Functional consequences of DECTIN-1 early stop codon polymorphism Y238X in rheumatoid arthritis.
BACKGROUND
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.
Plantinga
Theo S
TS
Department of Medicine, Radboud University Nijmegen Medical Centre, P,O, Box 9101, 6500 HB Nijmegen, The Netherlands. t.plantinga@aig.umcn.nl
Fransen
Jaap
J
Takahashi
Nozomi
N
Stienstra
Rinke
R
van Riel
Piet L
PL
van den Berg
Wim B
WB
Netea
Mihai G
MG
Joosten
Leo Ab
LA
D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000378:metabolism; D018388:Codon, Terminator; D004797:Enzyme-Linked Immunosorbent Assay; D015870:Gene Expression; D020022:Genetic Predisposition to Disease; D006801:Humans; D007150:Immunohistochemistry; D037181:Lectins, C-Type; D008565:Membrane Proteins / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013583:Synovial Membrane / Q000378:metabolism; D000099181:Dectin-1
D018388:Codon, Terminator; D037181:Lectins, C-Type; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D000099181:Dectin-1