The Experts below are selected from a list of 549 Experts worldwide ranked by ideXlab platform
Megumu K Saito - One of the best experts on this subject based on the ideXlab platform.
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Disease Modeling and Drug Discovery Using Induced Pluripotent Stem Cells From CINCA Syndrome Patients
Blood, 2012Co-Authors: Takayuki Tanaka, Ryuta Nishikomori, Akira Ohta, Masakatsu Yanagimachi, Toshio Heike, Tatsutoshi Nakahata, Shinya Yamanaka, Megumu K SaitoAbstract:Abstract 4680 Chronic infantile neurologic cutaneous and articular Syndrome (CINCA Syndrome; MIM #607715) is a dominantly inherited autoinflammatory disease characterized by systemic inflammation with an urticaria-like rash, neurological manifestations, and arthropathy. NLRP3 mutation is the first and so far the only identified mutation that is responsible for CINCA Syndrome. NLRP3 is expressed mainly in myelomonocytic lineage cells and chondrocytes, and acts as an intracellular sensor of danger signals from various cellular insults. In normal macrophages, a first stimulus, such as lipopolysaccharide (LPS), induces the synthesis of NLRP3 and the biologically inactive proIL-1β. A second stimulus, such as ATP, enhances the assembly of a protein complex called the NLRP3-inflammasome. The inflammasome contains caspase1, which executes the proteolytic maturation and secretion of IL-1β. While normal monocytes/macrophages show no or limited IL-1β secretion in response to LPS stimulation alone, CINCA patients9 cells exhibit robust IL-1β secretion, because the mutant NLRP3-inflammasome is auto-activated without the need for any second stimulus. While approximately half of CINCA patients carry heterozygous gain-of-function mutations of the NLRP3 gene, 30 to 40% of all patients have mutations in NLRP3 in only a small number of somatic cells. Since the population of mutant cells is relatively small (4.2–35.8% in blood cells), it remains controversial whether the small fraction of NLRP3-mutated cells actually causes the strong autoinflammation observed in CINCA patients, or whether the NLRP3 mutations found in mosaic patients are just a bystander, with all cells carrying an unknown mutation of another gene that causes the disease. The pathogenesis of CINCA Syndrome patients who carry NLRP3mutations as somatic mosaicism has not been precisely described because of the difficulty in separating live cells based on the presence or absence of the mutation. It is believed that most of the manifestations of CINCA Syndrome are caused by the excessive secretion of the proinflammatory cytokine, IL-1β, and this concept is supported by the efficacy of an IL-1 receptor antagonist (IL-1Ra) for decreasing most of the symptoms. However, an NLRP3-targeted therapeutic approach would be attractive because 1) the progressive arthropathy despite anti-IL-1 therapy indicates that the presence of additional proteins processed by the inflammasome is also involved in the pathogenesis of CINCA Syndrome 2) specific inhibition of the NLRP3-inflammasome can avoid unfavorable suppression of other IL-1β processing pathways in response to various triggers, and 3) these drugs may be also effective for various other NLRP3-related chronic inflammatory conditions, such as Alzheimer9s disease, diabetes, severe gout and atherosclerosis. Here, we report the generation of NLRP3-mutant and non-mutant induced pluripotent stem cell (iPSC) lines from two CINCA Syndrome patients with somatic mosaicism, and describe their differentiation into macrophages (iPS-MPs). We found that mutant cells are predominantly responsible for the pathogenesis in these mosaic patients because only mutant iPS-MPs showed the disease relevant phenotype of abnormal IL-1β secretion. Next, after confirming that the existing anti-inflammatory compounds inhibited the abnormal IL-1β secretion from iPS-MPs, we started drug screening for CINCA Syndrome and other NLRP3-related inflammatory conditions using a recently-established feeder-free differentiation protocol. Among the 3,939 chemically-potent low molecule compounds, 127 candidates inhibited IL-1β secretion by more than 30%. We then excluded compounds that also inhibited IL-6 secretion and selected 23 candidate compounds. We are now validating the potency of these compounds. Our results illustrate that patient-derived iPSCs are useful for dissecting somatic mosaicism, and that NLRP3-mutant iPSCs can provide a valuable platform for drug discovery for multiple NLRP3-related disorders. Disclosures: Yamanaka:iPierian: Membership on an entity9s Board of Directors or advisory committees.
