Tumor necrosis factor receptor–associated periodic syndrome: Toward a molecular understanding of the systemic autoinflammatory diseases

Abstract

Almost a decade has elapsed since the concept of autoinflammation was advanced to describe conditions characterized by ostensibly unprovoked inflammation, without the hightiter autoantibodies or antigen-specific T-cells found in known autoimmune diseases. This concept was introduced following the identification of mutations in the p55 tumor necrosis factor receptor (TNFR1) in patients with a dominantly inherited syndrome of systemic inflammation (TRAPS) (1). Systemic autoinflammatory diseases are caused by aberrant activation of the innate immune system. Some result in recurrent episodes of fever, localized serositis and skin rashes. Two hereditary recurrent fevers, familial Mediterranean fever (FMF) and the TNF receptor-associated periodic syndrome (TRAPS) were prototypes for this diagnostic category. In the past 10 years this concept has been extended to include a number of Mendelian disorders, including other hereditary recurrent fevers, as well as more common diseases with complex modes of inheritance including Behcet's disease and Crohn's disease (2). When the molecular basis of TRAPS was discovered it was considered an exceedingly rare disease with only a few families described in the literature. Over the past decade, more than 50 disease-associated mutations have been identified in hundreds of patients from a variety of ethnic backgrounds (3). Genotype-phenotype studies showed that mutations at cysteine residues are associated with a more severe phenotype and higher incidence of amyloidosis (4). Although, most TRAPS-associated mutations are fully penetrant, two TNFR1 variants, P46L and R92Q, have been also identified in asymptomatic family members, and at a low frequency in healthy populations. Tumor necrosis factor (TNF) is a pleiotropic cytokine that mediates a wide range of cellular activities primarily through its interaction with TNF receptor 1 (TNFR1; TNFRSF1A; CD120a; p55/p60). Triggering the TNF signaling cascade results in an array of responses, including apoptosis, inflammation and modulation of the immune response. TNFR1 is constitutively expressed on the cell surface in most tissues. It is a large polypeptide with an extracellular domain, consisting of 4 cysteine-rich domains (CRD), a transmembrane domain, and an intracellular death domain (DD). Each CRD includes 3 pairs of cysteine residues that form intramolecular disulfide bonds important in maintaining the 3dimensional conformation of the extracellular part of the receptor. Thus, a substitution at a cysteine residue has the potential to disrupt the relevant disulfide bond and result in significant structural perturbation. The first CRD, sometimes called the pre-ligand association domain (PLAD), allows for TNF-independent interactions of TNFR1 molecules,