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Seth L Masters - One of the best experts on this subject based on the ideXlab platform.
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mechanisms of nlrp1 mediated Autoinflammatory Disease in humans and mice
Journal of Molecular Biology, 2018Co-Authors: Jonas Moecking, Chienhsiung Yu, Matthias Geyer, Seth L MastersAbstract:NLRP1 was the first NOD-like receptor described to form an inflammasome, recruiting ASC to activate caspase-1, which processes interleukin-1β and interleukin-18 to their active form. A wealth of new genetic information has now redefined our understanding of this innate immune sensor. Specifically, rare loss-of-function variants in the N-terminal pyrin domain indicate that this part of NLRP1 is autoinhibitory and normally acts to prevent a familial Autoinflammatory skin Disease associated with cancer. In the absence of a ligand to trigger human NLRP1, these mutations have now confirmed the requirement of NLRP1 autolytic cleavage within the FIIND domain, which had previously been implicated in NLRP1 activation. Autolytic cleavage generates a C-terminal fragment of NLRP1 containing the CARD domain which then forms an ASC-dependent inflammasome. The CARD domain as an inflammasome linker is consistent with the observation that under some conditions, particularly for mouse NLRP1, caspase-1 can be engaged directly, and although it is no longer processed, it is still capable of producing mature IL-1β. Additional rare variants in a linker region between the LRR and FIIND domains of NLRP1 also cause Autoinflammatory Disease in both humans and mice. This new genetic information is likely to provide for more mechanistic insight in the years to come, contributing to our understanding of how NLRP1 functions as an innate immune sensor of infection and predisposes to autoimmune or Autoinflammatory Diseases.
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Familial autoinflammation with neutrophilic dermatosis reveals a regulatory mechanism of pyrin activation
Science translational medicine, 2016Co-Authors: Seth L Masters, Dominic De Nardo, Vasiliki Lagou, Isabelle Jéru, Paul J. Baker, Lien Van Eyck, David A. Parry, Dylan Lawless, Josselyn E. Garcia-perez, Laura F. DagleyAbstract:Pyrin responds to pathogen signals and loss of cellular homeostasis by forming an inflammasome complex that drives the cleavage and secretion of interleukin-1β (IL-1β). Mutations in the B30.2/SPRY domain cause pathogen-independent activation of pyrin and are responsible for the Autoinflammatory Disease familial Mediterranean fever (FMF). We studied a family with a dominantly inherited Autoinflammatory Disease, distinct from FMF, characterized by childhood-onset recurrent episodes of neutrophilic dermatosis, fever, elevated acute-phase reactants, arthralgia, and myalgia/myositis. The Disease was caused by a mutation in MEFV, the gene encoding pyrin (S242R). The mutation results in the loss of a 14-3-3 binding motif at phosphorylated S242, which was not perturbed by FMF mutations in the B30.2/SPRY domain. However, loss of both S242 phosphorylation and 14-3-3 binding was observed for bacterial effectors that activate the pyrin inflammasome, such as Clostridium difficile toxin B (TcdB). The S242R mutation thus recapitulated the effect of pathogen sensing, triggering inflammasome activation and IL-1β production. Successful therapy targeting IL-1β has been initiated in one patient, resolving pyrin-associated autoinflammation with neutrophilic dermatosis. This Disease provides evidence that a guard-like mechanism of pyrin regulation, originally identified for Nod-like receptors in plant innate immunity, also exists in humans.