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high incidence of nlrp3 somatic mosaicism in patients with chronic infantile neurologic cutaneous articular Syndrome results of an international multicenter collaborative study
Arthritis & Rheumatism, 2011Co-Authors: Naoko Tanaka, Megumu K Saito, Ryuta Nishikomori, Koichi Oshima, Naotomo Kambe, Kazushi Izawa, Mio Sakuma, Osamu Ohara, Takeshi Morimoto, Raphaela GoldbachmanskyAbstract:Chronic infantile neurologic, cutaneous, articular (CINCA) Syndrome (MIM no. #607715), also known as neonatal-onset multisystem inflammatory disease (NOMID), is a dominantly-inherited autoinflammatory disease that is characterized by neonatal onset and the triad of urticarial-like skin rash, neurologic manifestations, and arthritis/arthropathy. Patients often experience recurrent fever and systemic inflammation. NOMID/CINCA Syndrome is the most severe clinical phenotype of the cryopyrin-associated periodic Syndromes (CAPS) that also include the 2 less severe but phenotypically similar Syndromes familial cold autoinflammatory Syndrome (FCAS; MIM no. #120100) and Muckle-Wells Syndrome (MIM no. #191900). CAPS are caused by mutations in the NLRP3 gene, which is a member of the nucleotide-binding oligomerization domain–like receptor (NLR) family of the innate immune system (1, 2). NLRP3 is an intracellular “sensor” of danger signals arising from cellular insults, such as infection, tissue damage, and metabolic deregulation, and it has been highly conserved throughout evolution. NLRP3 associates with ASC and procaspase 1 to constitute a large multiprotein complex termed the NLRP3 inflammasome. When activated, the NLRP3 inflammasome converts the biologically inactive procaspase 1 into active caspase 1. Caspase 1 produces the cytokines interleukin-1β (IL-1β) and IL-18, which are mainly involved in the inflammatory response (3). Available research suggests that mutated NLRP3 induces autoactivation of the NLRP3 inflammasome in CAPS patients, resulting in an uncontrolled overproduction of IL-1β. Most CAPS patients carry heterozygous germline missense mutations in the NLRP3 coding region (“mutation-positive” patients) (4, 5). More than 80 different disease-causing mutations have been reported to date (6). However, ~40% of clinically diagnosed NOMID/CINCA Syndrome patients show no heterozygous germline NLRP3 mutation during conventional Sanger-sequencing-based genetic analyses (“mutation-negative” patients). Comparisons of NOMID/CINCA Syndrome patients with and without heterozygous germline NLRP3 mutations have revealed no differences in clinical features or response to treatment (4, 7). In a previous study, we identified a high incidence of somatic NLRP3 mosaicism in “mutation-negative” NOMID/CINCA Syndrome patients in Japan (8). We therefore hypothesized that somatic NLRP3 mosaicism may be implicated in the etiology of the disorder, although its precise contribution remains unclear. The aim of the present study was to evaluate both the frequency of NLRP3 somatic mosaicism in NOMID/CINCA Syndrome patients and the association between somatic mosaicism and clinical phenotype using an international cohort of mutation-negative NOMID/CINCA Syndrome patients.
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CAPS: cryopyrin-associated periodic Syndrome
Japanese Journal of Clinical Immunology, 2011Co-Authors: Megumu K SaitoAbstract:Cryopyrin-associated periodic Syndrome (CAPS) is an autoinflammatory Syndrome caused by heterozygous mutations of NLRP3 gene. CAPS consists of three phenotypically similar but distinct Syndromes: familial cold autoinflammatory Syndrome (FCAS), Muckle-Wells Syndrome and CINCA Syndrome. Among them, FCAS shows the mildest phenotype while CINCA is the severest. Common symptoms include sporadic or cold-induced nonpruritic urticarial rash and fever. Severe cases suffers from deafness, meningitis, articular contracture and secondary amyloidosis. Gain-of-function mutations of NLRP3 causes excessive production of a potent proinflammatory cytokine IL-1β, thereby evokes autoinflammatory symptoms of CAPS. Recent advances of anti-IL-1 therapy dramatically improved the prognosis of CAPS. Currently three anti-IL-1 medicines are available, and all of them significantly improved clinical symptoms of CAPS patients. Although long-term observation is still needed, the molecular-targeted therapy has opened up a new opportunity for managing CAPS.
