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Gene polymorphisms in the NALP3 inflammasome are associated with interleukin-1 production and severe inflammation: Relation to Common Inflammatory Diseases?
Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Rheumatology in Östergötland.ORCID iD: 0000-0002.3555-7162
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2008 (English)In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 58, no 3, 888-894 p.Article in journal (Refereed) Published
Abstract [en]

Objective: NALP3, ASC, and TUCAN are components of the NALP3 inflammasome, which triggers caspase 1-mediated interleukin-1β (IL-1β) release. Activating mutations in the gene encoding NALP3 (NLRP3) have recently been linked to familial periodic fever syndromes. We undertook this study to determine whether a patient with arthritis and antibiotic-resistant fever carried mutations in the genes encoding the NALP3 inflammasome.

Methods: Genetic analysis of NLRP3 and the gene encoding TUCAN (CARD-8) was performed on genomic DNA from the patient and from a population-based collection of DNA (806 subjects). For in vitro studies of IL-1β production and caspase 1 activity, blood was obtained from the patient at different time points after administration of anakinra, an IL-1 receptor antagonist, as well as from 5 healthy age- and sex-matched control subjects.

Results: Mutation analysis of the patient's genes encoding NALP3, ASC, and TUCAN revealed variations in the NLRP3 (Q705K) and CARD-8 (C10X) genes. The allele frequencies of these single-nucleotide polymorphisms (SNPs) in the population were 6.5% and 34%, respectively. The elevated activity of caspase 1 and the high levels of IL-1β measured in samples from the patient returned to normal levels after treatment with anakinra.

Conclusion: Our results indicate that the patient's symptoms were due to elevated levels of IL-1β, since treatment with anakinra effectively abolished the symptoms. The compound SNPs may explain the increased IL-1β levels and inflammatory symptoms observed, but further studies are needed to reveal a functional relationship. The prevalence of the polymorphisms (4% of the population carry both SNPs) in the general population may suggest a genetic predisposition for common inflammatory disorders.

Place, publisher, year, edition, pages
2008. Vol. 58, no 3, 888-894 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-19048DOI: 10.1002/art.23286OAI: oai:DiVA.org:liu-19048DiVA: diva2:222837
Available from: 2009-06-11 Created: 2009-06-09 Last updated: 2017-12-13Bibliographically approved
In thesis
1. Genetic variations in the NALP3 inflammasome: a susceptibility factor for inflammatory diseases
Open this publication in new window or tab >>Genetic variations in the NALP3 inflammasome: a susceptibility factor for inflammatory diseases
2009 (English)Licentiate thesis, comprehensive summary (Other academic)
Abstract [en]

Innate immunity has received impressive attention in the past decade owing to the discovery of the Toll like receptors (TLRs) and the NOD-like receptors (NLRs). While the TLRs specialize in fighting microbes at the cell surface, the NLRs complement by detecting and responding to intracellular microbes. Recently, the non-microbe sensing NLR called inflammasomes, have been identified, which senses metabolic stress as well as certain pathogenic microbes and elicits host’s inflammatory response.

The NLR, NALP3 (formerly known as cryopyrin) forms a large cytoplasmic complex called the ‘inflammasome’ when NALP3, activated by a stimuli, associates with the adaptor proteins ASC and CARD-8. This interaction leads to the activation of pro-inflammatory caspase-1 which subsequently results in the formation of Interleukin (IL)-1β and IL-18. Mutations in the gene encoding NALP3, termed NLRP3 can lead to its constitutive activation resulting in an uncontrolled production of IL-1β. These mutations have been implicated in hereditary inflammatory diseases, often grouped under cryopyrin associated periodic syndromes (CAPS).

