Dan Kastner, M.D., Ph.D.
Dr. Dan Kastner obtained his A.B. summa cum laude in philosophy from Princeton University in 1973 and a Ph.D. and M.D. from Baylor College of Medicine by 1982. After completing Internal Medicine residency and chief residency at Baylor, Dan moved to the National Institutes of Health (NIH) in 1985. He is currently the Scientific Director of the Division of Intramural Research of the National Human Genome Research Institute (NHGRI). Throughout his career at the NIH Dan’s research has focused on using genetic and genomic strategies to understand inherited disorders of inflammation, often stimulated by patients with relatively rare disorders seen at the NIH Clinical Center hospital. This work has provided detailed molecular explanations for these illnesses, has provided the conceptual basis for highly effective targeted therapies, and has informed our understanding of more common illnesses. Dan’s group also proposed the now widely accepted overarching concept of autoinflammatory disease to denote disorders of the evolutionarily ancient innate branch of the human immune system. Dan has won a number of awards and honors, including election to the National Academy of Sciences in 2010 and to the National Academy of Medicine in 2012, recognition as Federal Employee of the Year in 2018, and the Ross Prize in Molecular Medicine in 2019.
For almost 30 years the focus of the Inflammatory Disease Section (IDS) has been the identification of genes underlying inherited human disorders of inflammation, the elucidation of their function, and the application of these insights to the diagnosis and treatment of human disease. Stimulated by a chance encounter with a patient with familial Mediterranean fever (FMF), Dr. Kastner established a research group in the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) that mapped the gene for FMF to chromosome 16p, and then led an international consortium that identified the recessively inherited gene by positional cloning in 1997. The gene encodes what was then a novel protein (pyrin) that is the prototype for a motif found in some 20 human proteins involved in inflammation and apoptosis. Soon thereafter, Dr. Kastner's group discovered that dominantly-inherited mutations in the p55 tumor necrosis factor receptor cause an inherited fever disorder they named TRAPS (the TNF receptor-associated periodic syndrome), and proposed the now widely accepted concept of autoinflammatory disease to denote a broad group of innate immune disorders. Based on other clinical encounters, the Kastner group and their NIAMS colleagues discovered that mutations in NLRP3, a PYRIN domain-containing activator of interleukin 1β (IL-1β), cause a devastating disorder known as NOMID (neonatal-onset multisystem inflammatory disease), and that the gene mutated in the dominantly-inherited syndrome of pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) encodes a pyrin-binding protein. A subsequent therapeutic trial conducted at the NIH Clinical Center demonstrated that anakinra, a recombinant IL-1 receptor antagonist, dramatically attenuates inflammation and improves outcomes in NOMID patients. More recently, again collaborating with NIAMS colleagues, the group discovered a recessive disorder of neonatal pustulosis and multifocal osteomyelitis caused by loss-of-function mutations in the gene encoding the endogenous IL-1 receptor antagonist.
Since Dr. Kastner and his group moved from NIAMS to the NHGRI Intramural Research Program in late 2010, they have maintained a vigorous clinical research program that studies patients with both known and undiagnosed disorders of inflammation, and they participate in an inter-institute clinical program with investigators and trainees from NIAMS and the National Institute for Allergy and Infectious Diseases (NIAID). The IDS serves as a worldwide referral center for patients with recurrent fever syndromes and other autoinflammatory disorders, and, altogether, the Kastner group has evaluated over 2,000 patients under their natural history protocol. This protocol has served as the foundation for the discovery and characterization of several new autoinflammatory diseases and a springboard for therapeutic trials.
IDS research efforts currently focus in four major areas: the genetic analysis of monogenic disorders of inflammation, the study of genetically complex inflammatory diseases, investigations into the mechanisms by which mutations discovered by the IDS cause human illness, and the development of targeted therapies. Since the IDS moved to the NHGRI, the group has discovered a number of monogenic disorders, including phospholipase Cγ2-associated antibody deficiency and immune dysregulation (PLAID), a separate autoinflammatory condition denoted APLAID (autoinflammatory PLAID), the deficiency of adenosine deaminase type 2 (DADA2), haploinsufficiency of A20 (HA20), otulipenia, and cleavage-resistant RIPK1-induced autoinflammatory (CRIA) syndrome. Current investigations focus on the use of genomic sequencing methods to identify inherited disorders of inflammation, and the role of somatic mosaic mutations in the development of adult-onset autoinflammatory disease.
Recent IDS investigations on the genetically complex autoinflammatory diseases have focused on Behçet’s disease and the syndrome of periodic fever with aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA).
