Dan Kastner, M.D., Ph.D.
Division of Intramural Research
Inflammatory Disease Section
Office of the Clinical Director
A.B. Princeton University, 1973
M.D., Ph.D. Baylor College of Medicine, 1982
Dr. Dan Kastner obtained his A.B. summa cum laude in philosophy from Princeton University and a Ph.D. and M.D. from Baylor College of Medicine. After completing an Internal Medicine residency and chief residency also at Baylor, Dr. Kastner moved to the NIH in 1985. He completed clinical Rheumatology training in the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), and then rose through the NIAMS faculty ranks to become NIAMS Clinical Director from 2005 to 2010. From 2008 to 2011 he was also the first NIH Deputy Director for Intramural Clinical Research. Since late 2010 he has served as Scientific Director of the Division of Intramural Research of the National Human Genome Research Institute (NHGRI). Throughout his career at the NIH Dr. Kastner's research has focused on using genetic and genomic strategies to understand inherited disorders of inflammation, often stimulated by patients seen at the NIH Clinical Center. Dr. Kastner's laboratory identified the gene mutated in familial Mediterranean fever by positional cloning, discovered the genetic basis for a second recurrent fever syndrome they named TRAPS (TNF receptor-associated periodic syndrome), and made seminal genetic discoveries that establish other distinct illnesses as disorders of the IL-1 pathway, thus helping to define the role of IL-1 in human biology and establishing the conceptual basis for therapeutic trials with IL-1 inhibitors. More recently his laboratory has utilized genomic approaches in genetically complex disorders, such as Behçet's disease, and Dr. Kastner continues to maintain a very active clinical research program. His group also proposed the now widely accepted concept of autoinflammatory disease to denote disorders of innate immunity. Dr. Kastner has won a number of awards and honors, including election to the National Academy of Sciences in 2010 and to the Institute of Medicine of the National Academies in 2012.
For almost 25 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 1,700 patients under their natural history protocol. The group recently participated in a multicenter randomized placebo-controlled trial establishing a role for rilonacept, an IL-1 inhibitor, in FMF patients who are unresponsive to or intolerant of the standard treatment, colchicine. The IDS is also participating in a multicenter study of eprodisate in amyloidosis (a complication of the autoinflammatory diseases), and plans protocols evaluating an IL-1 inhibitor in the syndrome of periodic fever with aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA), the most common recurrent fever syndrome in children, and a trial of a reactive oxygen species inhibitor in TRAPS.
IDS laboratory efforts currently focus in three major areas: the genetic analysis of monogenic disorders of inflammation, the study of genetically complex inflammatory diseases, and investigations into the mechanisms by which mutations discovered by the IDS cause human illness. In a collaborative enterprise with NIAID investigators, the IDS defined a novel monogenic autoimmune disorder, denoted PLAID (phospholipase Cγ2-associated antibody deficiency and immune dysregulation), and a separate monogenic autoinflammatory condition, denoted APLAID (autoinflammatory PLAID), caused by activating mutations in the gene encoding phospholipase Cγ2. In another study recently published in the New England Journal of Medicine, the IDS used whole-exome sequencing to define a new autoinflammatory disorder, termed DADA2 (deficiency of adenosine deaminase 2), characterized by recurrent fevers and various forms of vascular pathology, including early-onset strokes and vasculitis. The group continues to apply this powerful sequencing technology to decipher other undiagnosed cases.
Beginning in 1997 with the inception of the North American Rheumatoid Arthritis Consortium (NARAC), the Kastner group has had a major interest in the genetically complex autoimmune and autoinflammatory diseases. Recent work has focused on Behçet's disease, 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. The IDS is currently coordinating a major multicenter effort to discover both common and rare variants that confer susceptibility to scleroderma, a serious autoimmune disease, in African Americans.
Mechanistic laboratory investigations have focused on FMF, TRAPS, and NOMID. By generating a series of knockout and knockin mouse lines, the IDS has shown that FMF-associated pyrin mutations lead to a gain-of-function in pyrin and induce IL-1β activation through a pathway independent of NLRP3. In collaboration with colleagues in NIAMS, the IDS has shown that TRAPS-associated TNFR1 mutations lead to protein-trafficking defects, mitochondrial reactive oxygen species activation, and MAP-kinase activation that induces the release of proinflammatory cytokines. In cellular and biochemical studies of NLRP3, the IDS has recently demonstrated an important role for intracellular ionized calcium and cyclic AMP in the regulation of IL-1β activation and discovered that NOMID-associated mutations cause decreased affinity of NLRP3 for cyclic AMP, findings that have therapeutic implications extending far beyond the relatively rare monogenic disorders of IL-1 activation. 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.
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 Medm357:997-986. 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]
Kastner DL (2015) Familial Mediterranean fever and other hereditary recurrent fevers, in Harrison's Principles of Internal Medicine, 19th ed., DL Kasper, AS Fauci, SL Hauser, DL Longo, JL Jameson, J Loscalzo, eds., pp. 2212-2215.
Siegel RM, Kastner DL (2016) The systemic autoinflammatory diseases, in Goldman's Cecil Medicine, 25th ed., L Goldman, AI Schafer, eds., pp. 1739-1744.
Ombrello AK, Kastner DL (2016) Hereditary periodic fever syndromes and other systemic autoinflammatory diseases, in Nelson Textbook of Pediatrics, 20th ed., RM Kliegman, BF Stanton, JW St. Geme, NF Schor, eds. pp. 1193-1204.
Barron KS, Kastner DL (2016) Periodic fever syndromes and other inherited autoinflammatory diseases, in Textbook of Pediatric Rheumatology, Seventh Edition, RE Petty, RM Laxer, CB Lindsley, LR Wedderburn, eds., pp. 609-626.