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Somatic mosaicism of CIAS1 in a patient with chronic infantile neurologic, cutaneous, articular Syndrome.
Arthritis and rheumatism, 2005Co-Authors: Megumu K Saito, Ryuta Nishikomori, Naotomo Kambe, Akihiro Fujisawa, Mami Nakata-hizume, Momoko Yoshimoto, Katsuyuki Ohmori, Ikuo Okafuji, Takakazu Yoshioka, Takashi KusunokiAbstract:Chronic infantile neurologic, cutaneous, articular Syndrome (CINCA Syndrome) is a severe inflammatory disease that was recently found to be associated with mutations in CIAS1. However, CIAS1 mutations have been detected in only half of CINCA Syndrome patients, and it remains unclear which genes are responsible for the Syndrome in the remaining patients. We describe here a patient with CINCA Syndrome who exhibited CIAS1 somatic mosaicism. We genetically analyzed the CIAS1 gene in various blood cells and the buccal mucosa of the patient. The production of interleukin-1β (IL-1β) by peripheral blood mononuclear cells (PBMCs) was measured by enzyme-linked immunosorbent assay, and the ability of the mutant CIAS1 gene to enhance ASC-dependent NF-κB activation was assessed to confirm that the mutations of CIAS1 found were responsible for the patient's clinical manifestations of the CINCA Syndrome. The patient had 1 heterologous single-nucleotide polymorphism, 587G>A (S196N), and 1 heterologous mutation, 1709A>G (Y570C), in exon 3 of CIAS1. The latter mutation was found to occur as somatic mosaicism. The patient's PBMCs produced a large amount of IL-1β in the absence of stimulation, unlike those from controls or from his mother, who also bore the S196N polymorphism. In addition, the Y570C mutation (with or without the S196N polymorphism) increased the ability of CIAS1 to induce ASC-dependent NF-κB activation, unlike the wild-type gene or the gene bearing the S196N polymorphism alone. The findings in this patient indicate that somatic mosaicism is one reason CIAS1 mutations have not been detected in some patients with CINCA Syndrome.
Ryuta Nishikomori - One of the best experts on this subject based on the ideXlab platform.
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CINCA Syndrome with surgical intervention for valgus deformity and flexion contracture of the knee joint a case report
Modern Rheumatology, 2017Co-Authors: Yuki Harada, Kenichi Fukiage, Ryuta Nishikomori, Shigeo Suzuki, Tohru FutamiAbstract:Chronic infantile neurological, cutaneous, and articular (CINCA) Syndrome is a systemic autoinflammatory disease caused by increased production of interleukin (IL)-1β. We present a case of CINCA Syndrome followed up to skeletal maturity. Joint contracture and valgus deformity of the knee had developed before diagnosis. Surgical interventions by soft tissue release and hemiepiphysiodesis improved the contracture and the deformity, and IL-1 receptor antagonist dramatically controlled systemic inflammation, and the patient lives without any disabilities.
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Understanding the pathophysiology of NOMID arthropathy for drug discovery by iPSCs technology
Pediatric Rheumatology, 2015Co-Authors: Kenji Nakagawa, Ryuta Nishikomori, Takayuki Tanaka, Tomoki Kawai, Takahiro Yasumi, Yusuke Okuno, Koji Yokoyama, Katsutsugu Umeda, Naoki Nakayama, Junya ToguchidaAbstract:NOMID, also known as CINCA Syndrome, is a dominantly inherited autoinflammatory disease caused by NLRP3 mutations. The pathophysiology of NOMID is explained by gain of function mutation of NLRP3, which activates NLRP3 inflammasome and produce an excess of IL-1β. This mechanism is supported by clinical observation that anti-IL-1 therapy is effective on its systemic inflammation. However, one of its characteristic features, epiphyseal overgrowth, is considered to be resistant to anti-IL-1 therapy, which raises a question that other mechanism than NLRP3 inflammasome may play a role in the epiphyseal overgrowth. In this study, we investigated the effect of mutated NLRP3 on chondrocytes using induced pluripotent stem cells (iPSCs) derived from NOMID patients, and tried to identify drugs to treat the abnormal chondrocytes overgrowth.