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an Autoinflammatory Disease with deficiency of the interleukin 1 receptor antagonist
The New England Journal of Medicine, 2009Co-Authors: Ivona Aksentijevich, Paul Dancey, Annet Van Royenkerkhoff, Ulf Tedgard, Joost Frenkel, Polly J Ferguson, Edward W Cowen, Seth L Masters, Ronald M. Laxer, Tuyethang PhamAbstract:BACKGROUND Autoinflammatory Diseases manifest inflammation without evidence of infection, high-titer autoantibodies, or autoreactive T cells. We report a disorder caused by mutations of IL1RN, which encodes the interleukin-1-receptor antagonist, with prominent involvement of skin and bone. METHODS We studied nine children from six families who had neonatal onset of sterile multifocal osteomyelitis, periostitis, and pustulosis. Response to empirical treatment with the recombinant interleukin-1-receptor antagonist anakinra in the first patient prompted us to test for the presence of mutations and changes in proteins and their function in interleukin-1-pathway genes including IL1RN. RESULTS We identified homozygous mutations of IL1RN in nine affected children, from one family from Newfoundland, Canada, three families from the Netherlands, and one consanguineous family from Lebanon. A nonconsanguineous patient from Puerto Rico was homozygous for a genomic deletion that includes IL1RN and five other interleukin-1-family members. At least three of the mutations are founder mutations; heterozygous carriers were asymptomatic, with no cytokine abnormalities in vitro. The IL1RN mutations resulted in a truncated protein that is not secreted, thereby rendering cells hyperresponsive to interleukin-1 beta stimulation. Patients treated with anakinra responded rapidly. CONCLUSIONS We propose the term deficiency of the interleukin-1-receptor antagonist, or DIRA, to denote this autosomal recessive Autoinflammatory Disease caused by mutations affecting IL1RN. The absence of interleukin-1-receptor antagonist allows unopposed action of interleukin-1, resulting in life-threatening systemic inflammation with skin and bone involvement. (ClinicalTrials.gov number, NCT00059748.)
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horror autoinflammaticus the molecular pathophysiology of Autoinflammatory Disease
Annual Review of Immunology, 2009Co-Authors: Seth L Masters, Ivona Aksentijevich, Anna Simon, Daniel L. KastnerAbstract:The Autoinflammatory Diseases are characterized by seemingly unprovoked episodes of inflammation, without high-titer autoantibodies or antigen-specific T cells. The concept was proposed ten years ago with the identification of the genes underlying hereditary periodic fever syndromes. This nosology has taken root because of the dramatic advances in our knowledge of the genetic basis of both mendelian and complex Autoinflammatory Diseases, and with the recognition that these illnesses derive from genetic variants of the innate immune system. Herein we propose an updated classification scheme based on the molecular insights garnered over the past decade, supplanting a clinical classification that has served well but is opaque to the genetic, immunologic, and therapeutic interrelationships now before us. We define six categories of Autoinflammatory Disease: IL-1β activation disorders (inflammasomopathies), NF-κB activation syndromes, protein misfolding disorders, complement regulatory Diseases, disturbances in cytokine signaling, and macrophage activation syndromes. A system based on molecular pathophysiology will bring greater clarity to our discourse while catalyzing new hypotheses both at the bench and at the bedside.
Daniel L. Kastner - One of the best experts on this subject based on the ideXlab platform.
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pseudodominance of Autoinflammatory Disease in a single turkish family explained by co inheritance of haploinsufficiency of a20 and familial mediterranean fever
Clinical and Experimental Rheumatology, 2019Co-Authors: Nobuyuki Horita, Ivona Aksentijevich, Daniel L. Kastner, Ahmet Gul, Elaine F RemmersAbstract:OBJECTIVES We investigated a Turkish family with multiple patients presenting with familial Mediterranean fever (FMF) and Behcet's Disease (BD)-like manifestations. The index case and the two daughters with Behcet-like Disease, were previously found to have a TNFAIP3 frameshift mutation. The high number of affected cases in this expanded family could be consistent with a dominantly inherited inflammatory Disease, although some individuals had clinical features more consistent with recessively inherited FMF. We sequenced DNA from members of this family to determine whether the TNFAIP3 frameshift mutation and/or MEFV variants could explain this Autoinflammatory Disease pedigree. METHODS Patients were clinically diagnosed to have FMF or BD. Sanger sequence targeting TNFAIP3 exon 5 and MEFV exon 10 was carried out. RESULTS The symptomatic mother of the index case and her affected maternal uncle had compound heterozygous FMF-associated MEFV mutations, p.Met680Ile and p.Arg761His. Two affected daughters of the maternal uncle also had compound heterozygous FMF-associated mutations, p.Met680Ile and p.Val726Ala. The index case and her two affected daughters had a TNFAIP3 frameshift mutation (c.799delG; p.Pro268Leufs*19), which is consistent with their HA20 diagnosis, and also carried a heterozygous MEFV p.Arg761His mutation. CONCLUSIONS Autoinflammatory Disease manifestations in a Turkish family with multiple affected cases could be explained by co-inheritance of pathogenic MEFV variants and a heterozygous HA20-associated mutation. FMF-associated p.Arg761His allele carried with the loss of function TNFAIP3 mutation by all three HA20 patients may contribute to their Autoinflammatory phenotype and could also be responsible for their favourable response to colchicine.
