In the past 10 years, auto inflammatory diseases have gained recognition as a distinct class of disorders that are characterized by recurrent episodes of systemic inflammation resulting in fevers, leukocyte-mediated tissue infiltration, and dysregulated cytokine production. The recent discovery of genetic determinants of this spectrum of disorders has resulted in new insights into these diseases. Unlike autoimmune diseases, autoinflammatory diseases are marked by the notable absences of autoantibodies or the critical role of self-reactive B and T lymphocytes.
Pyrin, cryopyrin, ASC, and NOD2 share structural domains common to molecules involved in inflammatory pathways.21,23,26,37 The pyrin domain is a member of the 6-helix bundle DD-fold superfamily. The NACHT domain contains a highly-conserved nucleotide-binding sequence. Abbreviation expansions are provided in the box at the end of this article.
Models: cryopyrin and pyrin associate with ASC to stimulate NFκB activation (A) and IL-1β cytokine processing (B), respectively. A, Association between cryopyrin and ASC activates the NFκB pathway. Pyrin inhibits activation of the NFκB pathway by disrupting the association between ASC and cryopyrin. Stimuli derived from pathogens may activate cryopyrin and/or pyrin. Mutations in cryopyrin or pyrin may lead to increased NFκB activation, resulting in dysregulated cytokine production, apoptosis, and inflammation. B, The ASC mediates activation of caspase 1, the IL-1β converting enzyme.26,35,39 Caspase 1 is required to generate active IL-1 from its precursor form (pro-IL-1β), which is initially produced by activated macrophages and monocytes. Together with additional caspases, pyrin, ASC, and caspase 1 may associate to form a signaling complex termed the “inflammasome.”26,40,41 Cryopyrin may associate with ASC and pyrin. Mutations in pyrin may lead to autoinflammatory disease by failing to regulate caspase-1 activity, resulting in increased cytokine production and inflammation. Abbreviation expansions are provided in the box at the end of this article.
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