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Genetic variation in proteins of the cryopyrin inflammasome influences susceptibility and severity of rheumatoid arthritis (the Swedish TIRA project)
Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences.ORCID iD: 0000-0002.3555-7162
Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences.ORCID iD: 0000-0002-0153-9249
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2008 (English)In: Rheumatology, ISSN 1462-0324, Vol. 47, no 4, 415-417 p.Article in journal (Refereed) Published
Abstract [en]

Objectives: The genetic background to RA is incompletely understood.As new cytokine-targeted therapies emerge, early predictorsof disease severity are becoming increasingly important. Theinflammasomes are essential regulators of cytokine production.We investigated whether two polymorphisms in the genes encodingcryopyrin (CIAS1) and TUCAN (CARD8) influence susceptibilityand disease course in RA.

Methods: Genotype frequencies were assessed in 174 Swedish patientswith early RA and 360 population-based controls without rheumaticdisease. Genotypes were categorized according to the presence(+) or absence (–) of two wild-type alleles and comparedbetween patients and controls. In the RA patients, antibodiestowards cyclic citrullinated peptides (anti-CCP) and the ‘sharedepitope’ (SE) were assessed, and medication and measuresof disease activity were monitored regularly during 3 yrs.

Results: The combination of CIAS1/TUCAN/–, ascompared with CIAS1/TUCAN +/+, was significantly more commonamong patients than in controls [odds ratio (OR) 2.2, 95% CI1.03–4.6]. This association was strengthened when patientswere divided into anti-CCP+ [OR 2.8 (1.1–6.7)] or presenceof 1 SE copy [OR 2.8 (1.3–6.2)]. At most time-points duringthe 3-yr follow-up, patients with CIAS1/TUCAN/–showed significantly higher disease activity. Furthermore, CIAS1/TUCAN/– patients proved to be much more likely to receiveTNF-blocking therapy [relative risk 20 (2.6–149)].

Conclusions: Compound polymorphisms in CIAS1 and TUCAN associatewith RA susceptibility and severity. The cryopyrin inflammasomeneeds further attention regarding a possible aetiopathogeneticconnection with RA.

Place, publisher, year, edition, pages
2008. Vol. 47, no 4, 415-417 p.
Keyword [en]
Disease course, Genetics, Inflammasome, Rheumatoid arthritis
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-14380DOI: 10.1093/rheumatology/kem372OAI: oai:DiVA.org:liu-14380DiVA: diva2:23362
Available from: 2007-04-20 Created: 2007-04-20 Last updated: 2015-08-31Bibliographically 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. Autoantibodies and genetic variation in rheumatoid arthritis: aspects on susceptibility and disease course
Open this publication in new window or tab >>Autoantibodies and genetic variation in rheumatoid arthritis: aspects on susceptibility and disease course
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation and subsequent destruction of synovial joints. Although its causes remain largely unknown, a substantial genetic contribution is known to exist. During the last decades the benefits of early aggressive treatment have become evident, and more potent therapeutic options have become available. These advances have increased the demands for rapid accurate diagnosis and prognostic markers of disease course and therapy response.

The ‘rheumatoid factor’ (RF) has long been used as a diagnostic and prognostic marker of RA. In this thesis, the utility of measuring antibodies to cyclic citrullinated peptides (CCP) was investigated. In a population-based arthritis incidence study, 69 very early arthritis patients (symptom duration < 3 months) were identified. The anti-CCP test, performed at baseline and related to diagnosis at the 2-year follow-up, had a diagnostic specificity for RA of 96% and a sensitivity of 44%, both of which were superior to RF. In a prospective cohort of 242 incident cases of RA (symptom duration < 1 year), 64% of the patients tested positive for anti-CCP at baseline (equal to RF). Despite receiving more active anti-rheumatic therapy, the anti-CCP-positive patients had a more aggressive disease course during 3 years as compared to those testing negative.

The 158VV genotype of Fcγ Receptor type IIIA (FcγRIIIA), which binds IgG with higher affinity than 158FF, was associated with an increased susceptibility to RA in men, but not in women. Previous studies report conflicting results, and none stratified according to gender. The 158V/F polymorphism of FcγRIIIA was not found to influence outcome of anti-tumour necrosis factor therapy in 282 RA patients, contradicting hints from previous studies. Genetic variation in proteins of the inflammasome, an interleukin-1 (IL-1) regulating intracellular protein complex, is associated with rare autoinflammatory conditions and possibly with Crohn’s disease. In this first study on genetic variation of the inflammasome in RA, we describe a compound polymorphism of the genes CIAS1 and TUCAN that associates both with susceptibility to RA and to the severity of the disease. Hypothetically, these genes may identify a subgroup of RA patients that would benefit from anti-IL-1 therapy.

This thesis work emphasizes the benefits of testing for anti-CCP in the diagnosis and outcome prediction in early arthritis. FcγRIIIA genotype is likely to affect RA susceptibility and further work should apply a gender perspective. Inflammasome genetics may influence the risk of developing RA. Additional studies are warranted to settle whether it also identifies a subgroup of RA patients benefiting from IL-1 targeted therapy.

Place, publisher, year, edition, pages
Institutionen för molekylär och klinisk medicin, 2007. 73 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 990
Keyword
Rheumatoid arthritis, autoantibodies, single-nucleotide polymorphisms, disease course
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:liu:diva-8618 (URN)978-91-85715-39-8 (ISBN)
Public defence
2007-04-20, Berzeliussalen, CampUS, Universitetssjukhuset i Linköping, Linköping, 09:00 (English)
Opponent
Supervisors
Available from: 2007-04-20 Created: 2007-04-20 Last updated: 2015-08-31
3. 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)
Opponent
Supervisors
Available from: 2011-08-18 Created: 2011-08-18 Last updated: 2011-10-03Bibliographically approved

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