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aberrant actin depolymerization triggers the pyrin inflammasome and Autoinflammatory Disease that is dependent on il 18 not il 1β
Journal of Experimental Medicine, 2015Co-Authors: Jae Jin Chae, Yong Hwan Park, Dominic De Nardo, Roslynn A Stirzaker, Hyunja Ko, Louise H Cengia, Ladina Dirago, Donald Metcalf, Andrew W Roberts, Daniel L. KastnerAbstract:Gain-of-function mutations that activate the innate immune system can cause systemic Autoinflammatory Diseases associated with increased IL-1β production. This cytokine is activated identically to IL-18 by an intracellular protein complex known as the inflammasome; however, IL-18 has not yet been specifically implicated in the pathogenesis of hereditary Autoinflammatory disorders. We have now identified an Autoinflammatory Disease in mice driven by IL-18, but not IL-1β, resulting from an inactivating mutation of the actin-depolymerizing cofactor Wdr1. This perturbation of actin polymerization leads to systemic autoinflammation that is reduced when IL-18 is deleted but not when IL-1 signaling is removed. Remarkably, inflammasome activation in mature macrophages is unaltered, but IL-18 production from monocytes is greatly exaggerated, and depletion of monocytes in vivo prevents the Disease. Small-molecule inhibition of actin polymerization can remove potential danger signals from the system and prevents monocyte IL-18 production. Finally, we show that the inflammasome sensor of actin dynamics in this system requires caspase-1, apoptosis-associated speck-like protein containing a caspase recruitment domain, and the innate immune receptor pyrin. Previously, perturbation of actin polymerization by pathogens was shown to activate the pyrin inflammasome, so our data now extend this guard hypothesis to host-regulated actin-dependent processes and Autoinflammatory Disease.
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Gain-of-Function Pyrin Mutations Induce NLRP3 Protein-Independent Interleukin-1β Activation and Severe Autoinflammation in Mice
Immunity, 2011Co-Authors: Jae Jin Chae, Young-hun Cho, Geun-shik Lee, Jun Cheng, Pu Paul Liu, Lionel Feigenbaum, Stephen I. Katz, Daniel L. KastnerAbstract:Summary Missense mutations in the C-terminal B30.2 domain of pyrin cause familial Mediterranean fever (FMF), the most common Mendelian Autoinflammatory Disease. However, it remains controversial as to whether FMF is due to the loss of an inhibitor of inflammation or to the activity of a proinflammatory molecule. We generated both pyrin-deficient mice and "knockin" mice harboring mutant human B30.2 domains. Homozygous knockin, but not pyrin-deficient, mice exhibited spontaneous bone marrow-dependent inflammation similar to but more severe than human FMF. Caspase-1 was constitutively activated in knockin macrophages and active IL-1β was secreted when stimulated with lipopolysaccharide alone, which is also observed in FMF patients. The inflammatory phenotype of knockin mice was completely ablated by crossing with IL-1 receptor-deficient or adaptor molecule ASC-deficient mice, but not NLRP3-deficient mice. Thus, our data provide evidence for an ASC-dependent NLRP3-independent inflammasome in which gain-of-function pyrin mutations cause Autoinflammatory Disease.
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horror autoinflammaticus the molecular pathophysiology of Autoinflammatory Disease
Annual Review of Immunology, 2009Co-Authors: Seth L Masters, Ivona Aksentijevich, Anna Simon, Daniel L. KastnerAbstract:The Autoinflammatory Diseases are characterized by seemingly unprovoked episodes of inflammation, without high-titer autoantibodies or antigen-specific T cells. The concept was proposed ten years ago with the identification of the genes underlying hereditary periodic fever syndromes. This nosology has taken root because of the dramatic advances in our knowledge of the genetic basis of both mendelian and complex Autoinflammatory Diseases, and with the recognition that these illnesses derive from genetic variants of the innate immune system. Herein we propose an updated classification scheme based on the molecular insights garnered over the past decade, supplanting a clinical classification that has served well but is opaque to the genetic, immunologic, and therapeutic interrelationships now before us. We define six categories of Autoinflammatory Disease: IL-1β activation disorders (inflammasomopathies), NF-κB activation syndromes, protein misfolding disorders, complement regulatory Diseases, disturbances in cytokine signaling, and macrophage activation syndromes. A system based on molecular pathophysiology will bring greater clarity to our discourse while catalyzing new hypotheses both at the bench and at the bedside.
