Publications (47) View all
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Article: The Contribution of SAA1 Polymorphisms to Familial Mediterranean Fever Susceptibility in the Japanese Population.
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ABSTRACT: Familial Mediterranean Fever (FMF) has traditionally been considered to be an autosomal-recessive disease, however, it has been observed that substantial numbers of patients with FMF possess only 1 demonstrable MEFV mutation. The clinical profile of familial Mediterranean fever (FMF) may be influenced by MEFV allelic heterogeneity and other genetic and/or environmental factors. In view of the inflammatory nature of FMF, we investigated whether serum amyloid A (SAA) and interleukin-1 beta (IL-1β) gene polymorphisms may affect the susceptibility of Japanese patients with FMF. The genotypes of the -13C/T SNP in the 5'-flanking region of the SAA1 gene and the two SNPs within exon 3 of SAA1 (2995C/T and 3010C/T polymorphisms) were determined in 83 Japanese patients with FMF and 200 healthy controls. The same samples were genotyped for IL-1β-511 (C/T) and IL-1 receptor antagonist (IL-1Ra) variable number of tandem repeat (VNTR) polymorphisms. There were no significant differences between FMF patients and healthy subjects in the genotypic distribution of IL-1β -511 (C/T), IL-1Ra VNTR and SAA2 polymorphisms. The frequencies of SAA1.1 allele were significantly lower (21.7% versus 34.0%), and inversely the frequencies of SAA1.3 allele were higher (48.8% versus 37.5%) in FMF patients compared with healthy subjects. The frequency of -13T alleles, associated with the SAA1.3 allele in the Japanese population, was significantly higher (56.0% versus 41.0%, p = 0.001) in FMF patients compared with healthy subjects. Our data indicate that SAA1 gene polymorphisms, consisting of -13T/C SNP in the 5'-flanking region and SNPs within exon 3 (2995C/T and 3010C/T polymorphisms) of SAA1 gene, are associated with susceptibility to FMF in the Japanese population.PLoS ONE 01/2013; 8(2):e55227. · 4.09 Impact Factor -
Article: Increased expression of a short splice variant of CTLA-4 exacerbates lupus in MRL/lpr mice.
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ABSTRACT: BACKGROUND.: CTLA-4 is a negative regulator of the immune response expressed by regulatory T cells and activated T cells. Polymorphisms in the CTLA4 gene have been associated with autoimmune diseases including systemic lupus erythematosus. Disease-associated polymorphisms have been shown to affect the production of the different CTLA-4 variants through an effect on alternative splicing. METHODS.: We have generated a MRL/lpr mouse strain that transgenically over-expresses a short isoform of CTLA-4 (1/4 CTLA-4) by backcrossing C57BL/6.1/4CTLA4 transgenic mice into the MRL/lpr strain for 9 generations. A new antibody was generated to detect the expression of the 1/4 CTLA-4 isoform. Routine methods were used to evaluate kidney pathology, humoral and cellular immunity. RESULTS.: We show that expression of the 1/4 CTLA-4 isoform accelerates autoimmune disease. Transgenic mice display early onset of mortality, increased renal pathology and higher titers of anti-DNA antibodies, when compared to wild type MRL/lpr mice. Acceleration of autoimmunity and disease pathology by the presence of the short (1/4) isoform of CTLA-4 was linked to increased numbers of activated T cells and B cells and heightened interferon gamma production, but not to altered expression of the full length CTLA-4 molecule or regulatory T cell numbers. CONCLUSIONS.: Our results indicate that the presence of the alternatively spliced 1/4 CTLA-4 isoform can further promote autoimmunity and autoimmune pathology in lupus-prone mice and suggest that altered splicing of CTLA4 contributes to the expression of autoimmune disease. © 2012 American College of Rheumatology.Arthritis & Rheumatism 11/2012; · 7.87 Impact Factor -
Article: Calcium/Calmodulin-Dependent Protein Kinase IV Suppresses IL-2 Production and Regulatory T Cell Activity in Lupus.
