[Ovarian cancer with swelling of the right upper arm, amyopathic dermatomyositis, and elevated serum KL-6].
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Aged↗
Biomedical subjects
Akito Tsutsumi
Publications and source records attributed to Akito Tsutsumi.
Diagnosis of chlamydia-induced reactive arthritis.
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Arthritis, Reactive↗
Overexpression of phosphorylated STAT-1alpha in the labial salivary glands of patients with Sjögren's syndrome.
OBJECTIVE: To clarify the molecular mechanisms of Sjögren's syndrome (SS), we analyzed the functional role of the STAT-1 gene, one of the interferon-gamma (IFNgamma)-inducible genes, in labial salivary glands (LSGs) from SS patients. METHODS: The expression of STAT-1 messenger RNA (mRNA) was examined by real-time polymerase chain reaction (PCR) analysis, and the phosphorylation of STAT-1 protein (Tyr(701) and Ser(727) pSTAT-1) was investigated by Western blot and immunohistochemical analyses. The expression of IFNgamma-inducible 10-kd protein (IP-10), IFN regulatory factor 1 (IRF-1), and Fas was also examined by real-time PCR and immunohistochemical analyses. RESULTS: STAT-1alpha and STAT-1beta mRNA were highly expressed in LSGs from SS patients. The level of STAT-1alpha protein in SS LSGs was higher than that in 3 control LSGs, whereas STAT-1beta protein was not clearly detected by Western blot analysis. Moreover, Tyr(701) and Ser(727) pSTAT-1alpha proteins were specifically detected in SS LSGs. Immunohistochemical analysis showed localization of Tyr(701) pSTAT-1 in infiltrating lymphocytes and the adjacent ductal epithelium from SS patients. Ser(727) pSTAT-1 was localized only in the ductal epithelium of SS LSGs. The STAT-1-inducible genes IP-10 and IRF-1 and the Fas genes were highly expressed in SS LSGs and were colocalized with Ser(727) pSTAT-1-positive, but not Tyr(701) pSTAT-1-positive, cells. CONCLUSION: We found evidence of the up-regulation of STAT-1alpha mRNA and protein in LSGs from SS patients, as well as the presence of pSTAT-1alpha in ductal epithelium from SS patients. Our findings suggest that STAT-1alpha, especially Ser(727) pSTAT-1, may function as a key molecule in the pathogenesis of SS.
Gene Expression↗
Low-field compact magnetic resonance imaging system for the hand and wrist in rheumatoid arthritis.
PURPOSE: To investigate the feasibility of an originally developed compact MRI system for evaluating rheumatoid arthritis (RA), and determine its advantages and disadvantages as an imaging modality for evaluating RA. MATERIALS AND METHODS: We prospectively studied 13 healthy controls with no clinical symptoms of arthritis, and 13 patients with hand and wrist pains (including pain from RA) with a 0.2 T permanent-magnet compact MR imager. All MR images were obtained while the subjects were in a sitting position. Coronal three-dimensional spin-echo T1-weighted images and coronal two-dimensional short tau inversion recovery (STIR) images were obtained with image matrix = 256 x 128 and field of view (FOV) = 20.48 cm. Plain radiograph findings and MRI findings of patients were compared. RESULTS: In three of the patients with suspected early RA (N = 7), early RA was evaluated based on STIR images. All RA patients showed morphologic or signal intensity changes that allowed an evaluation of RA from MR findings. Four of five RA patients showed high signal intensity on STIR images in the wrist, proximal interphalangeal (PIP) joint, or metacarpophalangeal (MCP) joint that suggested synovitis. Multiple erosions in the hand and wrist were seen in four RA patients, with low signal intensity on T1-weighted images. CONCLUSION: RA was correctly evaluated, and early RA could be identified with the compact MRI system. However, the current system has limitations, such as the nonselective STIR sequence used and magnetic field inhomogeneity.
Adult↗
Significance of antiprothrombin antibodies in patients with systemic lupus erythematosus: clinical evaluation of the antiprothrombin assay and the antiphosphatidylserine/prothrombin assay, and comparison with other antiphospholipid antibody assays.