Deborah L. Stone - One of the best experts on this subject based on the ideXlab platform.
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ancient familial mediterranean fever mutations in human pyrin and resistance to yersinia pestis
Nature Immunology, 2020Co-Authors: Yong Hwan Park, Deborah L. Stone, Amanda K. Ombrello, Elaine F Remmers, Wonyong Lee, Lawton K Chung, Zhao Shilei, Maya I Ivanov, Nicole A LoevenAbstract:Familial Mediterranean fever (FMF) is an Autoinflammatory Disease caused by homozygous or compound heterozygous gain-of-function mutations in MEFV, which encodes pyrin, an inflammasome protein. Heterozygous carrier frequencies for multiple MEFV mutations are high in several Mediterranean populations, suggesting that they confer selective advantage. Among 2,313 Turkish people, we found extended haplotype homozygosity flanking FMF-associated mutations, indicating evolutionarily recent positive selection of FMF-associated mutations. Two pathogenic pyrin variants independently arose >1,800 years ago. Mutant pyrin interacts less avidly with Yersinia pestis virulence factor YopM than with wild-type human pyrin, thereby attenuating YopM-induced interleukin (IL)-1β suppression. Relative to healthy controls, leukocytes from patients with FMF harboring homozygous or compound heterozygous mutations and from asymptomatic heterozygous carriers released heightened IL-1β specifically in response to Y. pestis. Y. pestis-infected MefvM680I/M680I FMF knock-in mice exhibited IL-1-dependent increased survival relative to wild-type knock-in mice. Thus, FMF mutations that were positively selected in Mediterranean populations confer heightened resistance to Y. pestis. Familial Mediterranean fever is an Autoinflammatory Disease caused by gain-of-function mutations in the pyrin inflammasome. Kastner and colleagues show that mutant pyrin better resists suppression by the plague bacterium Yersinia pestis and may have been positively selected in human Middle Eastern populations.
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mutations that prevent caspase cleavage of ripk1 cause Autoinflammatory Disease
Nature, 2020Co-Authors: Najoua Lalaoui, Diep Chau, Stuart Edward Boyden, Mario Stoffels, Tobias Kratina, Geryl Wood, Kate E Lawlor, Deborah L. StoneAbstract:RIPK1 is a key regulator of innate immune signalling pathways. To ensure an optimal inflammatory response, RIPK1 is regulated post-translationally by well-characterized ubiquitylation and phosphorylation events, as well as by caspase-8-mediated cleavage1–7. The physiological relevance of this cleavage event remains unclear, although it is thought to inhibit activation of RIPK3 and necroptosis8. Here we show that the heterozygous missense mutations D324N, D324H and D324Y prevent caspase cleavage of RIPK1 in humans and result in an early-onset periodic fever syndrome and severe intermittent lymphadenopathy—a condition we term ‘cleavage-resistant RIPK1-induced Autoinflammatory syndrome’. To define the mechanism for this Disease, we generated a cleavage-resistant Ripk1D325A mutant mouse strain. Whereas Ripk1−/− mice died postnatally from systemic inflammation, Ripk1D325A/D325A mice died during embryogenesis. Embryonic lethality was completely prevented by the combined loss of Casp8 and Ripk3, but not by loss of Ripk3 or Mlkl alone. Loss of RIPK1 kinase activity also prevented Ripk1D325A/D325A embryonic lethality, although the mice died before weaning from multi-organ inflammation in a RIPK3-dependent manner. Consistently, Ripk1D325A/D325A and Ripk1D325A/+ cells were hypersensitive to RIPK3-dependent TNF-induced apoptosis and necroptosis. Heterozygous Ripk1D325A/+ mice were viable and grossly normal, but were hyper-responsive to inflammatory stimuli in vivo. Our results demonstrate the importance of caspase-mediated RIPK1 cleavage during embryonic development and show that caspase cleavage of RIPK1 not only inhibits necroptosis but also maintains inflammatory homeostasis throughout life. Heterozygous mutateons in the caspase-8 cleavage site of RIPK1 cause a range of Autoinflammatory symptoms in humans, and caspase-8 cleavage of RIPK1 in a mouse model limits TNF-induced cell death and inflammation.
