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51.
Monogenic autoinflammatory diseases encompass a distinct and growing clinical entity of multisystem inflammatory diseases
with known genetic defects in the innate immune system. The diseases present clinically with episodes of seemingly unprovoked
inflammation (fever, rashes, and elevation of acute phase reactants). Understanding the genetics has led to discovery of new
molecules involved in recognizing exogenous and endogenous danger signals, and the inflammatory response to these stimuli.
These advances have furthered understanding of innate inflammatory pathways and spurred collaborative research in rheumatology
and infectious diseases. The pivotal roles of interleukin (IL)-1β in cryopyrin-associated periodic syndromes, tumor necrosis
factor (TNF) in TNF receptor-associated periodic syndrome, and links to inflammatory cytokine dysregulation in other monogenic
autoinflammatory diseases have resulted in effective therapies targeting proinflammatory cytokines IL-1β and TNF and uncovered
other new potential targets for anti-inflammatory therapies. 相似文献
52.
Leonardo O. Mendonca Louise Malle Frank X. Donovan Settara C. Chandrasekharappa Gina A. Montealegre Sanchez Megha Garg Ulf Tedgard Mariana Castells Shiv S. Saini Sourabh Dutta Raphaela Goldbach-Mansky Deepti Suri Adriana A. Jesus 《Journal of clinical immunology》2017,37(5):445-451
Purpose
Deficiency of interleukin-1 receptor antagonist (DIRA) is a rare life-threatening autoinflammatory disease caused by autosomal recessive mutations in IL1RN. DIRA presents clinically with early onset generalized pustulosis, multifocal osteomyelitis, and elevation of acute phase reactants. We evaluated and treated an antibiotic-unresponsive patient with presumed DIRA with recombinant IL-1Ra (anakinra). The patient developed anaphylaxis to anakinra and was subsequently desensitized.Methods
Genetic analysis of IL1RN was undertaken and treatment with anakinra was initiated.Results
A 5-month-old Indian girl born to healthy non-consanguineous parents presented at the third week of life with irritability, sterile multifocal osteomyelitis including ribs and clavicles, a mild pustular rash, and elevated acute phase reactants. SNP array of the patient’s genomic DNA revealed a previously unrecognized homozygous deletion of approximately 22.5 Kb. PCR and Sanger sequencing of the borders of the deleted area allowed identification of the breakpoints of the deletion, thus confirming a homozygous 22,216 bp deletion that spans the first four exons of IL1RN. Due to a clinical suspicion of DIRA, anakinra was initiated which resulted in an anaphylactic reaction that triggered desensitization with subsequent marked and sustained clinical and laboratory improvement.Conclusion
We report a novel DIRA-causing homozygous deletion affecting IL1RN in an Indian patient. The mutation likely is a founder mutation; the design of breakpoint-specific primers will enable genetic screening in Indian patients suspected of DIRA. The patient developed anaphylaxis to anakinra, was desensitized, and is in clinical remission on continued treatment.53.
54.
55.
The clinical continuum of cryopyrinopathies: novel CIAS1 mutations in North American patients and a new cryopyrin model 总被引:1,自引:0,他引:1
Aksentijevich I D Putnam C Remmers EF Mueller JL Le J Kolodner RD Moak Z Chuang M Austin F Goldbach-Mansky R Hoffman HM Kastner DL 《Arthritis and rheumatism》2007,56(4):1273-1285
OBJECTIVE: The cryopyrinopathies are a group of rare autoinflammatory disorders that are caused by mutations in CIAS1, encoding the cryopyrin protein. However, cryopyrin mutations are found only in 50% of patients with clinically diagnosed cryopyrinopathies. This study was undertaken to investigate the structural effect of disease-causing mutations on cryopyrin, in order to gain better understanding of the impact of disease-associated mutations on protein function. METHODS: We tested for CIAS1 mutations in 22 patients with neonatal-onset multisystem inflammatory disease/chronic infantile neurologic, cutaneous, articular syndrome, 12 with Muckle-Wells syndrome (MWS), 18 with familial cold-induced autoinflammatory syndrome (FCAS), and 3 probands with MWS/FCAS. In a subset of mutation-negative patients, we screened for mutations in proteins that are either homologous to cryopyrin or involved in the caspase 1/interleukin-1beta signaling pathway. CIAS1 and other candidate genes were sequenced, models of cryopyrin domains were constructed using structurally homologous proteins as templates, and disease-causing mutations were mapped. RESULTS: Forty patients were mutation positive, and 7 novel mutations, V262A, C259W, L264F, V351L, F443L, F523C, and Y563N, were found in 9 patients. No mutations in any candidate genes were identified. Most mutations mapped to an inner surface of the hexameric ring in the cryopyrin model, consistent with the hypothesis that the mutations disrupt a closed form of cryopyrin, thus potentiating inflammasome assembly. Disease-causing mutations correlated with disease severity only for a subset of known mutations. CONCLUSION: Our modeling provides insight into potential molecular mechanisms by which cryopyrin mutations can inappropriately activate an inflammatory response. A significant number of patients who are clinically diagnosed as having cryopyrinopathies do not have identifiable disease-associated mutations. 相似文献
56.