Antibodies against prothrombin are detected by enzyme immunoassays (EIA) in sera of patients with antiphospholipid syndrome (APS). However, there are two methods for antiprothrombin EIA; one that uses high binding plates (aPT-A), and another that utilizes phosphatidylserine bound plates (aPS/PT). We aimed to evaluate and compare aPT-A and aPS/PT in a clinical setting. We performed EIA for anti-PT, anti-PS/PT, IgG, and IgM anticardiolipin antibodies (aCL), and IgG beta2-glycoprotein I-dependent aCL (abeta2GPI/CL) with serum samples from 139 systemic lupus erythematosus (SLE) patients (16 with history of at least one thrombotic episode) and 148 controls. We observed that: (1) although titers of anti-PT and anti-PS/PT were significantly related with each other (P < 0.0001, rho = 0.548), titer of anti-PT and anti-PS/PT differed greatly in some samples; (2) odds ratio and 95% confidence interval for each assay was 3.556 (1.221-10.355) for aPT-A, 4.591 (1.555-15.560) for aPS/PT, 4.204 (1.250-14.148) for IgG aCL, 1.809 (0.354-9.232) for IgM aCL, and 7.246 (2.391-21.966) for abeta2GPI/CL. We conclude that, while all EIA performed in this study except IgM aCL are of potential value in assessing the risk of thrombosis, aPS/PT and abeta2GPI/CL seemed to be highly valuable in clinical practice, and that autoantibodies detected by anti-PT and anti-PS/PT are not completely identical.
Antibodies, Antiphospholipid↗
Altered peptide ligands control type II collagen-reactive T cells from rheumatoid arthritis patients.
We previously reported that peripheral blood mononuclear cells from HLA-DRB1*0101 Japanese patients with rheumatoid arthritis (RA) were highly reactive to 256-271 peptide of type II collagen (CII). In this report, we tried to regulate the CII reactivity of T cells from RA patients with HLA-DRB1*0101 by altered peptide ligand (APL), which is a single amino acid substitution of the T-cell epitope on CII 256-271 peptide. Antagonistic activity of 21 APLs was assessed using three different T-cell lines. Results showed that 262 (G-->A) APL of CII 256-271 exhibited antagonistic activity in all T-cell lines and it was suggested that the application of CII APL might be a new therapeutic strategy in the regulation of RA.
Amino Acid Sequence↗
T cell receptor BV gene repertoire of lymphocytes in bronchoalveolar lavage fluid of polymyositis/dermatomyositis patients with interstitial pneumonitis.
We analyzed the T cell receptor (TCR) repertoire of bronchoalveolar lavage fluid (BALF) lymphocytes from polymyositis (PM) and dermatomyositis (DM) patients with interstitial pneumonitis (IP) to elucidate the pathogenic mechanisms of IP in these disorders. Samples from 2 PM patients, 1 DM patient and 3 healthy controls were used. RNA was isolated from BALF, cDNAs were synthesized, and family PCR and Southern blot analysis were performed by primers specific for TCR BV1-25 and TCR BC to determine TCR repertoire. We examined single-strand conformation polymorphism (SSCP) to evaluate T cell clonality. The CDR3 region of TCR BV genes in BALF T cells were determined by DNA sequencer. Our examination showed that TCR repertoire of T cells in BALF was heterogeneous both in patients with PM/DM and control subjects. SSCP analysis demonstrated an increased number of accumulated T cell clones in BALF of three PM/DM patients, but not in the healthy subjects and the junctional sequence analysis showed the presence of conserved amino acid motifs (RGS, GLA, LQG, SGG, DRG, GTS, TSGR, GGS, GQA, GAG, GTG) in the TCR-CDR3 region of BALF lymphocytes from PM/DM patients, which were not detected in the control. Our findings suggest that T cells in BALF may recognize the restricted antigen and accumulate via antigen-driven stimulation, suggesting that T cells may play a crucial role in the development of IP in patients with PM/DM.
Adult↗
Gene transduction of tristetraprolin or its active domain reduces TNF-alpha production by Jurkat T cells.