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a20 haploinsufficiency ha20 clinical phenotypes and Disease course of patients with a newly recognised nf kb mediated Autoinflammatory Disease
Annals of the Rheumatic Diseases, 2018Co-Authors: Florence A Aeschlimann, Deborah L. Stone, Patrycja Hoffmann, Scott W Canna, Ahmet Gul, Ezgi Deniz Batu, Helen L Leavis, Seza Ozen, Daniella M Schwartz, Annet Van RoyenkerkofAbstract:Objectives The association between mutations in TNFAIP3 , encoding the NF-kB regulatory protein A20, and a new Autoinflammatory Disease has recently been recognised. This study aims at describing the clinical phenotypes and Disease course of patients with A20 haploinsufficiency (HA20). Methods Data for all cases from the initial publication, and additional cases identified through collaborations since, were collected using standardised data collection forms. Results A total of 16 patients (13 female) from seven families with a genetic diagnosis of HA20 were included. The Disease commonly manifested in early childhood (range: first week of life to 29 years of age). The main clinical symptoms were recurrent oral, genital and/or gastrointestinal ulcers (16/16), musculoskeletal (9/16) and gastrointestinal complaints (9/16), cutaneous lesions (8/16), episodic fever (7/16), and recurrent infections (7/16). Clinical phenotypes varied considerably, even within families. Relapsing-remitting Disease course was most common, and one patient died. Laboratory abnormalities included elevated acute-phase reactants and fluctuating presence of various autoantibodies such as antinuclear antibodies (4/10 patients tested) and anti-dsDNA (2/5). Tissue biopsy of different sites revealed non-specific chronic inflammation (6/12 patients tested), findings consistent with class V lupus nephritis in one patient, and pustules and normal results in two patients each. All patients were treated: 4/16 received colchicine and 12/16 various immunosuppressive agents. Cytokine inhibitors effectively suppressed systemic inflammation in 7/9 patients. Conclusions Early-onset recurrent oral, genital and/or gastrointestinal ulcers are the hallmark feature of HA20. Frequency and intensity of other clinical manifestations varied highly. Treatment regimens should be based on Disease severity, and cytokine inhibitors are often required to control relapses.
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biallelic hypomorphic mutations in a linear deubiquitinase define otulipenia an early onset Autoinflammatory Disease
Proceedings of the National Academy of Sciences of the United States of America, 2016Co-Authors: Qing Zhou, Deborah L. Stone, Yong Hwan Park, Erkan Demirkaya, Natalie Deuitch, Wanxia Li Tsai, Hye Sun Kuehn, Hongying Wang, Dan Yang, Amanda K. OmbrelloAbstract:Systemic Autoinflammatory Diseases are caused by mutations in genes that function in innate immunity. Here, we report an Autoinflammatory Disease caused by loss-of-function mutations in OTULIN (FAM105B), encoding a deubiquitinase with linear linkage specificity. We identified two missense and one frameshift mutations in one Pakistani and two Turkish families with four affected patients. Patients presented with neonatal-onset fever, neutrophilic dermatitis/panniculitis, and failure to thrive, but without obvious primary immunodeficiency. HEK293 cells transfected with mutated OTULIN had decreased enzyme activity relative to cells transfected with WT OTULIN, and showed a substantial defect in the linear deubiquitination of target molecules. Stimulated patients’ fibroblasts and peripheral blood mononuclear cells showed evidence for increased signaling in the canonical NF-κB pathway and accumulated linear ubiquitin aggregates. Levels of proinflammatory cytokines were significantly increased in the supernatants of stimulated primary cells and serum samples. This discovery adds to the emerging spectrum of human Diseases caused by defects in the ubiquitin pathway and suggests a role for targeted cytokine therapies.