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ABSTRACT: The activity of calcium/calmodulin-dependent protein kinase IV (CaMK4) is increased in T cells from patients with systemic lupus erythematosus (SLE) and has been shown to reduce IL-2 production by promoting the effect of the transcriptional repressor cAMP responsive element modulator-α on the IL2 promoter. In this article, we demonstrate that T cells from MRL/lpr mice display increased levels of CaMK4 in the nucleus, and that genetic deletion of Camk4 results in improved survival. We demonstrate that absence of CaMK4 restores IL-2 production, curbs increased T cell activation, and augments the number and activity of regulatory T cells. Analogously, silencing of CaMK4 in T cells from patients with SLE increases the expression of FoxP3 on stimulation in the presence of TGF-β. Our results demonstrate the importance of the serine/threonine kinase CaMK4 in the generation and function of regulatory T cells in patients with SLE and lupus-prone mice, and its potential to serve as a therapeutic target.The Journal of Immunology 08/2012; 189(7):3490-6. · 5.79 Impact Factor -
Article: Significant improvement in MRI-proven bone edema is associated with protection from structural damage in very early RA patients managed using the tight control approach.
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ABSTRACT: OBJECTIVE: To identify the value of magnetic resonance imaging (MRI)-proven bone edema in patients with very early rheumatoid arthritis (RA). METHODS: All of the 13 patients included in the study were positive at entry for MRI-proven bone edema of the wrist and finger joints and anti-cyclic citrullinated peptide antibodies or IgM-rheumatoid factor. A tight control approach was applied for 12 months. Plain MRI and radiographs of both wrist and finger joints were examined every 6 months. MRI was scored by the RA MRI scoring (RAMRIS) technique and plain radiographs were scored using the Genant-modified Sharp score. Variables that were correlated with plain radiographic changes at 12 months were examined. RESULTS: Simplified disease activity index (SDAI) remission was achieved in 7 patients, and a significant reduction in the RAMRIS bone edema score, which declined to <33 % as compared with the baseline, was achieved in 8 out of 13 patients. Four patients showed plain radiographic progression while 9 patients did not. Significant reductions in the RAMRIS bone edema score (p = 0.007) and the time-integrated SDAI (p = 0.031) were the variables involved in plain radiographic progression. CONCLUSIONS: Improvement in bone edema may be associated with protection against structural damage in very early RA patients managed using the tight control approach.Modern Rheumatology 06/2012; · 1.58 Impact Factor -
Article: Serum amyloid A triggers the mosodium urate -mediated mature interleukin-1β production from human synovial fibroblasts.
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ABSTRACT: Monosodium urate (MSU) has been shown to promote inflammasome activation and interleukin-1β (IL-1β) secretion in monocyte/macrophages, but the cellular pathway and nod-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome activation in synovial tissues, remain elusive. In this study, we investigated the effects of MSU on synovial fibroblasts to elucidate the process of MSU-mediated synovial inflammation. Human synovial fibroblasts were stimulated with MSU in the presence or absence of serum amyloid A (SAA). The cellular supernatants were analyzed by immunoblotting using anti-IL-1β or anti-caspase-1 antibodies. IL-1β or NLRP3 mRNA expressions were analyzed by real-time PCR or reverse transcription-PCR (RT-PCR) method. Neither SAA nor MSU stimulation resulted in IL-1β or interleukin-1α (IL-1α) secretions and pro-IL-1β processing in synovial fibroblasts. However, in SAA-primed synovial fibroblasts, MSU stimulation resulted in the activation of caspase-1 and production of active IL-1β and IL-1α. The effect of SAA on IL-1β induction was impaired in cells by silencing NLRP3 using siRNA or treating with caspase-1 inhibitor. In addition, SAA induced the secretion of cathepsin B and NLRP3 mRNA expression in synovial fibroblasts. Our data demonstrate that exposure of human synovial fibroblasts to SAA promotes MSU-mediated caspase-1 activation and IL-1β secretion in the absence of microbial stimulation. These findings provide insight into the molecular processes underlying the synovial inflammatory condition of gout.Arthritis research & therapy 05/2012; 14(3):R119. · 4.27 Impact Factor
