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Functional consequences of DECTIN-1 early stop codon polymorphism Y238X in rheumatoid arthritis.

Plantinga TS, Fransen J, Takahashi N, Stienstra R, van Riel PL, van den Berg WB, Netea MG, Joosten LA - Arthritis Res. Ther. (2010)

Bottom Line: Evaluation of dectin-1 mRNA expression in synovial tissue biopsies revealed an increased expression in RA specimens, compared with biopsies from OA and nonrheumatic patients.However, the presence of the DECTIN-1 Y238X polymorphism was not associated with RA susceptibility or disease severity.Although expression of dectin-1 was high in synovial tissue of RA patients, and reduced cytokine production was observed in macrophages of individuals bearing the DECTIN-1 Y238X polymorphism, loss of one functional allele of DECTIN-1 is not associated with either susceptibility to or severity of RA.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Medicine, Radboud University Nijmegen Medical Centre, P,O, Box 9101, 6500 HB Nijmegen, The Netherlands. t.plantinga@aig.umcn.nl

ABSTRACT

Introduction: Dectin-1, a pattern recognition receptor expressed by the innate immune system, is known to be a major receptor inducing Th17-type adaptive immune responses that have been demonstrated to mediate autoimmunity. In this study, dectin-1 mRNA and protein expression, as well as the recently characterized DECTIN-1 Y238X early stop codon polymorphism, were studied in relation to rheumatoid arthritis (RA) susceptibility and severity.

Methods: Dectin-1 mRNA expression was measured in synovial tissue specimens of RA, osteoarthritis (OA), and nonrheumatic patients. Dectin-1 protein expression and localization were assessed in RA synovial tissue specimens. Macrophages from individuals with different DECTIN-1 genotypes were examined for differences in cytokine responses on dectin-1 stimulation. Furthermore, clinical parameters of inflammation and bone destruction of 262 RA patients were correlated with the presence of the DECTIN-1 Y238X polymorphism.

Results: Evaluation of dectin-1 mRNA expression in synovial tissue biopsies revealed an increased expression in RA specimens, compared with biopsies from OA and nonrheumatic patients. Accordingly, dectin-1 protein expression in RA synovial tissue biopsies was moderate to high, especially on macrophage-like cells. Cytokine production capacity of macrophages bearing the DECTIN-1 Y238X polymorphism was demonstrated to be impaired on dectin-1 stimulation. However, the presence of the DECTIN-1 Y238X polymorphism was not associated with RA susceptibility or disease severity.

Conclusions: Although expression of dectin-1 was high in synovial tissue of RA patients, and reduced cytokine production was observed in macrophages of individuals bearing the DECTIN-1 Y238X polymorphism, loss of one functional allele of DECTIN-1 is not associated with either susceptibility to or severity of RA.

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(a) Dectin-1 mRNA expression of human synovial tissue obtained from six nonrheumatic control individuals, 20 rheumatoid arthritis patients (RAs), and 10 osteoarthritis patients (OAs). Dectin-1 mRNA expression was analyzed with oligonucleotide array (Affymetrix system). Values represent computed expression values. (b) Confirmation of microarray data by qPCR. Data are based on four control samples, seven samples obtained from RA patients, and 6 samples from OA patients. Relative expression is depicted compared with expression of the housekeeping gene GAPDH. Data are expressed as mean ± SD; *P ≤ 0.05; n.s., not significant.
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Figure 1: (a) Dectin-1 mRNA expression of human synovial tissue obtained from six nonrheumatic control individuals, 20 rheumatoid arthritis patients (RAs), and 10 osteoarthritis patients (OAs). Dectin-1 mRNA expression was analyzed with oligonucleotide array (Affymetrix system). Values represent computed expression values. (b) Confirmation of microarray data by qPCR. Data are based on four control samples, seven samples obtained from RA patients, and 6 samples from OA patients. Relative expression is depicted compared with expression of the housekeeping gene GAPDH. Data are expressed as mean ± SD; *P ≤ 0.05; n.s., not significant.

Mentions: To gain insight into the distribution and amount of dectin-1 expression in human synovial tissue, dectin-1 mRNA expression was measured in synovial tissue from RA, OA, and nonrheumatic patients with an oligonucleotide array and reevaluated with quantitative PCR. Microarray analysis revealed a 4-times elevated mRNA expression in RA synovial lesions compared with OA and nonrheumatic synovial tissues (Figure 1a). These findings were confirmed with quantitative PCR (Figure 1b). Furthermore, synovial biopsies from RA patients were immunohistochemically stained for dectin-1 protein expression. Dectin-1 protein appeared to be moderately to highly expressed in RA lesions and was preferentially expressed on the membranes of macrophage-like cells that infiltrated into the synovial tissue, which were present in the synovial sublining and in close proximity to blood vessels (Figure 2).


