Systemic autoinflammatory diseases are a relatively newly recognized category of illnesses, characterized by seemingly unprovoked inflammation in the absence of an infectious etiology. As these disorders lack the high titers of autoantibodies and self-reactive T lymphocytes characteristic of the more conventional autoimmune diseases, autoinflammation is considered a defect in the regulation of innate immunity (McDermott et al. 1999; Galon et al. 2000; Hull et al. 2003; Stojanov and Kastner 2005). Among the conditions first recognized as autoinflammatory were the hereditary periodic fever syndromes, which present with recurrent or in some cases fluctuating fevers and localized inflammation, often involving the skin, joints, or serosal membranes. Between flares, patients may experience few overt symptoms, although biochemical evidence of inflammation may continue at a subclinical level. Several other classes of autoinflammatory disease have subsequently been proposed, including pyogenic disorders such as the syndrome of pyogenic arthritis with pyoderma gangrenosum and acne (PAPA), and granulomatous disorders such as Blau syndrome and Crohn's disease.
The present review will focus on the six known hereditary periodic fevers, as well as PAPA and Blau syndromes, all of which are inherited as single-gene Mendelian illnesses (Table 1). Within the last several years, the six genes underlying these eight disorders have all been cloned (French FMF Consortium 1997; International FMF Consortium 1997; Drenth et al. 1999; Houten et al. 1999a; McDermott etal. 1999; Hoffman etal. 2001a; Miceli-Richard et al. 2001; Aganna et al. 2002; Aksentijevich et al. 2002; Dode et al. 2002; Feldmann et al. 2002; X. Wang et al. 2002; Wise et al. 2002). Identification of these genes has not only shed light on newly recognized pathways regulating innate immunity, but has uncovered heretofore unrecognized pathophysiologic connections among these disparate clinical conditions.
Table 1 Autoinflammatory disease genes and their protein products
Disease FCAS MWS Blau
Chromosomal 16p13.3 location
Gene structure 10 exons
Protein name Pyrin/
PYD, Coiled-coil, B-box,
B30.2/rfp/SPRY Regulation of pro-inflammatory cytokine release, NF-kB activation, apoptosis
15 exons 416 a.a.
Fer-CIP4, Coiled-coil, SH3, PEST Regulation of protein phospho-rylation, upstream regulator of pyrin, immune synapse construction
9 exons 920-1034 a.a. (depending on number of LRRs) Cryopyrin, NALP3, PYPAF1, CATERPILLER1.1 PYD, NACHT, LRR (7-11)
Regulation of proinflammatory cytokine release, NF-kB activation, apoptosis
12 exons 1040 a.a.
10 exons 455 a.a.
TNFRSF1A, P55, CD120a, TNFR1
11 exons 396 a.a.
Intracellular Binds TNF, NF-kB Phosphorylates sensor of bacterial activation, mevalonic acid, products, signal regulation of cholesterol transduction leukocyte synthesis, apoptosis isoprenoid synthesis
An updated list of mutations for each of these genes is available online at http://fmf.igh.cnrs.fr/infevers/
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