodner RD, Moak Z, Chuang M, Austin F, Goldbach-Mansky R, Hoffman HM, Kastner DL. The clinical continuum of cryopyrinopathies: Novel CIAS1 mutations inthe North American cohort of patients and a new cryopyrin model. Arthritis Rheumatol, 56(4):1273-1285. 2007. [PubMed]
Touitou I, Rittore C, Philibert L, Yagüe J, Shinar Y, Aksentijevich I. An international external quality assessment (EQA) for molecular diagnosis of hereditary recurrent fevers. A 3-year scheme demonstrates need for improvement. Eur J Hum Genet 17(7):890-6. 2009. [PubMed]
Ryan J, Aksentijevich I. TNF Receptor-Associated Periodic Syndrome (TRAPS): Towards a Molecular Understanding of the Systemic Autoinflammatory Diseases. Arthritis Rheumatol, 60(1):8-11. 2009. [PubMed]
Booty M, Chae JJ, Masters SL, Remmers EF, Barham B, Lee JM, Barron KS, Holland S, Kastner DL, Aksentijevich I. Familial Mediterranean fever with a single MEFV mutation: Where is the second hit? Arthritis Rheumatol, 60(6):1851-1861. 2009. [PubMed]
Aksentijevich I, Masters SL, Ferguson PJ, Dancey P, Frenkel J, Royen-Kerkhoff A, Laxer R, et al. Deficiency of the Interleukin-1 Receptor Antagonist (DIRA): A Systemic Autoinflammatory Disease of Skin and Bone. N Engl J Med, 360(23):2426-37. 2009.[PubMed]
Masters SL, Simon A, Aksentijevich I, Kastner DL. Horror autoinflamaticus: The molecular pathophysiology of autoinflammatory disease. Ann Rev Immunol, 27:621-68. 2009. [PubMed]
Ryan JG, Master SL, Booty MG, Alexander JD, Barham BK, Remmers EF, Barron KS, Kastner DL, Aksentijevich I. Clinical feature and functional significance of the P369S/R408Q variant in pyrin, the familial Mediterranean fever protein. Ann Rheum Dis, 69(7):1383-8. 2009. [PubMed]
Kastner DL, Aksentijevich I, Goldbach-Mansky R. Autoinflammatory diseases reloaded: A clinical perspective. Cell, 140:784-90. 2010. [PubMed]
Aksentijevich I, Kastner DL. Genetics of monogenic autoinflammatory diseases: past successes, future challenges. Nat Rev Rheumatol,5:469-78. 2011. [PubMed]
Ombrello MJ, Remmers EF, Sun G, Freeman A, Datta S, Bunney TD, Baxendale RW, Torabi-Parizi P, Subramanian N, Romberg N, Komarow H, Aksentijevich I et al. Genomic Deletions in PLCG2 Define a Syndrome of Cold Urticaria, Antibody Deficiency and Susceptibility to Autoimmunity and Infection. N Engl J Med, 366:330-8. 2012. [PubMed]
Zhou Q, Lee G-S, Brady J, Datta S, Katan M, Sheikh A, Martins MS, Bunney TD, Santich BH, Moir S, Kuhns DB, Long Priel D, Ombrello A, Stone D, Ombrello M, Khan J, Milner J, Kastner DL, and Aksentijevich I. A Hypermorphic Missense Mutation in PLCG2, Encoding Phospholipase Cγ2, Causes a Dominantly Inherited Autoinflammatory Disease with Immunodeficiency. Am J Hum Genet, 91(4):713-20. 2012. [PubMed]
Lee G-S, Subramanian S, Kim A, Aksentijevich I, Goldbach-Mansky R, Sacks DB, Germain RN, Kastner DL and Chae JJ. The calcium sensing receptor regulates the NLRP3 inflammasome through Ca2+ and cAMP. Nature, 6; 492(7427):123-7. 2012. [PubMed]
Balow JE Jr., Ryan J, Chae JJ, Booty MG, Bulua A, Stone D, Sun HW, Greene J, Barham B, Goldbach-Mansky RG, Kastner DL, and Aksentijevich I. Microarray-based gene expression profiling in patients with CAPS defines a disease-related-signature and IL-1-responsive transcripts. Ann Rheum Dis, 72(6):1064-70. 2013. [PubMed]
Zhou Q, Yang D, Ombrello AK, Zavialov AV, Toro C, Zavialov AV, Stone DL, Chae JJ, Rosenzweig SD, Bishop K, Barron KS, Kuehn HS, Hoffmann P, Negro A, Tsai WL, Cowen EW, Pei W, Milner JD, Silvin C, Heller T, Chin DT, Patronas NJ, Barber JS, Lee CC, Wood GM, Ling A, Kelly SJ, Kleiner DE, Mullikin JC, Ganson NJ, Kong HH, Hambleton S, Candotti F, Quezado MM, Calvo KR, Alao H, Barham BK, Jones A, Meschia JF, Worrall BB, Kasner SE, Rich SS, Goldbach-Mansky R, Abinun M, Chalom E, Gotte AC, Punaro M, Pascual V, Verbsky JW, Torgerson TR, Singer NG, Gershon TR, Ozen S, Karadag O, Fleisher TA, Remmers EF, Burgess SM, Moir SL, Gadina M, Sood R, Hershfield MS, Boehm M, Kastner DL, Aksentijevich I. Early-onset stroke and vasculopathy associated with mutations in ADA2. N Engl J Med, 370:911-20. 2014. [PubMed]
