TNF receptor signalling in autoinflammatory diseases

Abstract

Autoinflammatory syndromes are a group of disorders characterized by recurring episodes of inflammation as a result of specific defects in the innate immune system. Patients with autoinflammatory disease present with recurrent outbreaks of chronic systemic inflammation that are mediated by innate immune cells, for the most part. A number of these diseases arise from defects in the tumour necrosis factor receptor (TNFR) signalling pathway leading to elevated levels of inflammatory cytokines. Elucidation of the molecular mechanisms of these recently defined autoinflammatory diseases has led to a greater understanding of the mechanisms of action of key molecules involved in TNFR signalling, particularly those involved in ubiquitination, as found in haploinsufficiency of A20 (HA20), otulipenia/OTULIN-related autoinflammatory syndrome (ORAS) and linear ubiquitin chain assembly complex (LUBAC) deficiency. In this review, we also address other TNFR signalling disorders such as TNFR-associated periodic syndrome (TRAPS), RELA haploinsufficiency, RIPK1-associated immunodeficiency and autoinflammation, X-linked ectodermal dysplasia and immunodeficiency (X-EDA-ID) and we review the most recent advances surrounding these diseases and therapeutic approaches currently used to target these diseases. Finally, we explore therapeutic advances in TNF-related immune-based therapies and explore new approaches to target disease-specific modulation of autoinflammatory diseases.

Functional analysis of a novel G87V TNFRSF1A mutation in patients with TNF receptor-associated periodic syndrome

“…The extracellular domain of TNF‐R1 consists of four cysteine‐rich domains characterized by structurally important intramolecular disulfide bonds . Both G87V and T90I mutations exist in exon 3, in which G87V and T90I are located in the cysteine‐rich domain (Fig.…”

“…Tumor necrosis factor (TNF) receptor‐associated periodic syndrome (TRAPS; OMIM: 142680) is the second most common inherited autosomal dominant autoinflammatory disease . It is clinically characterized by recurrent fevers, myalgia, skin rashes and abdominal pain .…”

“…TNF‐R1 consists of an extracellular domain involved in ligand binding, a transmembrane domain, and an intracellular region . The binding of TNF to TNF‐R1 induces the recruitment of several intracellular adaptor proteins leading to downstream signaling events that activate inflammatory and apoptotic processes . Almost all known TRAPS mutations are point mutations that result in single amino acid substitutions in the extracellular domain of TNF‐R1 .…”

“…The former types of mutations are associated with severe clinical phenotypes . Further, such high‐penetrance mutations affect the structure of the TNF‐R1 protein and interfere with its proper trafficking . As a result, mutant TNF‐R1 accumulates excessively in the endoplasmic reticulum (ER) , with increased ER stress subsequently causing inflammatory responses .…”

“…For example, dysregulated trafficking of mutant TNF‐R1 is not obvious in such mutations, as shown by the normal cell surface expression of mutant TNF‐R1 . Although the pathogenic mechanisms underlying some high‐penetrance TRAPS mutations have been proposed , most TRAPS mutations have not been functionally analyzed and associated mechanisms have not been fully elucidated.…”