Tristetraprolin (TTP) is a physiological regulator of tumor necrosis factor (TNF)-alpha production. It destabilizes TNF-alpha mRNA by binding to the AU-rich element located in the 3' region of TNF-alpha mRNA. We wished to determine how transducing the TTP gene or its fragment gene encoding its biological active site, the tandem zinc finger (TZF) domain, affects TNF-alpha production, cell viability and growth of Jurkat T cells. Jurkat T cells were transduced with either the TTP or the TZF gene using retrovirus vectors. Cell growth and apoptosis was analyzed. Expression of genes before or after appropriate stimuli was measured by real-time PCR. In addition, production of the TNF-alpha protein was measured by enzyme immunoassay. The transduction of either gene reduced TNF-alpha mRNA levels under unstimulated conditions, and reduced the response to phytohemagglutinin stimulation. Production of TNF-alpha protein upon stimulation was also decreased in TTP/TZF-transduced cells. Transduction of either gene also affected the expression of granulocyte-macrophage colony-stimulating factor mRNA in a similar fashion, but not that of c-myc. The growth rate of TTP-transduced Jurkat T cells tended to be slower than that of TZF- or mock-transduced cells. TTP-transduced cells were more susceptible to campthothecin-induced apoptosis than others. Our results indicate that either TTP or TZF gene transduction using retrovirus vectors can reduce the production of TNF-alpha in Jurkat T cells although some differences were noted between TTP and TZF in cell growth and occurrence of apoptosis. These results suggest that TTP may be a potential target for new therapies against RA.
Animals↗
Expression of TNF-alpha, tristetraprolin, T-cell intracellular antigen-1 and Hu antigen R genes in synovium of patients with rheumatoid arthritis.
Post-transcriptional regulation through the AU-rich element (ARE) by ARE binding proteins (ARBPs) has an important role in controlling the production of cytokines, including tumor necrosis factor (TNF)-alpha. Therefore, expression of ARBPs may influence, or may be influenced, by the severity of rheumatoid arthritis (RA). We measured the gene expression of ARBPs, including tristetraprolin, T-cell intracellular antigen (TIA)-1 and Hu antigen R (HuR), in synovial tissues from RA and osteoarthritis patients. cDNA was constructed from synovial tissues obtained from 21 patients with RA, and those from 12 patients with osteoarthritis. Gene expression was measured using the TaqMan PCR real-time quantification method. No significant differences were observed in the expression of tristetraprolin, TIA-1 or HuR genes between RA and osteo-arthritis synovium samples. No significant relationships between expression of tristetraprolin, TIA-1 or HuR genes and TNF-alpha gene expression serum CRP levels in samples from RA patients were observed. A significant positive relationship was observed between gene expression levels of TIA-1 and HuR. While HuR stabilizes TNF-alpha mRNA and enhances TNF-alpha production, TIA-1 acts as a post-transcriptional silencer, and suppresses the production of the TNF-alpha protein. The clear positive relationship between the expression of these two ARBPs may imply that the expression of either gene affects the expression of the other, or the mechanisms that control the expression of these genes have some factors in common.
Aged↗
Antigenic structures recognized by anti-beta2-glycoprotein I auto-antibodies.
Beta2-glycoprotein I (beta2-GPI) is a major antigen for anti-cardiolipin antibodies and their epitopes are cryptic. Conformation of each domain of beta2-GPI was optimized from its crystal structure by energy minimization and by molecular dynamics simulation. Three electrostatic interactions, i.e. D193-K246, D222-K317 and E228-K308, were observed between domains IV and V in the optimized structure that was constructed based on the consensus sequences obtained by the phage-displayed random peptide library. Antigenic structures determined by the epitope mapping mainly consisted of hydrophobic amino acids located on two discontinuous sequences in domain IV. These amino acid clusters, as an epitope, were covered by domain V and were of a hidden nature. A similar but incomplete counterpart to the epitopic clusters was found in domain I but was not in domains II or III. Binding of anti-beta2-GPI auto-antibodies to solid-phase beta2-GPI was significantly reduced either by L replacement for W235, a common amino acid component for the epitopes, or by V replacement for all of D193, D222 and E228. Structural analysis indicated a hypothesis that these electrostatic interactions between domains IV and V retained exposure to W235 and that epitope spreading occurred in the region surrounding W235. Thus, epitopic structures recognized by anti-beta2-GPI auto-antibodies are cryptic and inter-domain electrostatic interactions are involved in their in exposure.
Amino Acid Substitution↗
A functional variant of Fcgamma receptor IIIA is associated with rheumatoid arthritis in individuals who are positive for anti-glucose-6-phosphate isomerase antibodies.