Vliegen R Dresen R Beets G Daniels-Gooszen A Kessels A van Engelshoven J Beets-Tan R 《Abdominal imaging》2008,33(5):604-610
PURPOSE: To evaluate the accuracy of Multi-detector row CT (MDCT) for the prediction of tumor invasion of the mesorectal fascia (MRF). MATERIALS AND METHODS: A total of 35 patients with primary rectal cancer underwent preoperative staging magnetic resonance imaging (MRI) and MDCT. The tumor relationship to the MRF, expressed in 3 categories (1--tumor free MRF = tumor distance > or = 1 mm; 2--threatened = distance < 1 mm; 3--invasion = distance 0 mm) was determined on CT by two observers at patient level and at different anatomical locations. A third expert reader evaluated the MRF tumor relationship on MRI, which served as reference standard. Receiver operating characteristic curves (ROC-curves) and areas under these curves (AUC) were calculated. The inter-observer agreement of CT was determined by using linear weighted kappa statistics. RESULTS: The AUC of CT for MRF invasion was 0.71 for observer 1 and 0.62 for observer 2. The inter-observer agreement was kappa = 0.34. The performance of CT at mid-high rectal levels was statistically significant better compared to low anterior (obs.1: AUC = 0.88 vs. 0.50; obs 2: AUC = 0.84 vs. 0.31; P < or = 0.040). CONCLUSION: Multi-detector row CT has a poor accuracy for predicting MRF invasion in low-anterior located tumors.The accuracy of CT significantly improves for tumors in the mid-high rectum. There is a high inconsistency among readers. 相似文献
57.
Odile Launay Christine Sadorge Nathalie Jolly Béatrice Poirier Stéphane Béchet Diane van der Vliet Valérie Seffer Nicola Fenner Kelly Dowling Raphaela Giemza Julie Johnson Anna Ndiaye Muriel Vray Philippe Sansonetti Philippe Morand Claire Poyart David Lewis Marie-Lise Gougeon 《Vaccine》2009
SC599 vaccine is a live Shigella dysenteriae 1 strain attenuated by deletion of invasion [icsA], iron chelation [ent, fep] and shiga toxin A subunit [stxA] genes. In a preliminary Phase 1 single dose prospective study, we showed that SC599 vaccine was well tolerated, and the maximum tolerable dose was greater than 108 CFU [Sadorge C, Ndiaye A, Beveridge N, Frazer S, Giemza R, Jolly N, et al. Phase 1 clinical trial of live attenuated Shigella dysenteriae type-1 ΔicsA Δent Δfep ΔstxA:HgR oral vaccine SC599 in healthy human adult volunteers. Vaccine 2008; 26(7):978–8]. In this Phase 2 trial, three groups of volunteers ingested a single dose of SC599 [105 CFU, n = 38; 107 CFU, n = 36] or placebo [n = 37]. Both 105 and 107 CFU doses were immunogenic, inducing significant IgA and IgG LPS-specific ASCs and antibody responses, comparable in magnitude to those of other strains that prevented illness following experimental challenge. In the intention to treat analysis, 34.2% and 44.4% IgA ASC responders were detected in the 105 and 107 CFU groups respectively (p < 0001 vs placebo for both groups), as well as 31.6% and 33.3% serum IgA responders (p < 001 and p < 0.001 vs placebo for 105 and 107 CFU groups, respectively). No difference between the two vaccine groups was observed. No stxB-specific antibody response was detected in the vaccines. SC599 excretion occurred in 23.7 and 30.6% of subjects in the 105 and 107 CFU groups, respectively. SC599 vaccine was well tolerated, and the reported adverse events were mainly digestive. These results indicate that a single oral immunization of SC599 vaccine elicits a significant circulating IgA ASC and serum antibody response that may confer protection against the most severe symptoms of Shigellosis in responders to the vaccine. 相似文献
58.