This thesis describes a patient with a long history of arthritis and antibiotic resistant fever, but without the typical symptoms of CAPS. The patient was found to be a heterozygous carrier of two common polymorphisms Q705K in NLRP3 and C10X in the CARD-8. Experimental studies showed elevated levels of caspase-1 and IL-1β in the patient, and a total clinical remission was achieved by IL-1β blockade. These two polymorphisms combined, were found to occur in approximately 4% of the control population, suggesting the possibility of a genetic predisposition for inflammation in these individuals. Therefore, a cohort of rheumatoid arthritis (RA) patients, where elevated IL-1β could be one of the reasons behind chronic inflammation, was investigated. We found that carrying the combined polymorphisms resulted in increased RA susceptibility and a more severe disease course. Hypothetically, this subgroup of patients might benefit from IL-1β blockade. Additional studies are warranted to elucidate the functional effects of the two polymorphisms and to determine whether they identify a subgroup of patients that could benefit from IL-1 targeted therapy. Given the structural similarity of NALP3 to other NALPs, the possibility of involvement of the alternative, homologous genes cannot be eliminated.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2009. 30 p.
Series
Linköping Studies in Health Sciences. Thesis, ISSN 1100-6013 ; 97
Keyword
Inflammasome, Interleukin-1 beta, NALP3, autoinflammation
National Category
Medical Genetics
Identifiers
urn:nbn:se:liu:diva-19144 (URN)978-91-7393-632-3 (ISBN)
Presentation
2009-06-03, Elsabrändströmssalen, södra entrén, Campus Valla, Linköpings universitet, Linköping, 13:00 (English)
Opponent
Supervisors
Available from: 2009-06-16 Created: 2009-06-12 Last updated: 2009-06-22Bibliographically approved
2. Genetic Variations in the NLRP3 Inflammasome: Susceptibility Factor for Chronic Inflammation
Open this publication in new window or tab >>Genetic Variations in the NLRP3 Inflammasome: Susceptibility Factor for Chronic Inflammation
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

NLRP3 has been recognized as one of the key components of innate immunity. Upon activation, NLRP3 forms a multiprotein complex called as the ‘inflammasome’ which leads to the activation of pro-inflammatory caspase-1 which subsequently results in the formation of Interleukin (IL)-1β and IL-18. Mutations in the NLRP3 gene can lead to its constitutive activation resulting in an uncontrolled production of IL-1β. These mutations have been implicated in hereditary inflammatory diseases, often grouped under Cryopyrin associated periodic syndromes (CAPS, cryopyrin being an alternative name for NLRP3).

Paper I in this thesis presents the case of a patient with a long history of arthritis and antibiotic resistant fever, but without the typical symptoms of CAPS. The patient was a heterozygous carrier of two common polymorphisms, Q705K in NLRP3 and C10X in CARD-8. Experimental studies indicated elevated activity of caspase-1 and IL-1β levels in the patient and a total clinical remission was achieved by IL-1β blockade. These two polymorphisms simultaneously occur in almost 4% of the control population, suggesting the possibility of a genetic predisposition for inflammation in these individuals. We, therefore, investigated a cohort of rheumatoid arthritis (RA) patients in paper II, and found that carrying the combined polymorphisms resulted in increased RA susceptibility and a more severe disease course. Hypothetically, this subgroup might benefit from IL-1β blockade. Paper III presents two patients: siblings, who did not fit into a typical CAPS phenotype. The inflammatory symptoms in both the patients appeared in adult life. A novel and functional M299V mutation in NLRP3 was detected in the siblings who neither had common symptoms nor the same disease severity. Consequent with inflammasome activation, abnormally elevated caspase-1 activity and IL-1β levels were seen. Patients in papers I and III highlight the risk of missing out such patients if attempting a very conventional diagnosis. Paper IV dissects the functional role of Q705K in NLRP3 using THP-1 cells in an in vitro model. Moderately elevated IL-1β and IL-18 levels could be observed in the THP-1 cells expressing Q705K, as compared to the wild type expressing cells, indicating a gain-of-function. Due to the presence of this alteration in healthy individuals it can be classified as a low-penetrance alteration. Additional studies are warranted to elucidate the mechanistic details of this polymorphism.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2011. 69 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1250
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-70077 (URN)978-91-7393-116-8 (ISBN)
Public defence
2011-09-09, Linden, Hälsouniversitetet, Campus US, Linköpings universitet, Linköping, 09:00 (English)
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Available from: 2011-08-18 Created: 2011-08-18 Last updated: 2011-10-03Bibliographically approved

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Verma, DeeptiLerm, MariaBlomgran Julinder, RobertEriksson, PerSöderkvist, Peter

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Department of Clinical and Experimental MedicineFaculty of Health SciencesMedical MicrobiologyRheumatologyDepartment of Rheumatology in ÖstergötlandCell Biology
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