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Use of TNF inhibitors in the treatment of PAPA syndrome
Pediatric Rheumatology, 2015Co-Authors: Deborah L. Stone, Raphaela Goldbach-mansky, Amanda K. Ombrello, A Almeida De Jesus, Patrycja Hoffmann, Anne Jones, Karyl S. Barron, Dl KastnerAbstract:PAPA syndrome (pyogenic arthritis, pyoderma gangrenosum and acne syndrome) is a rare Autoinflammatory Disease caused by mutations in the PSTPIP1 gene. This Disease is difficult to treat, but the combination of prednisone, an IL-1 inhibitor and a TNF-inhibitor has, in our experience, helped even the most severely affected patients. Treatment with anakinra appears to prevent most of the severe joint manifestations, and treatment with a TNF-inhibitor is most effective for treating and preventing the pyoderma gangrenosum lesions.
Kate E Lawlor - One of the best experts on this subject based on the ideXlab platform.
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mutations that prevent caspase cleavage of ripk1 cause Autoinflammatory Disease
Nature, 2020Co-Authors: Najoua Lalaoui, Diep Chau, Stuart Edward Boyden, Mario Stoffels, Tobias Kratina, Geryl Wood, Kate E Lawlor, Deborah L. StoneAbstract:RIPK1 is a key regulator of innate immune signalling pathways. To ensure an optimal inflammatory response, RIPK1 is regulated post-translationally by well-characterized ubiquitylation and phosphorylation events, as well as by caspase-8-mediated cleavage1–7. The physiological relevance of this cleavage event remains unclear, although it is thought to inhibit activation of RIPK3 and necroptosis8. Here we show that the heterozygous missense mutations D324N, D324H and D324Y prevent caspase cleavage of RIPK1 in humans and result in an early-onset periodic fever syndrome and severe intermittent lymphadenopathy—a condition we term ‘cleavage-resistant RIPK1-induced Autoinflammatory syndrome’. To define the mechanism for this Disease, we generated a cleavage-resistant Ripk1D325A mutant mouse strain. Whereas Ripk1−/− mice died postnatally from systemic inflammation, Ripk1D325A/D325A mice died during embryogenesis. Embryonic lethality was completely prevented by the combined loss of Casp8 and Ripk3, but not by loss of Ripk3 or Mlkl alone. Loss of RIPK1 kinase activity also prevented Ripk1D325A/D325A embryonic lethality, although the mice died before weaning from multi-organ inflammation in a RIPK3-dependent manner. Consistently, Ripk1D325A/D325A and Ripk1D325A/+ cells were hypersensitive to RIPK3-dependent TNF-induced apoptosis and necroptosis. Heterozygous Ripk1D325A/+ mice were viable and grossly normal, but were hyper-responsive to inflammatory stimuli in vivo. Our results demonstrate the importance of caspase-mediated RIPK1 cleavage during embryonic development and show that caspase cleavage of RIPK1 not only inhibits necroptosis but also maintains inflammatory homeostasis throughout life. Heterozygous mutateons in the caspase-8 cleavage site of RIPK1 cause a range of Autoinflammatory symptoms in humans, and caspase-8 cleavage of RIPK1 in a mouse model limits TNF-induced cell death and inflammation.
Ivona Aksentijevich - One of the best experts on this subject based on the ideXlab platform.
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pseudodominance of Autoinflammatory Disease in a single turkish family explained by co inheritance of haploinsufficiency of a20 and familial mediterranean fever
Clinical and Experimental Rheumatology, 2019Co-Authors: Nobuyuki Horita, Ivona Aksentijevich, Daniel L. Kastner, Ahmet Gul, Elaine F RemmersAbstract:OBJECTIVES We investigated a Turkish family with multiple patients presenting with familial Mediterranean fever (FMF) and Behcet's Disease (BD)-like manifestations. The index case and the two daughters with Behcet-like Disease, were previously found to have a TNFAIP3 frameshift mutation. The high number of affected cases in this expanded family could be consistent with a dominantly inherited inflammatory Disease, although some individuals had clinical features more consistent with recessively inherited FMF. We sequenced DNA from members of this family to determine whether the TNFAIP3 frameshift mutation and/or MEFV variants could explain this Autoinflammatory Disease pedigree. METHODS Patients were clinically diagnosed to have FMF or BD. Sanger sequence targeting TNFAIP3 exon 5 and MEFV exon 10 was carried out. RESULTS The symptomatic mother of the index case and her affected maternal uncle had compound heterozygous FMF-associated MEFV mutations, p.Met680Ile and p.Arg761His. Two affected daughters of the maternal uncle also had compound heterozygous FMF-associated mutations, p.Met680Ile and p.Val726Ala. The index case and her two affected daughters had a TNFAIP3 frameshift mutation (c.799delG; p.Pro268Leufs*19), which is consistent with their HA20 diagnosis, and also carried a heterozygous MEFV p.Arg761His mutation. CONCLUSIONS Autoinflammatory Disease manifestations in a Turkish family with multiple affected cases could be explained by co-inheritance of pathogenic MEFV variants and a heterozygous HA20-associated mutation. FMF-associated p.Arg761His allele carried with the loss of function TNFAIP3 mutation by all three HA20 patients may contribute to their Autoinflammatory phenotype and could also be responsible for their favourable response to colchicine.