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PW02-029 - Single cell fluorescent immunoassay of CINCA/NOMID
Pediatric Rheumatology, 2013Co-Authors: Kenji Nakagawa, Ryuta Nishikomori, Toshio Heike, Kazushi Izawa, Nanako Shimura, Yoshitaka Shirasaki, Mai Yamagishi, Tomoki Kawai, Takahiro Yasumi, Osamu OharaAbstract:CINCA Syndrome, also known as NOMID, is a rare autoinflammatory disease caused by the NLRP3 mutations. It has been known that conventional genetic analysis failed to detect disease-causing mutations in approximately 40% of patients. We have recently identified NLRP3 somatic mosaicism on 70% of these ”mutation-negative” patients in the international collaborative study (Tanaka N. and Izawa K. et al., Arthritis Rheum, 2011), and found no significant differences on systemic inflammation between heterozygous germline mutations and somatic mosaicism. This raises a question how a small number of NLRP3-mutated cells cause systemic inflammation as severely as 100% of germline mutations.
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Disease Modeling and Drug Discovery Using Induced Pluripotent Stem Cells From CINCA Syndrome Patients
Blood, 2012Co-Authors: Takayuki Tanaka, Ryuta Nishikomori, Akira Ohta, Masakatsu Yanagimachi, Toshio Heike, Tatsutoshi Nakahata, Shinya Yamanaka, Megumu K SaitoAbstract:Abstract 4680 Chronic infantile neurologic cutaneous and articular Syndrome (CINCA Syndrome; MIM #607715) is a dominantly inherited autoinflammatory disease characterized by systemic inflammation with an urticaria-like rash, neurological manifestations, and arthropathy. NLRP3 mutation is the first and so far the only identified mutation that is responsible for CINCA Syndrome. NLRP3 is expressed mainly in myelomonocytic lineage cells and chondrocytes, and acts as an intracellular sensor of danger signals from various cellular insults. In normal macrophages, a first stimulus, such as lipopolysaccharide (LPS), induces the synthesis of NLRP3 and the biologically inactive proIL-1β. A second stimulus, such as ATP, enhances the assembly of a protein complex called the NLRP3-inflammasome. The inflammasome contains caspase1, which executes the proteolytic maturation and secretion of IL-1β. While normal monocytes/macrophages show no or limited IL-1β secretion in response to LPS stimulation alone, CINCA patients9 cells exhibit robust IL-1β secretion, because the mutant NLRP3-inflammasome is auto-activated without the need for any second stimulus. While approximately half of CINCA patients carry heterozygous gain-of-function mutations of the NLRP3 gene, 30 to 40% of all patients have mutations in NLRP3 in only a small number of somatic cells. Since the population of mutant cells is relatively small (4.2–35.8% in blood cells), it remains controversial whether the small fraction of NLRP3-mutated cells actually causes the strong autoinflammation observed in CINCA patients, or whether the NLRP3 mutations found in mosaic patients are just a bystander, with all cells carrying an unknown mutation of another gene that causes the disease. The pathogenesis of CINCA Syndrome patients who carry NLRP3mutations as somatic mosaicism has not been precisely described because of the difficulty in separating live cells based on the presence or absence of the mutation. It is believed that most of the manifestations of CINCA Syndrome are caused by the excessive secretion of the proinflammatory cytokine, IL-1β, and this concept is supported by the efficacy of an IL-1 receptor antagonist (IL-1Ra) for decreasing most of the symptoms. However, an NLRP3-targeted therapeutic approach would be attractive because 1) the progressive arthropathy despite anti-IL-1 therapy indicates that the presence of additional proteins processed by the inflammasome is also involved in the pathogenesis of CINCA Syndrome 2) specific inhibition of the NLRP3-inflammasome can avoid unfavorable suppression of other IL-1β processing pathways in response to various triggers, and 3) these drugs may be also effective for various other NLRP3-related chronic inflammatory conditions, such as Alzheimer9s disease, diabetes, severe gout and atherosclerosis. Here, we report the generation of NLRP3-mutant and non-mutant induced pluripotent stem cell (iPSC) lines from two CINCA Syndrome patients with somatic mosaicism, and describe their differentiation into macrophages (iPS-MPs). We found that mutant cells are predominantly responsible for the pathogenesis in these mosaic patients because only mutant iPS-MPs showed the disease relevant phenotype of abnormal IL-1β secretion. Next, after confirming that the existing anti-inflammatory compounds inhibited the abnormal IL-1β secretion from iPS-MPs, we started drug screening for CINCA Syndrome and other NLRP3-related inflammatory conditions using a recently-established feeder-free differentiation protocol. Among the 3,939 chemically-potent low molecule compounds, 127 candidates inhibited IL-1β secretion by more than 30%. We then excluded compounds that also inhibited IL-6 secretion and selected 23 candidate compounds. We are now validating the potency of these compounds. Our results illustrate that patient-derived iPSCs are useful for dissecting somatic mosaicism, and that NLRP3-mutant iPSCs can provide a valuable platform for drug discovery for multiple NLRP3-related disorders. Disclosures: Yamanaka:iPierian: Membership on an entity9s Board of Directors or advisory committees.