Behçet's disease is a potentially life-threatening cause of oral and genital ulceration, ocular inflammation, and vascular inflammation that is common in countries lying on Marco Polo's ancient Silk Route. With collaborators in Turkey and Japan, the IDS has used state-of-the-art genome-wide association methods and deep resequencing to dramatically advance our understanding of both HLA and non-HLA susceptibility loci for Behçet's disease. PFAPA is the most common periodic fever syndrome in children, oftentimes manifesting clocklike regularity in its febrile episodes. Current studies have leveraged new insights into Behçet’s disease genetics to advance our understanding of the genetics and pathophysiology of PFAPA. The IDS is also collaborating with NIAMS colleagues to discover both common and rare variants that confer susceptibility to scleroderma, a serious autoimmune disease, in African Americans.
Recent IDS mechanistic investigations have focused on the molecular steps by which bacterial toxins activate the pyrin inflammasome. Ongoing studies demonstrate an important role for pyrin in resistance to Yersinia pestis, the agent of the bubonic plague, and suggest that the plague may have selected for high FMF carrier frequencies in Mediterranean and Middle Eastern populations.
The IDS will continue to develop and utilize animal models, coupled with cellular and molecular biologic approaches, to understand the mechanisms of inherited inflammatory disease and to establish the conceptual underpinnings for new therapeutic trials. A recent IDS paper established an important role for tumor necrosis factor inhibitors in the treatment of DADA2.
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, 326:1509-1513. 1992. [PubMed]
International FMF Consortium (Kastner DL, corresponding author). Ancient missense mutations in a new member of the RoRet gene family are likely to cause familial Mediterranean fever. Cell, 90:797-807. 1997. [PubMed]
McDermott MF, Aksentijevich I, Galon J, McDermott EM, Ogunkolade BW, Centola M, Mansfield E, Gadina M, Karenko L, Pettersson T, McCarthy J, Frucht DM, Aringer M, Torosyan Y, Teppo A-M, Wilson M, Karaarslan HM, Wan Y, Todd I, Wood G, Schlimgen R, Kumarajeewa TR, Cooper SM, Vella JP, Amos CI, Mulley J, Quane KA, Molloy MG, Ranki A, Powell RJ, Hitman GA, O'Shea JJ, Kastner DL. Germline mutations in the extracellular domains of the 55 kDa TNF receptor, TNFR1, define a family of dominantly inherited autoinflammatory syndromes. Cell, 97:133-144. 1999. [PubMed]
Aksentijevich I, Nowak M, Mallah M, Chae JJ, Watford WT, Hoffman SR, Stein L, Russo R, Goldsmith D, Dent P, Rosenberg HF, Austin F, Remmers EF, Balow JE Jr, Rosenzweig S, Komarow H, Shoham NG, Wood G, Jones J, Mangra N, Carrero H, Adams BS, Moore TL, Schikler K, Hoffman H, Lovell DJ, Lipnick R, Barron K, O'Shea JJ, Kastner DL, Goldbach-Mansky R. 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 Rheum, 46:3340-3348. 2002. [PubMed]
Shoham NG, Centola M, Mansfield E, Hull KM, Wood G, Wise CA, Kastner DL. Pyrin binds the PSTPIP1/CD2BP1 protein, defining PAPA syndrome and familial Mediterranean fever as disorders in the same pathway. Proc Natl Acad Sci USA, 100:13501-13506. 2003. [PubMed]