Anti-glucose-6-phosphate isomerase (GPI) antibodies are known to be arthritogenic autoantibodies in K/BxN mice, although some groups have reported that few healthy humans retain these antibodies. The expression of Fcgamma receptors (FcgammaRs) is genetically regulated and has strong implications for the development of experimental arthritis. The interaction between immune complexes and FcgammaRs might therefore be involved in the pathogenesis of some arthritic conditions. To explore the relationship between functional polymorphisms in FcgammaRs (FCGR3A-158V/F and FCGR2A-131H/R) and arthritis in individuals positive for anti-GPI antibodies, we evaluated these individuals with respect to FCGR genotype. Genotyping for FCGR3A-158V/F and FCGR2A-131H/R was performed by PCR amplification of the polymorphic site, followed by site specific restriction digestion using the genome of 187 Japanese patients with rheumatoid arthritis (including 23 who were anti-GPI antibody positive) and 158 Japanese healthy individuals (including nine who were anti-GPI antibody positive). We report here on the association of FCGR3A-158V/F functional polymorphism with anti-GPI antibody positive status. Eight out of nine healthy individuals who were positive for anti-GPI antibodies possessed the homozygous, low affinity genotype FCGR3A-158F (odds ratio = 0.09, 95% confidence interval 0.01-0.89; P = 0.0199), and probably were 'protected' from arthritogenic antibodies. Moreover, among those who were homozygous for the high affinity genotype FCGR3A-158V/V, there were clear differences in anti-human and anti-rabbit GPI titres between patients with rheumatoid arthritis and healthy subjects (P = 0.0027 and P = 0.0015, respectively). Our findings provide a molecular model of the genetic regulation of autoantibody-induced arthritis by allele-specific affinity of the FcgammaRs.
Adult↗
Mannose binding lectin: genetics and autoimmune disease.
Mannose binding lectin (MBL) is a serum protein with structure and functions similar to those of complement factor C1q, and is a key molecule in innate immunity. Interestingly, absence or extremely low concentration of serum MBL (MBL deficiency) seems to be a risk factor for occurrence of autoimmune diseases, in particular systemic lupus erythematosus. In addition, individuals with MBL deficiency are at risk of infection when in immunocompromised conditions. The concentration of serum MBL is greatly influenced by relatively common single nucleotide polymorphisms of the MBL gene. Therefore, typing of the MBL gene, or measurement of serum MBL may be valuable for determining the risk of infections in patients with systemic autoimmune diseases, who frequently undergo immunosuppressive therapies. MBL deficiency may also be a risk factor for atherosclerosis and arterial thrombosis, both being common complications of autoimmune diseases. On the other hand, MBL may be pathological in tissue injuries, and the precise roles of MBL in autoimmune diseases, and the value of MBL gene typing or serum MBL measurement in a clinical setting are yet to be clarified. Recently, presence of anti-MBL autoantibodies in sera of SLE patients has been reported. The significance of this autoantibody remains to be elucidated.
Animals↗
Clinical characteristics of anti-glucose-6-phosphate isomerase antibody-positive Japanese patients with rheumatoid arthritis.
Anti-glucose-6-phosphate isomerase (GPI) antibodies (Abs) are known to be arthritogenic in mice. These Abs are elevated in several forms of arthritic condition in humans, although their prevalence in rheumatoid arthritis (RA) patients is still in debate. Some RA patients have increased levels of anti-GPI Abs, but their clinical manifestation and relevance to other Abs are not clearly elucidated. The aims of this study were to explore the clinical and hematological characteristics of RA with anti-GPI Abs, and to compare their prevalence in RA patients, systemic lupus erythematosus (SLE) patients, and healthy subjects (HS) in a Japanese population. Anti-GPI Abs were positive in 16 patients with RA (12%, n = 137), in 10 patients with SLE (8%, n = 131), and in 6 HS (4%, n = 139). C-reactive protein (CRP), immunoglobulin G, and the antinuclear antibody titer were higher in anti-GPI-positive patients than in those who were negative (P = 0.049, P = 0.0003, and P = 0.002, respectively). Moreover, the positivity of anti-GPI Abs was correlated with CRP more than with rheumatoid factor in RA patients. It is unclear whether anti-GPI Abs can predict the progress of disease, but the prevalence of these Abs was higher in active RA patients with severe arthritis, suggesting that anti-GPI Abs may be related to the pathogenesis of severe forms of arthritis.
Journal Article↗
Lack of relationship between mannose-binding lectin variant alleles and risk of arterial thrombosis in Japanese patients with systemic lupus erythematosus.
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Letter↗
Identification of three novel peptides that inhibit CD40-CD154 interaction.