Martinon F, Aksentijevich I. New players driving inflammation in monogenic autoinflammatiry diseases. Nat Rev Rheumatol, 11(1):11-20. 2014. [PubMed]
Aksentijevich I. Update on genetics and pathogenesis of autoinflammatory diseases: the last two years. Semin Immunopathol,37(4):395-401. 2015. [PubMed]
Zhou Q, Wang H, Schwartz DM, Stoffels M, Park YH, Zhang Y, Yang D, Demirkaya E, Takeuchi M, Tsai WL, Lyons JJ, Yu X, Ouyang C, Chen C, Chin DT, Zaal K, Chandrasekharappa SC, Hanson EP, Yu Z, Mullikin JC, Hasni SA, Wertz I, Ombrello AK, Stone DL, Hoffmann P, Jones A, Barham BK, Leavis HL, Royen-Kerkof A, Sibley C, Batu ED, Gül A, Siegel RM, Boehm M, Milner JD, Ozen S, Gadina M, Chae JJ, Laxer RM, Kastner DL, Aksentijevich I. Loss-of-function mutations in TNFAIP3 leading to A20 haploinsufficiency cause an early onset autoinflammatory syndrome. Nat Genet, 48(1):67-73. 2016. [PubMed]
Brehm A, Liu Y, Sheikh A, Marrero B, Omoyinmi E, Zhou Q, Montealegre G, Biancotto A, Reinhardt A, Almeida de Jesus A, Pelletier M, Tsai WL, Remmers EF, Kardava L, Hill S,Kim H, Lachmann HJ, Megarbane A, Chae JJ, Brady J, Castillo RD, Brown D, Casano AV, Ling G, Chapelle D, Huang Y, Stone D, Chen Y, Sotzny F, Lee CR, Kastner DL, Torrelo A, Zlotogorski A, Moir S, Gadina M, McCoy P, Wesley R, Rother K, Hildebrand PW, Brogan P, Kruger E, Aksentijevich I, Goldbach-Mansky R. Additive loss-of-function mutations in proteasome-subunit-genes induce type 1-interferon production in CANDLE/PRAAS. J Clin Invest, 125(11):4196-211. 2016. [PubMed]
Zhou Q, Yu X, Demirkaya E, Deuitch N, Stone D, Tsai WL, Kuehn SH, Wang H, Yang D, Park HY, Ombrello AK, Blake M, Romeo T, Remmers EF, Chae JJ, Jam Mullikin JC, Güzel F, Milner JD,Boehm M, Rosenzweig SD, Gadina M, Welch SB, Ozen S, Topaloglu R, Abinun M, Kastner DL, Aksentijevich I. Biallelic hypomorphic mutations in a linear deubiquitinase define otulipenia, an early onset autoinflmmatory disease. Proc Natl Acad Sci USA, 113 (36):10127-32. 2016. [PubMed]
Aksentijevich I. and McDermott MF. Lessons from characterization and treatment of autoinflammatory diseases. Curr Opin Rheumatol, 29 (2):187-194. 2017. [PubMed]
Aksentijevich I. and Zhou Q. NF-kB pathway in autoinflammatory diseases: Dysregulation of protein modifications by ubiquitin defines a new category od autoinflammatory diseases. 2017. [PubMed]
Demirkaya E, Zhou Q, Smith CK, Ombrello Mj, Deuitich N, Tsai WL, Hoffman P, Remmers EF, Takeuchi M, Pak YH, Chae JJ, Barut K, Simsek D, Adrovic A, Sahin S, Caliskan S, CHandrasekharappa SC, Hasni SA, Ombrello AK, GadinaM, Kastner DL, Kaplan MJ, Kasapcopur, Aksentijevich I. Deficiency of complement 1r subcomponent in early-onset systemic lupus erythematosus: the role of disease-modifying alleles in a monogenic disease. Arthritis Rheumatol, 69 (9):1832-1839. 2017. [PubMed]
Manthiram K, Zhou Q, Aksentijevich I, Kastner DL.The monogenic autoinfalmamtory diseases definenew pathways in human innate immunity and inflammation. Nat Immunol, 18 (8): 832-842. 2017. [PubMed]
Giannelou A, Wang H, Zhou Q, Park YH, Abu-Asab MS, Ylaya K, Stone DL, Anna Sediva A, Sleiman R, Sramkova L, Bhatla D, Serti E, Tsai WL, Yang D, Bishop K, Carrington B, Pei W, Deuitch N, Brooks S, Edwan JH, Joshi S, Prader S, Kaiser D, Owen WC, Al Sonbul A, Zhang Y, Niemela JE, Burgess SM, Boehm M,Rehermann B, Chae JJ, Quezado MM, Ombrello AK, Buckley RH, Grom AA, Remmers EF, Jana M. Pachlopnik JM, Su HC, Gutierrez-Cruz G, Hewitt SM, Sood R, Risma K, Calvo KR,Rosenzweig SD, Gadina M, Hafner M, Sun HW, Kastner DL, and Aksentijevich I. Aberrant tRNA processing causes an autoinflammatory syndrome responsive to TNF inhibitors. Ann Rheum Dis. 2018. [PubMed]
Last updated: May 18, 2022