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Induced pluripotent stem cells from CINCA Syndrome patients as a model for dissecting somatic mosaicism and drug discovery.
Blood, 2012Co-Authors: Takayuki Tanaka, Ryuta Nishikomori, Kazutoshi Takahashi, Mayu Yamane, Shota Tomida, Saori Nakamura, Koichi Oshima, Akira Niwa, Naotomo Kambe, Hideki HaraAbstract:Chronic infantile neurologic cutaneous and articular (CINCA) Syndrome is an IL-1–driven autoinflammatory disorder caused mainly by NLRP3 mutations. The pathogenesis of CINCA Syndrome patients who carry NLRP3 mutations as somatic mosaicism has not been precisely described because of the difficulty in separating individual cells based on the presence or absence of the mutation. Here we report the generation of NLRP3mutant and nonmutant-induced pluripotent stem cell (iPSC) lines from 2 CINCA Syndrome patients with somatic mosaicism, and describe their differentiation into macrophages (iPS-MPs). We found that mutant cells are predominantly responsible for the pathogenesis in these mosaic patients because only mutant iPSMPs showed the disease relevant phenotype of abnormal IL-1 secretion. We also confirmed that the existing antiinflammatory compounds inhibited the abnormal IL-1 secretion, indicating that mutant iPS-MPs are applicable for drug screening for CINCA Syndrome and other NLRP3-related inflammatory conditions. Our results illustrate that patient-derived iPSCs are useful for dissecting somatic mosaicism and that NLRP3-mutant iPSCs can provide a valuable platform for drug discovery for multiple NLRP3-related disorders. (Blood. 2012;120(6):1299-1308)
Kenji Nakagawa - One of the best experts on this subject based on the ideXlab platform.
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Somatic NLRP3 mosaicism in Muckle-Wells Syndrome
Pediatric Rheumatology, 2015Co-Authors: Eva González-roca, Anna Mensa-vilaro, S Plaza, Mc Anton, J Rius, Estibaliz Ruiz-ortiz, Jaume Campistol, Alejandro Souto, Jeronima Cañellas, Kenji NakagawaAbstract:Familial cold autoinflammatory Syndrome, Muckle-Wells Syndrome (MWS), and chronic, infantile, neurological, cutaneous and articular (CINCA) Syndrome are dominantly inherited autoinflammatory diseases associated to gain-of-function NLRP3 mutations. All these diseases are currently considered as different phenotypes of the cryopyrin-associated periodic Syndromes (CAPS). A variable degree of somatic NLRP3 mosaicism has been recently detected in ≈35% of patients with CINCA. However, no data are currently available regarding the relevance of this genetic mechanism in other CAPS phenotypes.
