Daniel Kastner, M.D., Ph.D.
NIH Distinguished Investigator
Metabolic, Cardiovascular and Inflammatory Disease Genomics Branch
Building 50, Room 5222
50 South Drive
Bethesda, MD 20892
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.
Inflamed blood vessels in a child's brain (illustration)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.
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.
Manthiram K, Zhou Q, Aksentijevich I, Kastner DL. The monogenic autoinflammatory diseases define new pathways in human innate immunity and inflammation. Nat Immunol. 2017;18(8):832-842.
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.
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. 2017;49(3):438-443.
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.
Related Scientific Focus Areas
This page was last updated on August 25th, 2017