59.
The rare case of a patient with carpal tunnel syndrome caused by thrombosis of a persistent median artery is presented. Progressive pain in the wrist and dysesthesias in the third and fourth fingers were the atypical complaints. High-resolution ultrasonography revealed a bifid median nerve that was compressed by an occluded median artery. The intraoperative findings are described, and emphasis is placed on the importance of using high-resolution ultrasonography for presurgical diagnosis. 相似文献
60.
Aksentijevich I Nowak M Mallah M Chae JJ Watford WT Hofmann SR Stein L Russo R Goldsmith D Dent P Rosenberg HF Austin F Remmers EF Balow JE Rosenzweig S Komarow H Shoham NG Wood G Jones J Mangra N Carrero H Adams BS Moore TL Schikler K Hoffman H Lovell DJ Lipnick R Barron K O'Shea JJ Kastner DL Goldbach-Mansky R 《Arthritis and rheumatism》2002,46(12):3340-3348
OBJECTIVE: Neonatal-onset multisystem inflammatory disease (NOMID; also known as chronic infantile neurologic, cutaneous, articular [CINCA] syndrome) is characterized by fever, chronic meningitis, uveitis, sensorineural hearing loss, urticarial skin rash, and a characteristic deforming arthropathy. We investigated whether patients with this disorder have mutations in CIAS1, the gene which causes Muckle-Wells syndrome and familial cold autoinflammatory syndrome, two dominantly inherited disorders with some similarities to NOMID/CINCA syndrome. METHODS: Genomic DNA from 13 patients with classic manifestations of NOMID/CINCA syndrome and their available parents was screened for CIAS1 mutations by automated DNA sequencing. Cytokine messenger RNA (mRNA) levels were assessed by real-time polymerase chain reaction on peripheral blood leukocyte mRNA, and serum cytokine levels were assayed by enzyme-linked immunosorbent assay. Protein expression was assessed by Western blotting of lysates from plastic-adherent peripheral blood mononuclear cells. RESULTS: In 6 of the 13 patients, we found 6 heterozygous missense substitutions in CIAS1. Five of the 6 mutations are novel. None of these sequence changes was observed in a panel of >900 chromosomes from healthy controls. Two distinct nucleotide changes in a single codon in unrelated patients resulted in the same amino acid change. In 4 mutation-positive children whose parental DNA was available, no mutation was found in the parental DNA, supporting the conclusion that the mutations arose de novo. Consistent with the recently discovered role of CIAS1 in the regulation of interleukin-1 (IL-1), we found evidence of increased IL-1beta, as well as tumor necrosis factor, IL-3, IL-5, and IL-6, but not transforming growth factor beta, in a mutation-positive patient compared with normal controls. CONCLUSION: Our data increase the total number of known germline mutations in CIAS1 to 20, causing a spectrum of diseases ranging from familial cold autoinflammatory syndrome to Muckle-Wells syndrome to NOMID/CINCA syndrome. Mutations in CIAS1 were only found in approximately 50% of the cases identified clinically as NOMID/CINCA syndrome, which raises the possibility of genetic heterogeneity. IL-1 regulation by CIAS1 suggests that IL-1 receptor blockade may constitute a rational approach to the treatment of NOMID/CINCA syndrome. 相似文献