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Understanding the pathophysiology of NOMID arthropathy for drug discovery by iPSCs technology
Pediatric Rheumatology, 2015Co-Authors: Kenji Nakagawa, Ryuta Nishikomori, Takayuki Tanaka, Tomoki Kawai, Takahiro Yasumi, Yusuke Okuno, Koji Yokoyama, Katsutsugu Umeda, Naoki Nakayama, Junya ToguchidaAbstract:NOMID, also known as CINCA Syndrome, is a dominantly inherited autoinflammatory disease caused by NLRP3 mutations. The pathophysiology of NOMID is explained by gain of function mutation of NLRP3, which activates NLRP3 inflammasome and produce an excess of IL-1β. This mechanism is supported by clinical observation that anti-IL-1 therapy is effective on its systemic inflammation. However, one of its characteristic features, epiphyseal overgrowth, is considered to be resistant to anti-IL-1 therapy, which raises a question that other mechanism than NLRP3 inflammasome may play a role in the epiphyseal overgrowth. In this study, we investigated the effect of mutated NLRP3 on chondrocytes using induced pluripotent stem cells (iPSCs) derived from NOMID patients, and tried to identify drugs to treat the abnormal chondrocytes overgrowth.
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somatic nlrp3 mosaicism in muckle wells Syndrome a genetic mechanism shared by different phenotypes of cryopyrin associated periodic Syndromes
Annals of the Rheumatic Diseases, 2015Co-Authors: Kenji Nakagawa, Jaume Campistol, Alejandro Souto, Jeronima Cañellas, Eva Gonzalezroca, Toshinao Kawai, Hiroaki Umebayashi, Syuji Takei, Norimoto Kobayashi, Jose Luis CallejasrubioAbstract:Familial cold autoinflammatory Syndrome, Muckle-Wells Syndrome (MWS), and chronic, infantile, neurological, cutaneous and articular (CINCA) Syndrome are dominantly inherited autoinflammatory diseases associated to gain-of-function NLRP3 mutations and included in the cryopyrin-associated periodic Syndromes (CAPS). A variable degree of somatic NLRP3 mosaicism has been detected in ≈35% of patients with CINCA. However, no data are currently available regarding the relevance of this mechanism in other CAPS phenotypes. Objective To evaluate somatic NLRP3 mosaicism as the disease-causing mechanism in patients with clinical CAPS phenotypes other than CINCA and NLRP3 mutation-negative. Methods NLRP3 analyses were performed by Sanger sequencing and by massively parallel sequencing. Apoptosis-associated Speck-like protein containing a CARD (ASC)-dependent nuclear factor kappa-light chain-enhancer of activated B cells (NF-κB) activation and transfection-induced THP-1 cell death assays determined the functional consequences of the detected variants. Results A variable degree (5.5–34.9%) of somatic NLRP3 mosaicism was detected in 12.5% of enrolled patients, all of them with a MWS phenotype. Six different missense variants, three novel (p.D303A, p.K355T and p.L411F), were identified. Bioinformatics and functional analyses confirmed that they were disease-causing, gain-of-function NLRP3 mutations. All patients treated with anti-interleukin1 drugs showed long-lasting positive responses. Conclusions We herein show somatic NLRP3 mosaicism underlying MWS, probably representing a shared genetic mechanism in CAPS not restricted to CINCA Syndrome. The data here described allowed definitive diagnoses of these patients, which had serious implications for gaining access to anti-interleukin 1 treatments under legal indication and for genetic counselling. The detection of somatic mosaicism is difficult when using conventional methods. Potential candidates should benefit from the use of modern genetic tools.
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PW02-029 - Single cell fluorescent immunoassay of CINCA/NOMID
Pediatric Rheumatology, 2013Co-Authors: Kenji Nakagawa, Ryuta Nishikomori, Toshio Heike, Kazushi Izawa, Nanako Shimura, Yoshitaka Shirasaki, Mai Yamagishi, Tomoki Kawai, Takahiro Yasumi, Osamu OharaAbstract:CINCA Syndrome, also known as NOMID, is a rare autoinflammatory disease caused by the NLRP3 mutations. It has been known that conventional genetic analysis failed to detect disease-causing mutations in approximately 40% of patients. We have recently identified NLRP3 somatic mosaicism on 70% of these ”mutation-negative” patients in the international collaborative study (Tanaka N. and Izawa K. et al., Arthritis Rheum, 2011), and found no significant differences on systemic inflammation between heterozygous germline mutations and somatic mosaicism. This raises a question how a small number of NLRP3-mutated cells cause systemic inflammation as severely as 100% of germline mutations.
