Dan Kastner, M.D., Ph.D.
NIH Distinguished Investigator
Medical Genetics Branch
Building 50, Room 5222
50 South Drive
Bethesda, MD 20892
The Inflammatory Disease Section studies the genetics, pathophysiology, and treatment of inherited disorders of inflammation through an integrated clinical and laboratory program. Having recently moved to NHGRI from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), the group has investigated Mendelian and genetically complex inflammatory disorders for the last twenty years, and proposed the now widely-accepted concept of autoinflammatory disease for a class of disorders of innate immunity.
Many of the Section's most important projects began with patient encounters in the NIH Clinical Center. As a rheumatology fellow, Dr. Kastner saw a patient with Familial Mediterranean Fever (FMF), a recessively inherited disorder characterized by episodes of fever, serositis, arthritis, and skin rash. The Kastner group utilized classical linkage analysis to map the FMF gene to chromosome 16p, and subsequently led an international consortium that identified the underlying gene by positional cloning in 1997. The gene encodes a protein (pyrin) that is the prototype for a motif found in some 20 human proteins involved in inflammation and apoptosis. Animal model studies carried out in the laboratory demonstrated that the pyrin protein regulates inflammation through interleukin 1 (IL-1), a cytokine produced in white blood cells. This finding has advanced new therapies targeting IL-1 in FMF patients who are unresponsive to, or intolerant of colchicine, the previously established treatment for this illness.
Following an Irish patient with prolonged febrile episodes similar to FMF, the Kastner group discovered that mutations in the 55 kDa receptor for tumor necrosis factor (TNF) define a dominantly-inherited syndrome that the group named TNF receptor-associated periodic syndrome, or TRAPS. Drawing upon functional immunologic studies of TRAPS patients, the group pioneered the use of etanercept, a recombinant TNF receptor fusion protein, for the treatment of TRAPS. Based on another patient seen in the clinic, the group discovered that mutations in NLRP3, which encodes a pyrin domain-containing regulator of IL-1, cause a devastating inflammatory disorder of the skin, bones, and central nervous system known as neonatal-onset multisystem inflammatory disease, or NOMID. Mutations in another protein identified in the Section as a pyrin-binding molecule cause the dominantly inherited syndrome of pyogenic arthritis, pyoderma gangrenosum, and acne. Subsequently, a therapeutic trial conducted at the NIH Clinical Center established that anakinra, a recombinant IL-1 receptor antagonist, dramatically attenuates inflammation in patients with NOMID. More recently, in collaboration with colleagues at NIAMS, the Kastner group discovered a recessively inherited, anakinra-responsive illness known as DIRA (deficiency in the IL-1 receptor antagonist), which is caused by mutations in the endogenous IL-1 receptor antagonist gene.
With the North American Rheumatoid Arthritis Consortium, the Section discovered that variants in the T-cell signaling molecule STAT4 predispose to rheumatoid arthritis, systemic lupus erythematosus, and Sjögren's syndrome. In 2010 the Section completed a genome-wide association study demonstrating that variants of the genes encoding interleukin 10 (IL-10) and the interleukin 23 (IL-23) receptor predispose an individual to Behçet's disease, a genetically complex disorder characterized by the triad of oral, ocular, and genital inflammation.
The Section continues to pursue a vigorous program in translational research. Its clinicians have seen a total of over 1300 patients with various autoinflammatory diseases at the NIH Clinical Center. In the laboratory, work aimed at better understanding the genetics of Behçet's disease is ongoing, now focusing on disease subsets, common copy number variants, and deep resequencing for rare variants. Members of the group are currently leading an international consortium searching for susceptibility loci for systemic onset juvenile idiopathic arthritis (also known as Still's disease) using a genome-wide association approach. Whole-exome sequencing is being used in selected families with apparent monogenic disorders to discover new inherited disease loci. The group continues to study pyrin and related proteins, using animal models and biochemical approaches. In collaboration with NIAMS, the Kastner group also continues active therapeutic clinical protocols in several autoinflammatory diseases.
Lee GS, Subramanian N, Kim AI, Aksentijevich I, Goldbach-Mansky R, Sacks DB, Germain RN, Kastner DL, Chae JJ. The calcium-sensing receptor regulates the NLRP3 inflammasome through Ca2+ and cAMP. Nature. 2012;492(7427):123-7.
Park YH, Wood G, Kastner DL, Chae JJ. Pyrin inflammasome activation and RhoA signaling in the autoinflammatory diseases FMF and HIDS. Nat Immunol. 2016;17(8):914-21.
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. Nat Genet. 2013;45(2):202-7.
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. 2014;370(10):911-20.
Boyden SE, Desai A, Cruse G, Young ML, Bolan HC, Scott LM, Eisch AR, Long RD, Lee CC, Satorius CL, Pakstis AJ, Olivera A, Mullikin JC, Chouery E, Mégarbané A, Medlej-Hashim M, Kidd KK, Kastner DL, Metcalfe DD, Komarow HD. Vibratory Urticaria Associated with a Missense Variant in ADGRE2. N Engl J Med. 2016;374(7):656-63.