Breaking down complex autoinflammatory diseases, and building up new hope

1997

Challenge

In some individuals, the immune system attacks the body’s own tissues, causing inflammation. The recent discovery that a subset of autoinflammatory diseases has genetic components complicates diagnosis, making development of therapeutics a challenge.

Advance

IRP researcher Daniel L. Kastner, M.D., Ph.D., and colleagues identified, classified, and characterized more than 10 new hereditary autoinflammatory disease pathways, including FMF, TRAPS, NOMID, and DIRA. IRP scientists develop and test new therapies aimed at reducing inflammation in these diseases, in some cases completely reversing them.

Impact

Patients with complex genetic autoinflammatory disorders may soon no longer need to experience trial and error prescribing in an effort to control their debilitating symptoms. For some diseases, genetic analyses combined with molecular studies of the affected pathways can inform the selection of targeted therapeutics and provide immediate and sustained relief.

Publications

International FMF Consortium (Kastner DL, corresponding author). (1997). Ancient missense mutations in a new member of the RoRet gene family are likely to cause familial Mediterranean fever. Cell. 90(4), 797-807.

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 AM, 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. (1999). Germline mutations in the extracellular domains of the 55 kDa TNF receptor, TNFR1, define a family of dominantly inherited autoinflammatory syndromes. Cell. 97(1), 133-144.

Aksentijevich I, Nowak M, Mallah M, Chae JJ, Watford WT, Hofmann 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. (2002). 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(12), 3340-3348.