Disease causing mutations in the TNF and TNFR superfamilies: Focus on molecular mechanisms driving disease.

The tumor necrosis factor (TNF) and TNF receptor (TNFR) superfamilies comprise multidomain proteins with diverse roles in cell activation, proliferation and cell death. These proteins play pivotal roles in the initiation, maintenance and termination of immune responses and have vital roles outside the immune system. The discovery and analysis of diseases associated with mutations in these families has revealed crucial mechanistic details of their normal functions.

Murine insulin growth factor-like (IGFL) and human IGFL1 proteins are induced in inflammatory skin conditions and bind to a novel tumor necrosis factor receptor family member, IGFLR1.

Psoriasis is a human skin condition characterized by epidermal hyperproliferation and infiltration of multiple leukocyte populations. In characterizing a novel insulin growth factor (IGF)-like (IGFL) gene in mice (mIGFL), we found transcripts of this gene to be most highly expressed in skin with enhanced expression in models of skin wounding and psoriatic-like inflammation. A possible functional ortholog in humans, IGFL1, was uniquely and significantly induced in psoriatic skin samples.

Concerted action of wild-type and mutant TNF receptors enhances inflammation in TNF receptor 1-associated periodic fever syndrome.

TNF, acting through p55 tumor necrosis factor receptor 1 (TNFR1), contributes to the pathogenesis of many inflammatory diseases. TNFR-associated periodic syndrome (TRAPS, OMIM 142680) is an autosomal dominant autoinflammatory disorder characterized by prolonged attacks of fevers, peritonitis, and soft tissue inflammation. TRAPS is caused by missense mutations in the extracellular domain of TNFR1 that affect receptor folding and trafficking.

Falling into TRAPS--receptor misfolding in the TNF receptor 1-associated periodic fever syndrome.

TNF receptor-associated periodic syndrome (TRAPS) is a dominantly inherited disease caused by missense mutations in the TNF receptor 1 (TNFR1) gene. Patients suffer from periodic bouts of severe abdominal pain, localised inflammation, migratory rashes, and fever. More than 40 individual mutations have been identified, all of which occur in the extracellular domain of TNFR1.

Dominant-negative effect of the heterozygous C104R TACI mutation in common variable immunodeficiency (CVID).

B cells from patients with common variable immunodeficiency (CVID) who are heterozygous for transmembrane activator and CAML interactor (TACI) mutation C104R, which abolishes ligand binding, fail to produce Igs in response to TACI ligand. It is not known whether this is due to haploinsufficiency or dominant interference. Using in vitro transfection assays, here we demonstrate that C104R and the corresponding murine TACI mutant, C76R, which also does not bind ligand, dominantly interfere with TACI signaling.

Recent advances in the molecular pathogenesis of hereditary recurrent fevers.

Purpose Of Review: To discuss recent developments in the molecular basis of several hereditary recurrent fever syndromes, specifically the cryopyrin-associated periodic syndromes, familial Mediterranean fever and the tumor necrosis factor receptor associated periodic syndrome.

Recent Findings: Mutations of CIAS1, the gene encoding cryopyrin/NALP3, lead to a spectrum of disease states termed the cryopyrinopathies. Recently, cryopyrin-deficient mice have been used to show that the protein is a key regulator of interleukin-1beta production that functions by recognizing stimuli such as bacterial RNA and infectious agents.

Abnormal disulfide-linked oligomerization results in ER retention and altered signaling by TNFR1 mutants in TNFR1-associated periodic fever syndrome (TRAPS).

Tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS) is an autosomal dominant systemic autoinflammatory disease associated with heterozygous mutations in TNF receptor 1 (TNFR1). Here we examined the structural and functional alterations caused by 9 distinct TRAPS-associated TNFR1 mutations in transfected cells and a mouse "knock-in" model of TRAPS. We found that these TNFR1 mutants did not generate soluble versions of the receptor, either through membrane cleavage or in exosomes.

Ectopic T cell receptor expression causes B cell immunodeficiency in transgenic mice.

Mice expressing transgenic T cell receptors (TCR) are used to explore important questions in immunity. However, transgene expression may have unexpected effects. We previously reported a B cell immunodeficiency, comprising decreased B cell numbers and diminished antibody responses, in mice that express a transgenic TCR specific for nicotinic acetylcholine receptor; the mice were generated using cassette vectors designed specifically for transgenic TCR expression [see Kouskoff et al.

T cell receptor transgenic mice recognizing the immunodominant epitope of the Torpedo californica acetylcholine receptor.

Myasthenia gravis (MG) is an autoimmune disease caused by T cell-dependent antibody-mediated reduction of acetylcholine receptors (AChR) at the neuromuscular junction. Immunization of animals with Torpedo californica AChR (TAChR) results in an experimental model of MG. We used the variable regions of alpha and beta T cell receptor (TCR) genes recognizing an immunodominant peptide containing amino acids 146-162 from the alpha subunit of TAChR presented in the context of I-A(b) to generate TCR-transgenic mice.