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an Autoinflammatory Disease with deficiency of the interleukin 1 receptor antagonist
The New England Journal of Medicine, 2009Co-Authors: Ivona Aksentijevich, Paul Dancey, Annet Van Royenkerkhoff, Ulf Tedgard, Joost Frenkel, Polly J Ferguson, Edward W Cowen, Seth L Masters, Ronald M. Laxer, Tuyethang PhamAbstract:BACKGROUND Autoinflammatory Diseases manifest inflammation without evidence of infection, high-titer autoantibodies, or autoreactive T cells. We report a disorder caused by mutations of IL1RN, which encodes the interleukin-1-receptor antagonist, with prominent involvement of skin and bone. METHODS We studied nine children from six families who had neonatal onset of sterile multifocal osteomyelitis, periostitis, and pustulosis. Response to empirical treatment with the recombinant interleukin-1-receptor antagonist anakinra in the first patient prompted us to test for the presence of mutations and changes in proteins and their function in interleukin-1-pathway genes including IL1RN. RESULTS We identified homozygous mutations of IL1RN in nine affected children, from one family from Newfoundland, Canada, three families from the Netherlands, and one consanguineous family from Lebanon. A nonconsanguineous patient from Puerto Rico was homozygous for a genomic deletion that includes IL1RN and five other interleukin-1-family members. At least three of the mutations are founder mutations; heterozygous carriers were asymptomatic, with no cytokine abnormalities in vitro. The IL1RN mutations resulted in a truncated protein that is not secreted, thereby rendering cells hyperresponsive to interleukin-1 beta stimulation. Patients treated with anakinra responded rapidly. CONCLUSIONS We propose the term deficiency of the interleukin-1-receptor antagonist, or DIRA, to denote this autosomal recessive Autoinflammatory Disease caused by mutations affecting IL1RN. The absence of interleukin-1-receptor antagonist allows unopposed action of interleukin-1, resulting in life-threatening systemic inflammation with skin and bone involvement. (ClinicalTrials.gov number, NCT00059748.)
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horror autoinflammaticus the molecular pathophysiology of Autoinflammatory Disease
Annual Review of Immunology, 2009Co-Authors: Seth L Masters, Ivona Aksentijevich, Anna Simon, Daniel L. KastnerAbstract:The Autoinflammatory Diseases are characterized by seemingly unprovoked episodes of inflammation, without high-titer autoantibodies or antigen-specific T cells. The concept was proposed ten years ago with the identification of the genes underlying hereditary periodic fever syndromes. This nosology has taken root because of the dramatic advances in our knowledge of the genetic basis of both mendelian and complex Autoinflammatory Diseases, and with the recognition that these illnesses derive from genetic variants of the innate immune system. Herein we propose an updated classification scheme based on the molecular insights garnered over the past decade, supplanting a clinical classification that has served well but is opaque to the genetic, immunologic, and therapeutic interrelationships now before us. We define six categories of Autoinflammatory Disease: IL-1β activation disorders (inflammasomopathies), NF-κB activation syndromes, protein misfolding disorders, complement regulatory Diseases, disturbances in cytokine signaling, and macrophage activation syndromes. A system based on molecular pathophysiology will bring greater clarity to our discourse while catalyzing new hypotheses both at the bench and at the bedside.
