Introduction

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

PAPA

Disease FCAS MWS Blau

NOMID

TRAPS

HIDS

Locus

MEFV

Chromosomal 16p13.3 location

Gene structure 10 exons

Protein size

Protein name Pyrin/

marenostrin

Domains

Putative function(s)

PYD, Coiled-coil, B-box,

B30.2/rfp/SPRY Regulation of pro-inflammatory cytokine release, NF-kB activation, apoptosis

PSTPIP1/CD2BP1 15q24

15 exons 416 a.a.

PSTPIP1, CD2BP1,

Fer-CIP4, Coiled-coil, SH3, PEST Regulation of protein phospho-rylation, upstream regulator of pyrin, immune synapse construction

CIAS1 1q44

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

NOD2/CARD15 16q12

12 exons 1040 a.a.

NOD2, CARD15,

TNFRSF1A 12p13.2

10 exons 455 a.a.

TNFRSF1A, P55, CD120a, TNFR1

MVK 12q24

11 exons 396 a.a.

ATP-binding

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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