Goldbach-Mansky R, Dailey NJ, Canna SW, Gelabert A, Jones J, Rubin BI, Kim HJ, Brewer C, Zelewski C, Wiggs E, Hill S, Turner ML, Karp BI, Aksentijevich I, Pucino F, Penzak S, Haverkamp MH, Stein L, Adams BS, Moore TL, Fuhlbrigge RC, Shaham B, Jarvis JN, O'Neill K, Vehe RK, Beitz LO, Gardner G, Hannan WP, Warren RW, Horn W, Cole JL, Paul SM, Hawkins PN, Pham TH, Snyder C, Wesley RA, Hoffman SC, Holland SM, Butman JA, Kastner DL. Neonatal onset multisystem inflammatory disease responsive to IL-1b inhibition. N Engl J Med, 355:581-592. 2006. [PubMed]
Remmers EF, Plenge RM, Lee AT, Graham RR, Hom G, Behrens TW, deBakker PIW, Le JM, Lee H-Y, Batliwalla F, Li W, Masters SL, Booty MG, Carulli JP, Padyukov L, Alfredsson L, Klareskog L, Chen WV, Amos CI, Criswell LA, Seldin MF, Kastner DL, Gregersen PK. A variant form of STAT4 increases genetic susceptibility to rheumatoid arthritis and systemic lupus erythematosus. N Engl J Med, 357:997-986. 2007. [PubMed]
Remmers EF, Plenge RM, Lee AT, Graham RR, Hom G, Behrens TW, de Bakker PIW, Le JM, Lee H-S, Batliwalla F, Li W, Masters SL, Booty MG, Carulli JP, Padyukov L, Alfredsson L, Klareskog L, Chen WV, Amos CI, Criswell LA, Seldin MF, Kastner DL, Gregersen PK. STAT4 and the risk of rheumatoid arthritis and systemic lupus erythematosus. N Engl J Med, 357:977-986. 2007. [PubMed]
Aksentijevich I, Masters SL, Ferguson PJ, Dancey P, Frenkel J, van Royen-Kerkhoff A, Laxer R, Tedgård U, Cowen EW, Pham T-H, Booty M, Estes JD, Sandler NG, Plass N, Stone D, Turner ML, Hill S, Butman JA, Schneider R, Babyn P, El-Shanti HI, Pope E, Barron K, Bing X, Laurence A, Lee C-CR, Chapelle D, Clarke GI, Ohson K, Nicholson M, Gadina M, Yang B, Korman BD, Gregersen PK, van Hagen M, Hak AE, Huizing M, Rahman P, Douek DC, Remmers EF, Kastner DL, Goldbach-Mansky R. An autoinflammatory disease with deficiency of the interleukin-1-receptor antagonist. N Engl J Med, 360:2426-2437. 2009. [PubMed]
Remmers EF, Cosan F, Kirino Y, Ombrello MJ, Abaci N, Satorius C, Le JM, Yang B, Korman BD, Cakris A, Aglar O, Emrence Z, Azakli H, Ustek D, Tugal-Tutkun I, Akman-Demir G, Chen W, Amos CI, Dizon MB, Kose AA, Azizlerli G, Erer B, Brand OJ, Kaklamani VG, Kaklamanis P, Ben-Chetrit E, Stanford M, Fortune F, Ghabra M, Ollier WER, Cho Y-H, Bang D, O'Shea J, Wallace GR, Gadina M, Kastner DL, Gül A. Genome-wide association study identifies variants in the MHC class I, IL10, and IL23R-IL12RB2 regions associated with Behçet's disease. Nature Genet, 42:698-702. 2010. [PubMed]
Bulua AC, Simon A, Maddipati R, Pelletier M, Park H. Kim K-Y, Sack MN, Kastner DL, Siegel RM. Mitochondrial reactive oxygen species promote production of pro-inflammatory cytokines and are elevated in a TNFR1-associated periodic syndrome (TRAPS). J Exp Med, 208:519-533. 2011. [PubMed]
Stojanov S, Lapidus S, Chitkara P, Feder H, Salazar JC, Fleisher TA, Brown MR, Edwards KM, Ward MM, Colbert RA, Sun H-W, Wood GM, Barham BK, Jones A, Aksentijevich I, Goldbach-Mansky R, Athreya B, Barron KS, Kastner DL. Periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) is a disorder of innate immunity and Th1 activation responsive to IL-1 blockade. Proc Natl Acad Sci USA, 108:7148-7153. 2011. [PubMed]
Chae JJ, Cho Y-H, Lee G-S, Cheng J, Liu PP, Feigenbaum L, Katz SI, Kastner DL. Gain-of-function pyrin mutations induce NLRP3 protein-independent interleukin-1b activation and severe autoinflammation in mice. Immunity, 34;755-768. 2011. [PubMed]
Ombrello MJ, Remmers EF, Sun G, Freeman AF, Datta S, Torabi-Parizi P, Subramanian N, Bunney TD, Baxendale RW, Romberg N, Komarow H, Aksentijevich I, Kim HS, Ho J, Cruse G, Jung MY, Gilfillian A, Metcalfe DD, Nelson C, O'Brien M, Wisch L, Stone K, Douek DC, Gandhi C, Wanderer AA, Lee H, Nelson S, Shianna KV, Cirulli ET, Goldstein DB, Long EO, Moir S, Meffre E, Holland S, Kastner DL, Katan M, Hoffman HM, Milner JD. Cold urticaria, immunodeficiency, and autoimmunity related to PLCG2 deletions. N Engl J Med, 366:330-338. 2012. [PubMed]