Jose Luis Callejasrubio - One of the best experts on this subject based on the ideXlab platform.
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somatic nlrp3 mosaicism in muckle wells Syndrome a genetic mechanism shared by different phenotypes of cryopyrin associated periodic Syndromes
Annals of the Rheumatic Diseases, 2015Co-Authors: Kenji Nakagawa, Jaume Campistol, Alejandro Souto, Jeronima Cañellas, Eva Gonzalezroca, Toshinao Kawai, Hiroaki Umebayashi, Syuji Takei, Norimoto Kobayashi, Jose Luis CallejasrubioAbstract:Familial cold autoinflammatory Syndrome, Muckle-Wells Syndrome (MWS), and chronic, infantile, neurological, cutaneous and articular (CINCA) Syndrome are dominantly inherited autoinflammatory diseases associated to gain-of-function NLRP3 mutations and included in the cryopyrin-associated periodic Syndromes (CAPS). A variable degree of somatic NLRP3 mosaicism has been detected in ≈35% of patients with CINCA. However, no data are currently available regarding the relevance of this mechanism in other CAPS phenotypes. Objective To evaluate somatic NLRP3 mosaicism as the disease-causing mechanism in patients with clinical CAPS phenotypes other than CINCA and NLRP3 mutation-negative. Methods NLRP3 analyses were performed by Sanger sequencing and by massively parallel sequencing. Apoptosis-associated Speck-like protein containing a CARD (ASC)-dependent nuclear factor kappa-light chain-enhancer of activated B cells (NF-κB) activation and transfection-induced THP-1 cell death assays determined the functional consequences of the detected variants. Results A variable degree (5.5–34.9%) of somatic NLRP3 mosaicism was detected in 12.5% of enrolled patients, all of them with a MWS phenotype. Six different missense variants, three novel (p.D303A, p.K355T and p.L411F), were identified. Bioinformatics and functional analyses confirmed that they were disease-causing, gain-of-function NLRP3 mutations. All patients treated with anti-interleukin1 drugs showed long-lasting positive responses. Conclusions We herein show somatic NLRP3 mosaicism underlying MWS, probably representing a shared genetic mechanism in CAPS not restricted to CINCA Syndrome. The data here described allowed definitive diagnoses of these patients, which had serious implications for gaining access to anti-interleukin 1 treatments under legal indication and for genetic counselling. The detection of somatic mosaicism is difficult when using conventional methods. Potential candidates should benefit from the use of modern genetic tools.
Donato Rigante - One of the best experts on this subject based on the ideXlab platform.
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Resolution of femoral metaphyseal dysplasia in CINCA Syndrome after long-term treatment with interleukin-1 blockade.
Clinical rheumatology, 2018Co-Authors: Donato Rigante, Elena Verrecchia, Raffaele Manna, Raffaella Marrocco, Antonio Maria LeoneAbstract:Chronic infantile neurological cutaneous articular (CINCA) Syndrome is a rare autoinflammatory disorder driven by uncontrolled hypersecretion of interleukin (IL)-1, which can be clinically depicted by striking cutaneous, neurologic, and skeletal features. Little is known about the exact pathogenesis of CINCA bone disease, which mainly involves the knees. We report a 20-year-old CINCA patient, who was consecutively treated firstly with anakinra, started at 7 years, then with full dose canakinumab, started at 17 years, focusing on the typical bone abnormalities of the Syndrome: the comparison of radiographs of knees performed at 7 and 20 years has shown the disappearance of a typical metaphyseal dysplasia occurring in the femurs of this CINCA patient, regularly treated with IL-1 blockade for a period of 13 years. A review of the medical literature reveals poor information on the skeletal response of CINCA Syndrome to IL-1-inhibiting therapies. This contribution confirms the protean striking effects of IL-1 blockade in this peculiar autoinflammatory disorder, showing for the first time the reversal of the characteristic CINCA metaphyseal dysplasia over long-term treatment.