The CD40-CD154 interaction is an attractive target for therapeutic intervention in various autoimmune disorders, including rheumatoid arthritis, systemic lupus erythematosus (SLE), multiple sclerosis, and myasthenia gravis. In this study, to develop a new disruption strategy of the CD40-CD154 interaction, we screened for peptides with inhibitory effects on such ligation. 2 x 10(11) phage display libraries displaying liner peptides of 12-mer amino acids were screened by CD40-Ig binding assay and eight phages which expressed a different respective peptide (40BP-1 to -8) were able to specifically bind to CD40. Competitive inhibition analyses showed that 3 of the 8 peptides (40BP-N1-1 - APELPNMTPSWT; 40BP-N1-2 - APRPHTSYSPLP; and 40BP-N1-3 - GMTAPPPPRLTQ) blocked CD40-CD154 interaction when used at high concentrations. A consensus sequence (APxPPxxT) was conserved in these three peptides. These peptides may constitute a useful and novel strategy for the inhibition of the interaction between CD40 and CD154 molecules.
Journal Article↗
Immunoglobulin G from anti-glucose-6-phosphate isomerase antibodies positive patient with rheumatoid arthritis induces synovitis in cynomolgus monkeys.
Anti-glucose-6-phosphate isomerase (GPI) antibodies (Abs) solely induce arthritis in mice. High titers of anti-GPI Abs are found in some patients with rheumatoid arthritis (RA), but their pathogenic role remains elusive. The aim of this study was to evaluate the pathogenic role of anti-GPI Abs in cynomolgus monkeys. IgG fractions were separated from sera of anti-GPI Abs-positive RA patients and healthy subjects and directly injected into the metacarpophalangeal joints of 4 cynomolgus monkeys. At day 16, the joints were harvested and examined histologically and immunohistochemically. The expression of C5a receptor (C5aR) molecule in the synovium was quantified by real-time PCR using cDNA from monkey joints. In monkey joints, IgG including anti-GPI Abs resulted in recruitment of granulocytes and mononuclear cells, strong deposition of human IgG on the articular surface, and overexpression of C5aR, but no joint swelling. No infiltrated cells or IgG deposition were observed in monkeys injected with IgGs from healthy subjects. Our results suggest that IgG fraction from RA patients including anti-GPI Abs may play a crucial role in the generation of synovitis in monkeys, although the pathogenesis of anti-GPI Abs in RA patients is still uncertain.
Animals↗
Two cases of systemic lupus erythematosus complicated with colonic ulcers.
We report two cases of systemic lupus erythematosus (SLE) complicated with colonic ulcerations. One patient was successfully cured by steroid therapy, while the other did not respond to steroid but oral mesalazine was effective. Systemic lupus erythematosus is frequently accompanied by gastrointestinal symptoms, but colonic lesions are quite rare, and the regular treatment is not fixed yet. The high-dose steroidal regimen may be effective for microvasculitis, although it may increase the risk of perforated ulcer of the intestinal tract, which is a life-threatening complication. Further analysis of its outcomes, and establishment of the regular guideline for its treatment are expected.
Adult↗
Analysis of abnormally expressed genes in synovium from patients with rheumatoid arthritis using a column gel electrophoresis-coupled subtractive hybridization technique.
Rheumatoid arthritis (RA) is a chronic disease of unknown pathogenesis. To identify abnormally expressed genes in synovium from RA patients, we performed column gel electrophoresis-coupled subtractive hybridization (CGESH). CGESH is a newly developed subtractive hybridization technique to achieve sufficient enrichment of DNA sequences. CGESH was performed using restricted enzyme digested cDNA synthesized from mRNA of synovial tissues from one RA patient and one osteoarthritis (OA) patient. The obtained subtraction libraries (RA-OA) were screened by dot blot hybridization. The clones showing higher hybridization with the RA-OA probe were identified by sequence analysis and homology search. Their DNA sequencing revealed that the genes of HLA-DRB1, sequestosome 1, elongation factor 1alpha were included. Furthermore, a functionally unknown gene (FLJ00133) was also identified. It is reported that sequestosome 1 is a scaffold in the signal transduction of TNFalpha and interleukin 1, which are the important cytokines involved in the pathogenesis of RA. It is possible that other genes identified by the CGESH technique would be associated with the pathogenesis of RA, although there is no direct evidence yet. Our results imply that the CGESH technique is a useful tool to detect genes involved in the pathogenesis of RA. Further investigation of the functional roles of candidate genes should shed light on the pathogenesis of RA.
Arthritis, Rheumatoid↗