Zhou Q, Lee G-S, Brady J, Sheikh A, Katan M, Martins MS, Bunney TD, Datta S, Milner J, Ombrello A, Stone D, Ombrello MJ, Khan J, Kastner DL, Aksentijevich I. Exome sequencing identifies a hypermorphic missense mutation in the PLCG2 gene as the cause of a dominantly inherited autoinflammatory disease with immunodeficiency. Am J Hum Genet, 91:713-720. 2012. [PubMed]
Lee G-S, Subramanian N, Kim A, Aksentijevich I, Goldbach-Mansky R, Sacks DB, Germain RN, Kastner DL, Chae JJ. The calcium-sensing receptor regulates the NLRP3 inflammasome through intracellular Ca2+ and cAMP. Nature 492:123-127, 2012. [PubMed]
Kirino Y, Bertsias G, Ishigatsubo Y, Mizuki N, Tugal-Tutkun I, Seyahi E, Ozyazgan Y, Sacli FS, Erer B, Inoko H, Emrence Z, Cakar A, Abaci N, Ustek D, Satorius C, Ueda A, Takeno M, Kim Y, Wood GM, Ombrello MJ, Meguro A, Gül A, Remmers EF, Kastner DL. Genome-wide association analysis identifies new susceptibility loci for Behçet's disease and epistasis between HLA-B*51 and ERAP1. Nature Genet, 45:202-207. 2013. [PubMed]
Kirino Y, Zhou Q, Ishigatsubo Y, Mizuki N, Tugal-Tutkun I, Seyahi E, Ozyazgan Y, Ugurlu S, Erer B, Abaci N, Ustek D, Meguro A, Ueda A, Takeno M, Inoko H, Ombrello MJ, Satorius C, Maskeri B, Mullikin JC, Sun H-W, Gutierrez-Cruz G, Kim Y, Wilson AF, Kastner DL, Gül A, Remmers EF. Targeted resequencing implicates the familial Mediterranean fever gene MEFV and the toll-like receptor 4 gene TLR4 in Behçet's disease. Proc Natl Acad Sci USA, 110:8134-8139. 2013. [PubMed]
Zhou Q, Yang D, Ombrello AK, Zavialov AV, Toro C, Zavialov AV, Stone DL, Chae JJ, Rosenzweig SD, Bishop K, Barron K, 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 C-CR, Wood GM, Ling A, Kelly SJ, Kleiner DE, Mullikin J, Ganson NJ, Kong HH, Hambleton S, Candotti F, Quezado MM, Calvo K, Alao H, Barham BK, Jones A, Meschia JF, Worrall BB, Kasner SE, Rich SS, Goldbach-Mansky R, Abinum M, Chalom E, Gotte AC, Punaro M, Pascual V, Verbsky J, Torgerson TR, Singer NG, Gershon TR, Ozen S, Karadag O, Fleisher TA, Remmers EF, Burgess SM, Moir SL, Gadina M, Sood R, Hershfield M, Boehm M, Kastner DL, Aksentijevich I. Early-onset stroke and vasculopathy associated with mutations in ADA2. N Engl J Med, 370:911-920. 2014. [PubMed]
Ombrello MJ, Kirino Y, de Bakker PI, Gül A, Kastner DL, Remmers EF. Behçet disease-associated MHC class I residues implicate antigen binding and regulation of cell-mediated cytotoxicity. Proc Natl Acad Sci USA, 111:8867-8872. 2014. [PubMed]
Zhou Q, Wang H, Schwartz DM, Stoffels M, Park YH, Zhang Y, Yang D, Demirkaya E, Takeuchi M, Tsai WL, Layons JJ, Yu X, Ouyang C, Chen C, Chin DT, Zaal K, Chandrasekharappa SC, Hanson EP, Yu Z, Mullikin JC, Hasni SA, Wertz IE, Ombrello AK, Stone DL, Hoffmann P, Jones A, Barham BK, Leavis HL, van Royen-Kerkof A, Sibley C, Batu ED, Gül A, Siegel RM, Boehm M, Milner JD, Ozen S, Gadina M, Chae J, Laxer RM, Kastner DL, Aksentijevich I. Loss-of-function mutations in TNFAIP3 leading to A20 haploinsufficiency cause an early-onset autoinflammatory disease. Nature Genet, 48:67-73. 2016. [PubMed]
