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ABSTRACT: 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. This review focuses on mutations causing four different diseases, which represent distinct pathological mechanisms that can exist within these superfamilies: autoimmune lymphoproliferative syndrome (ALPS; FAS mutations), common variable immunodeficiency (CVID; TACI mutations), tumor necrosis factor receptor associated periodic syndrome (TRAPS; TNFR1 mutations) and hypohidrotic ectodermal dysplasia (HED; EDA1/EDAR mutations). In particular, we highlight how mutations have revealed information about normal receptor-ligand function and how such studies might direct new therapeutic approaches.
Trends in Molecular Medicine 07/2011; 17(9):494-505. · 10.35 Impact Factor
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ABSTRACT: 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 a psoriatic-like inflammation.
A possible functional ortholog in humans, IGFL1 was uniquely and significantly induced in psoriatic skin samples. In vitro
IGFL1 expression was upregulated in cultured primary keratinocytes stimulated with TNFα, but not by other psoriasis associated
cytokines. Finally, using a secreted and transmembrane protein library, we discovered high-affinity interactions between
human IGFL1 and mIGFL and the TMEM149 ectodomain. TMEM149 (renamed here as IGFLR1) is an uncharacterized gene with structural
similarity to the tumor necrosis factor receptor family. Our studies demonstrate that IGFLR1 is expressed primarily on the
surface of mouse T cells. The connection between mIGFL and IGFLR1 receptor, suggests mIGFL may influence T cell biology within
inflammatory skin conditions.
Journal of Biological Chemistry 03/2011; · 4.77 Impact Factor
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ABSTRACT: 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. In vitro IGFL1 expression was up-regulated in cultured primary keratinocytes stimulated with tumor necrosis factor α but not by other psoriasis-associated cytokines. Finally, using a secreted and transmembrane protein library, we discovered high affinity interactions between human IGFL1 and mIGFL and the TMEM149 ectodomain. TMEM149 (renamed here as IGFLR1) is an uncharacterized gene with structural similarity to the tumor necrosis factor receptor family. Our studies demonstrate that IGFLR1 is expressed primarily on the surface of mouse T cells. The connection between mIGFL and IGFLR1 receptor suggests mIGFL may influence T cell biology within inflammatory skin conditions.
Journal of Biological Chemistry 03/2011; 286(21):18969-81. · 4.77 Impact Factor
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Anna Simon,
Heiyoung Park,
Ravikanth Maddipati, Adrian A Lobito,
Ariel C Bulua,
Adrianna J Jackson,
Jae Jin Chae,
Rachel Ettinger,
Heleen D de Koning,
Anthony C Cruz,
Daniel L Kastner,
Hirsh Komarow,
Richard M Siegel
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ABSTRACT: 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. These mutations lead to loss of normal function rather than gain of function, and thus the pathogenesis of TRAPS is an enigma. Here we show that mutant TNFR1 accumulates intracellularly in peripheral blood mononuclear cells of TRAPS patients and in multiple cell types from two independent lines of knockin mice harboring TRAPS-associated TNFR1 mutations. Mutant TNFR1 did not function as a surface receptor for TNF but rather enhanced activation of MAPKs and secretion of proinflammatory cytokines upon stimulation with LPS. Enhanced inflammation depended on autocrine TNF secretion and WT TNFR1 in mouse and human myeloid cells but not in fibroblasts. Heterozygous TNFR1-mutant mice were hypersensitive to LPS-induced septic shock, whereas homozygous TNFR1-mutant mice resembled TNFR1-deficient mice and were resistant to septic shock. Thus WT and mutant TNFR1 act in concert from distinct cellular locations to potentiate inflammation in TRAPS. These findings establish a mechanism of pathogenesis in autosomal dominant diseases where full expression of the disease phenotype depends on functional cooperation between WT and mutant proteins and also may explain partial responses of TRAPS patients to TNF blockade.
Proceedings of the National Academy of Sciences 05/2010; 107(21):9801-6. · 9.68 Impact Factor
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ABSTRACT: 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. This effect was dependent on preassociation of the mutants with WT TACI in the absence of ligand. The mutants did not interfere with ligand binding by WT TACI, suggesting that they may act by disrupting ligand-induced receptor rearrangement and signaling. This work demonstrates that TACI preassembles as an oligomeric complex prior to ligand binding and provides a mechanistic insight into how the heterozygous C104R TACI mutation can potentially lead to CVID.
Journal of Clinical Investigation 07/2007; 117(6):1550-7. · 15.39 Impact Factor
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ABSTRACT: 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. In the present review we discuss new findings describing aberrant trafficking and function of TNFR1 harbouring TRAPS mutations, challenging the hypothesis that TRAPS pathology is driven by defective receptor shedding, and we suggest that TNFR1 might acquire novel functions in the endoplasmic reticulum, distinct from its role as a cell surface receptor. We also describe the clinical manifestations of TRAPS, current treatment regimens, and the widening array of patient mutations.
