Environmental Factor, February 2010, National Institute of Environmental Health Sciences
Kastner Kicks Off Clinical Seminar Series
By Laura Hall
"When the immune system turns against its host, it can be a horrific thing," said Daniel Kastner, M.D., Ph.D., as he explained how he and his colleagues tracked down the genetic and molecular causes of a series of rare autoinflammatory diseases that had puzzled doctors for years. Kastner's lively Jan. 22 presentation was the inaugural talk of the NIEHS Clinical Director's Seminar Series.
Kastner(https://www.niams.nih.gov/Research/Ongoing_Research/Branch_Lab/Clinical_Director/default.asp) is the deputy director for Intramural Clinical Research for all of NIH as well as the clinical director and director of Translational Research for the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) Intramural Research Program. Acting Clinical Director Darryl Zeldin, M.D., hosted the seminar. Kastner began his presentation, titled "Horror Autoinflammaticus: The Expanding Spectrum of Systemic Autoinflammatory Diseases," with his experience trying to understand the causes of familial Mediterranean fever (FMF).
Kastner had patients with FMF, a disease characterized by recurrent episodes of painful inflammation in the abdomen, lungs, and joints, which is often accompanied by fevers and a rash. What puzzled doctors about FMF and other similar inherited skin and bone inflammatory diseases was that the sporadic bouts of fevers and uncontrolled inflammation occurred throughout the body and mimicked infections and allergic conditions in their symptoms. However, the patients did not show any markers or evidence of infection, allergy, or immunodeficiency.
Knowing the disease was inherited, Kastner and his colleagues screened genes from FMF patients and their families searching for the disease gene and discovered the Mediterranean fever gene (MEFV), which encodes for the protein pyrin. Surprisingly, pyrin is involved in the innate immune system response to "danger" -- pathogenic invaders like bacteria.
Unlike the adaptive immune response, which can "learn" to recognize and "remember" new sorts of invaders, the innate immune system recognizes a set repertoire of proteins from different kinds of pathogens. Pyrin is found in white blood cells, which go to the site of injury or disease to fight microbial invaders and help with tissue repair during the inflammatory response. The mutant pyrin proteins cause a much greater production of a pro-inflammatory cytokine, or chemical immune mediator, called interleukin-1 beta (IL-1b) causing excessive inflammation.
FMF became the prototype for other similar disorders with episodes of seemingly unprovoked inflammation. Investigators found that deficiency of the IL-1 receptor antagonist (DIRA) and the cryopyrin-associated periodic syndromes (CAPS), such as neonatal-onset multisystem inflammatory disease (NOMID), were the result of genetic variants of the innate immune system.
Knowing the molecular basis for these diseases led to treatment options that, in some cases, actually prevented the disease symptoms. "Daniel Kastner gave us an excellent example of translational research in action when he spoke about his pioneering work on the genetic basis of systemic autoinflammatory diseases," said Zeldin. "It was an excellent start for our new Clinical Director's Seminar Series." NIEHS initiated the series as a follow up to the July 2009 ribbon cutting and clinical seminars celebrating the formal opening of its new Clinical Research Unit (see story(https://www.niehs.nih.gov/news/newsletter/2009/june/cru.cfm)).
(Laura Hall is a biologist in the NIEHS Laboratory of Pharmacology currently on detail as a writer for the Environmental Factor.)