Boyden SE, Desai A, Cruse G, Young ML, Bolan HC, Scott LM, Eisch AR, Long RD, Lee C-CR, Satorius CL, Pakstis AJ, Olivera A, Mullikin JC, Chouery E, Mégarbané, Medlej-Hashim M, Kidd KK, Kastner DL, Metcalfe DD, Komarow HD. Vibratory urticaria associated with a missense variant in ADGRE2. N Engl J Med, 375(1):95. 2016. [PubMed]
Chung LK, Park YH, Zheng Y, Brodsky IE, Hearing P, Kastner DL, Chae JJ, Bliska JB. The Yersinia Virulence Factor YopM Hijacks Host Kinases to Inhibit Type III Effector-Triggered Activation of the Pyrin Inflammasome. Cell Host Microbe, 20(3):296-306. 2016. [PubMed]
Stoffels M, Kastner DL Old dogs, new tricks: monogenic autoinflammatory disease unleashed. Annu Rev Genom Hum Genet, 17:18.1-18.28. 2016. [PubMed]
Zhou Q, Yu X, Demirkaya E, Deuitch N, Stone D, Tsai WL, Kuehn HS, Wang H, Yang D, Park YH, Ombrello AK, Blake M, Romeo T, Remmers EF, Chae JJ, Mullikin JC, Güzel F, Milner JD, Boehm M,Rosenzweig SD, Gadina M, Welch SB, Özen S, Topaloglu R, Abinum M, Kastner DL, Aksentijevich I. Biallelic hypomorphic mutations in a linear deubiquitinase define otulipenia, an early-onset autoinflammatory disease. Proc Natl Acad Sci USA, 113:10127-10132. 2016. [PubMed]
Park YH, Wood G, Kastner DL, Chae JJ (2016) Pyrin inflammasome activation and RhoA signaling in the autoinflammatory diseases FMF and HIDS. Nat Immunol, 17:914-921. 2016. [PubMed]
Takeuchi M, Mizuki N, Meguro A, Ombrello MJ, Kirino Y, Satorius C, Le J, Blake M, Erer B, Kawagoe T, Ustek D, Tugal-Tutkun I, Seyahi E, Ozyazgan Y, Sousa I, Davatchi F, Francisco V, Shahram F, Abdollahi BS, Nadji A, Shafiee NM, Ghaderibarmi F, Ohno S, Ueda A, Ishigatsubo Y, Gadina M, Oliveira SA, Gül A, Kastner DL, Remmers EF. Dense genotyping of immune-related loci implicates host responses to microbial exposure in Behçet's disease susceptibility. Nat Genet, 49:438-443. 2017. [PubMed]
Manthiram K, Zhou Q, Aksentijevich I, Kastner DL. The monogenic autoinflammatory diseases define new pathways in human innate immunity and inflammation. Nat Immunol. 18:832-842. 2017. [PubMed]
Ombrello AK, Qin J, Hoffmann P, Kuman P, Stone D, Jones A, Romeo T, Barham B, Pinto-Patarroyo G, Toro C, Soldatos A, Zhou Q, Deuitch N, Aksentijevich I, Sheldon SL, Kelly S, Man A, Barron K, Hershfield M, Flegel WA, Kastner DL. Treatment strategies for the deficiency of adenosine deaminase 2. N Engl J Med 380:1582-1584. 2019. [PubMed]
Lalaoui N, Boyden SE, Oda H, Wood GM, Stone DL, Chau D, Liu L, Stoffels M, Kratina T, Lawlor KE, Zaal KJM, Hoffmann PM, Etemadi N, Shield-Artin K, Biben C, Tsai WL, Blake MD, Kuehn HS, Yang D, Anderton H, Silke N, Wachsmuth L, Zheng L, Sampaio Moura N, Beck DB, Gutierrez-Cruz G, Ombrello AK, Pinto-Patarroyo GP, Kueh AJ, Herold MJ, Hall C, Wang H, Chae JJ, Dmitrieva NI, McKenzie M, Light A, Barham BK, Jones A, Romeo TM, Zhou Q, Aksentijevich I, Mullikin JC, Gross AJ, Shum AK, Hawkins ED, Masters S, Lenardo MJ, Boehm M, Rosenzweig SD, Pasparakis M, Voss AK, Gadina M, Kastner DL, Silke J. Mutations that prevent caspase-8 cleavage of RIPK1 cause inflammation in humans and mouse. Nature 577:103-108. 2020.
Inflammatory Disease Section Staff
- Nurse Practitioner
- Inflammatory Disease Section
- Inflammatory Disease Section
- Clinical Post Baccalaureate Fellow
- Inflammatory Disease Section
- Program Support Staff
- Inflammatory Disease Section
- Nurse Practitioner
- National Institute of Arthritis and Musculoskeletal and Skin Diseases
- Infectious Disease Fellow
- National Institute of Allergy and Infectious Diseases
- Clinical Fellow
- NHGRI Medical Genetics and Genomic Medicine fellowship Program
Last updated: February 17, 2020