Functional consequences of DECTIN-1 early stop codon polymorphism Y238X in rheumatoid arthritis.

Plantinga TS, Fransen J, Takahashi N, Stienstra R, van Riel PL, van den Berg WB, Netea MG, Joosten LA - Arthritis Res. Ther. (2010)

(a) Dectin-1 mRNA expression of human synovial tissue obtained from six nonrheumatic control individuals, 20 rheumatoid arthritis patients (RAs), and 10 osteoarthritis patients (OAs). Dectin-1 mRNA expression was analyzed with oligonucleotide array (Affymetrix system). Values represent computed expression values. (b) Confirmation of microarray data by qPCR. Data are based on four control samples, seven samples obtained from RA patients, and 6 samples from OA patients. Relative expression is depicted compared with expression of the housekeeping gene GAPDH. Data are expressed as mean ± SD; *P ≤ 0.05; n.s., not significant.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2875660&req=5

Figure 1: (a) Dectin-1 mRNA expression of human synovial tissue obtained from six nonrheumatic control individuals, 20 rheumatoid arthritis patients (RAs), and 10 osteoarthritis patients (OAs). Dectin-1 mRNA expression was analyzed with oligonucleotide array (Affymetrix system). Values represent computed expression values. (b) Confirmation of microarray data by qPCR. Data are based on four control samples, seven samples obtained from RA patients, and 6 samples from OA patients. Relative expression is depicted compared with expression of the housekeeping gene GAPDH. Data are expressed as mean ± SD; *P ≤ 0.05; n.s., not significant.
Mentions: To gain insight into the distribution and amount of dectin-1 expression in human synovial tissue, dectin-1 mRNA expression was measured in synovial tissue from RA, OA, and nonrheumatic patients with an oligonucleotide array and reevaluated with quantitative PCR. Microarray analysis revealed a 4-times elevated mRNA expression in RA synovial lesions compared with OA and nonrheumatic synovial tissues (Figure 1a). These findings were confirmed with quantitative PCR (Figure 1b). Furthermore, synovial biopsies from RA patients were immunohistochemically stained for dectin-1 protein expression. Dectin-1 protein appeared to be moderately to highly expressed in RA lesions and was preferentially expressed on the membranes of macrophage-like cells that infiltrated into the synovial tissue, which were present in the synovial sublining and in close proximity to blood vessels (Figure 2).

Bottom Line: Evaluation of dectin-1 mRNA expression in synovial tissue biopsies revealed an increased expression in RA specimens, compared with biopsies from OA and nonrheumatic patients.However, the presence of the DECTIN-1 Y238X polymorphism was not associated with RA susceptibility or disease severity.Although expression of dectin-1 was high in synovial tissue of RA patients, and reduced cytokine production was observed in macrophages of individuals bearing the DECTIN-1 Y238X polymorphism, loss of one functional allele of DECTIN-1 is not associated with either susceptibility to or severity of RA.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Medicine, Radboud University Nijmegen Medical Centre, P,O, Box 9101, 6500 HB Nijmegen, The Netherlands. t.plantinga@aig.umcn.nl

ABSTRACT

Introduction: Dectin-1, a pattern recognition receptor expressed by the innate immune system, is known to be a major receptor inducing Th17-type adaptive immune responses that have been demonstrated to mediate autoimmunity. In this study, dectin-1 mRNA and protein expression, as well as the recently characterized DECTIN-1 Y238X early stop codon polymorphism, were studied in relation to rheumatoid arthritis (RA) susceptibility and severity.

Methods: Dectin-1 mRNA expression was measured in synovial tissue specimens of RA, osteoarthritis (OA), and nonrheumatic patients. Dectin-1 protein expression and localization were assessed in RA synovial tissue specimens. Macrophages from individuals with different DECTIN-1 genotypes were examined for differences in cytokine responses on dectin-1 stimulation. Furthermore, clinical parameters of inflammation and bone destruction of 262 RA patients were correlated with the presence of the DECTIN-1 Y238X polymorphism.

Results: Evaluation of dectin-1 mRNA expression in synovial tissue biopsies revealed an increased expression in RA specimens, compared with biopsies from OA and nonrheumatic patients. Accordingly, dectin-1 protein expression in RA synovial tissue biopsies was moderate to high, especially on macrophage-like cells. Cytokine production capacity of macrophages bearing the DECTIN-1 Y238X polymorphism was demonstrated to be impaired on dectin-1 stimulation. However, the presence of the DECTIN-1 Y238X polymorphism was not associated with RA susceptibility or disease severity.

Conclusions: Although expression of dectin-1 was high in synovial tissue of RA patients, and reduced cytokine production was observed in macrophages of individuals bearing the DECTIN-1 Y238X polymorphism, loss of one functional allele of DECTIN-1 is not associated with either susceptibility to or severity of RA.

Show MeSH
Related in: MedlinePlus