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.
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.
Posted: September 25, 2014