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Switch from anakinra to canakinumab in a severe case of CINCA Syndrome
International journal of rheumatic diseases, 2015Co-Authors: Donato Rigante, Elena Verrecchia, Benedetto Falsini, Raffaele MannaAbstract:A boy with CINCA Syndrome is reported, focusing on the therapeutic switch from anakinra to canakinumab
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monogenic autoinflammatory Syndromes state of the art on genetic clinical and therapeutic issues
International Journal of Rheumatology, 2013Co-Authors: Francesco Caso, Luisa Costa, Mariangela Atteno, Adele Compagnone, Paolo Caso, Bruno Frediani, Orso Maria Lucherini, Antonio Vitale, Donato Rigante, Mauro GaleazziAbstract:Monogenic autoinflammatory Syndromes (MAISs) are caused by innate immune system dysregulation leading to aberrant inflammasome activation and episodes of fever and involvement of skin, serous membranes, eyes, joints, gastrointestinal tract, and nervous system, predominantly with a childhood onset. To date, there are twelve known MAISs: familial Mediterranean fever, tumor necrosis factor receptor-associated periodic Syndrome, familial cold urticaria Syndrome, Muckle-Wells Syndrome, CINCA Syndrome, mevalonate kinase deficiency, NLRP12-associated autoinflammatory disorder, Blau Syndrome, early-onset sarcoidosis, PAPA Syndrome, Majeed Syndrome, and deficiency of the interleukin-1 receptor antagonist. Each of these conditions may manifest itself with more or less severe inflammatory symptoms of variable duration and frequency, associated with findings of increased inflammatory parameters in laboratory investigation. The purpose of this paper is to describe the main genetic, clinical, and therapeutic aspects of MAISs and their most recent classification with the ultimate goal of increasing awareness of autoinflammation among various internal medicine specialists.
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Post-inflammatory retinal dystrophy in CINCA Syndrome
Rheumatology international, 2009Co-Authors: Donato Rigante, Adele Compagnone, Achille Stabile, Angelo Maria Minnella, Laura Avallone, Lucia Ziccardi, Giulia Bersani, G. Stifano, Benedetto FalsiniAbstract:Right chorioretinitis and bilateral pseudopapilledema were firstly appreciated in a 9-month-old child with neonatal findings of aseptic chronic meningitis, framed in the context of CINCA Syndrome at 1 year. Therapeutical response to various combinations of drugs was inconsistent until 7 years, when anakinra was started with immediate clinical and laboratory improvement. A state of severe retinal dystrophy of post-inflammatory origin became evident on funduscopy, optical coherence tomography and visual electrophysiology tests at the age of 10 years, which remained stationary after 1 year of anakinra treatment.
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12.3 Long-term follow up of patients with CINCA Syndrome: efficacy and tolerability of Anakinra treatment
Pediatric Rheumatology, 2008Co-Authors: Giulia Paloni, Donato Rigante, M Gattorno, M Alessio, Marco Cattalini, Francesco Zulian, Loredana LeporeAbstract:Oral presentation We report the long-term follow up of 15 Italian patients affected by Chronic Infantile Neurological Cutaneous and Articular (CINCA) Syndrome (7 males and 8 females, mean age 13, 5 years). We report the updating of the survey following the introduction of the IL-1 receptor antagonist therapy (Anakinra). 11 patients were treated with subcutaneous injections, at a daily dosage of 1 mg/Kg in children and up to 100 mg in adults, 2 refused the therapy, and the others did not require the treatment due to a mild presentation of the disease so far. In treated patients fever, rash, articular involvement, conjunctivitis, uveitis disappeared or improved. Laboratory data normalized in most of the cases within the first month. The neurologic symptoms ameliorated, papilledema disappeared in four out of eleven treated patients while dysmorphisms (typical facies) and bone alterations constantly persist. No further CINCA related signs and symptoms appeared after Anakinra was introduced. The medication showed very good tolerability: we observed local erythema at the site of injection in 2 out of 11 subjects, and oral aphtosys in another. The untreated subjects kept presenting all their symptoms of CINCA Syndrome and the disease went on with its poor manifestation. We found no differences in the response to Anakinra therapy between CIAS1-mutated and not mutated patients. In summary, our study demonstrates that a long lasting treatment with Anakinra appears to be safe and highly effective in patients affected by CINCA Syndrome.