Arthritis research & therapy 02/2007; 9(4):217. · 4.27 Impact Factor
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ABSTRACT: 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.
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. Tumor necrosis factor receptor-associated periodic syndrome was initially thought to be caused by deficient metalloprotease-induced tumor necrosis factor receptor shedding, however new findings suggest that mutations in this receptor may result in inappropriate protein folding, leading to a host of other functional abnormalities that may cause inflammatory disease. Finally, data are emerging that address the possible function of the C-terminal B30.2 domain of pyrin, the familial Mediterranean fever protein. This motif has recently been shown to interact with and inhibit caspase-1, and the modeled structure of this complex highlights how mutations may affect the binding interface.
Recent reports have advanced our understanding of the structural and functional biology underlying the hereditary recurrent fevers, and are beginning to suggest possible mechanisms by which specific mutations cause disease.
Current Opinion in Allergy and Clinical Immunology 01/2007; 6(6):428-33. · 4.11 Impact Factor
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ABSTRACT: 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. Mutant receptors did not bind TNF and failed to function as dominant-negative inhibitors of TNFR1-induced apoptosis. Instead, TRAPS mutant TNFR1 formed abnormal disulfide-linked oligomers that failed to interact with wild-type TNFR1 molecules through the preligand assembly domain (PLAD) that normally governs receptor self-association. TRAPS mutant TNFR1 molecules were retained intracellularly and colocalized with endoplasmic reticulum (ER) markers. The capacity of mutant receptors to spontaneously induce both apoptosis and nuclear factor kappaB (NF-kappaB) activity was reduced. In contrast, the R92Q variant of TNFR1 behaved like the wild-type receptor in all of these assays. The inflammatory phenotype of TRAPS may be due to consequences of mutant TNFR1 protein misfolding and ER retention.
Blood 09/2006; 108(4):1320-7. · 9.90 Impact Factor
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Annals of the New York Academy of Sciences 01/2006; 998(1):379 - 383. · 3.15 Impact Factor
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ABSTRACT: 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. J. Immunol. Methods 1995. 180: 273-280]. We now show data suggesting that this defect is due to the expression and accumulation of TCR alpha and beta chains inside B cells and induction of an endoplasmic reticulum stress response, causing apoptosis at the pre B-I and later B cell stage. Thus, inappropriate transgene expression can profoundly affect B cells, leading to a previously undescribed mechanism of immunodeficiency.
European Journal of Immunology 04/2004; 34(3):890-8. · 5.10 Impact Factor
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Adrian A Lobito,
Bingzhi Yang,
Marcela F Lopes,
Alexei Miagkov,
Robert N Adams,
Gregory R Palardy,
Michele M Johnson,
Hugh I McFarland,
Michael Recher,
Daniel B Drachman,
Michael J Lenardo
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ABSTRACT: 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. We found that the transgenic TCR was strongly positively selected and that transgenic T cells proliferated robustly to the immunodominant peptide and TAChR. Unexpectedly, there was a variable paucity of B cells in the blood and spleen from transgenic mice, which averaged about 16% of peripheral blood lymphocytes, compared to 55% in wild-type B6 mice. Unselected transgenic mice immunized with TAChR exhibited weak anti-TAChR antibody responses. However, transgenic mice selected to have relatively higher B cell numbers produced anti-TAChR titers equal to B6 mice and a predominance of Th1-induced antibody isotypes were observed in certain experiments. The incidence and severity of clinical disease was variable following immunizations. These mice should be useful for studying the pathogenesis and treatment of MG.
European Journal of Immunology 08/2002; 32(7):2055-67. · 5.10 Impact Factor
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ABSTRACT: Cross-linking of the B cell antigen receptor (BCR) induces resistance to Fas (APO-1 / CD95)-dependent apoptosis and thereby regulates one mechanism of B cell selection during antigen stimulation. To investigate the molecular mechanism by which BCR signaling regulates the Fas pathway, we examined the expression of constituents of the death-inducing signaling complex (DISC), including Fas, FADD, caspase-8 and cellular FLICE-inhibitory protein (c-FLIP). No significant changes in the cellular levels of Fas, FADD or caspase-8 were observed after BCR cross-linking. By contrast, the long isoform of c-FLIP (c-FLIPL) was significantly up-regulated by BCR cross-linking in primary B cells and in two B cell lines, A20 and WEHI-279. Moreover, transfection of c-FLIPL into A20 cells inhibited Fas-dependent apoptosis and suppressed recruitment of caspase-8 to the DISC. BCR cross-linking or FLIP overexpression also protects B cells from TRAIL-induced apoptosis. Thus, BCR signaling up-regulates c-FLIPL and suppresses the Fas- and TRAIL-receptor apoptosis pathways which could be important for tolerance and selection of antigen-specific B cells.
European Journal of Immunology 12/1999; 30(1):155 - 163. · 5.10 Impact Factor
