Developmental Considerations of Sperm Protein 17 Gene Expression in Rheumatoid Arthritis Synoviocytes

Rheumatoid arthritis (RA) is an autoimmune disease characterized by proliferative synovial tissue. We used mRNA differential display and library subtraction to compare mRNA expression in RA and osteoarthritis (OA) synoviocytes. We initially compared the mRNA expression patterns in 1 female RA and 1 OA synovia and found a differentially expressed 350 bp transcript in the RA synoviocytes which was, by sequence analysis, 100% homologous to sperm protein 17 (Sp17). Moreover, the Sp17 transcript was found differentially expressed in a RA synovial library that was subtracted with an OA synovial library. Using specific primers for full length Sp17, a 1.1 kb transcript was amplified from the synoviocytes of 7 additional female RA patients, sequenced and found to 100% homologous to Sp17. Thus, we found the unexpected expression of Sp17, a thought to be gamete-specific protein, in the synoviocytes of 8/8 female RA patients in contrast to control OA synoviocytes. Interestingly, Sp17's structural relationship with cell-binding and recognition proteins, suggests that Sp17 may function in cell-cell recognition and signaling in the RA synoviocyte. Further, Sp17 could have a significant regulatory role in RA synoviocyte gene transcription and/or signal transduction. Thus, Sp17 could have an important role in RA synoviocyte proliferation or defective apoptosis. Finally, the presence of Sp17 in synoviocytes has interesting developmental considerations

A Comparative Analysis of the Murine Thymic Microenvironment in Normal, Autoimmune, and Immunodeficiency States

It is widely accepted that the thymic microenvironment regulates normal thymopoiesis through a highly coordinated and complex series of cellular and cytokine interactions. A direct corollary of this is that abnormalities within the microenvironment could be of etiologic significance in T-cell-based diseases. Our laboratory has developed a large panel of monoclonal antibodies (mAbs) that react specifically with epithelial or nonepithelial markers in the thymus. We have taken advantage of these reagents to characterize the thymic microenvironment of several genetic strains of mice, including BALB/cJ, C57BL/6J, NZB/BlnJ, SM/J, NOD/Ltz, NOD/Ltz-scid/sz, C57BL/6J-Hcph me/Hcph me, and ALY/NscJcl-aly/aly mice, and littermate control animals. We report herein that control mice, including strains of several backgrounds, have a very consistent phenotypic profile with this panel of monoclonal antibodies, including reactivity with thymic epithelial cells in the cortex, the medulla and the corticomedullary junction, and the extracellular matrix. In contrast, the disease-prone strains studied have unique, abnormal staining of thymic cortex and medulla at both the structural and cellular levels. These phenotypic data suggest that abnormalities in interactions between developing thymocytes and stromal cells characterize disease-prone mice

Rebamipide, an Amino Acid Analog of 2(1H)-Quinolinone, Inhibits the Formation of Human Osteoclasts

Objectives. Drug repositioning or drug reprofiling (DR) has recently been growing in importance. DR has a significant advantage over traditional drug development because the repositioned drug has already passed toxicity tests; its safety is known, and the risk of adverse toxicology is reduced. In the current study, we investigated the role of rebamipide, a mucosa-protecting agent, with recently reported anti-inflammatory function, in human osteoclastogenesis. Methods. Peripheral blood mononuclear cells (PBMCs) were cultured in the presence of M-CSF and sRANKL. Osteoclast formation was evaluated by immunohistological staining for CD51/61 (vitronectin receptors). Osteoclast formation, in the presence or absence of rebamipide (0, 1, and 3 mM), was observed by time-lapse photography and actin ring formation. The number of absorption sites and area of absorption were calculated using Osteologic™ plates. Pit formation was studied by 3D-SEM. Results. Rebamipide inhibited human osteoclast formation at 3 mM, a pharmacological concentration, and inhibited resorbing activity dose-dependently. Rebamipide induced the degradation of actin rings in mature osteoclasts. This mechanism may involve inhibiting the osteoclast fusion pathway through reducing the expression of DC-specific transmembrane protein (DC-STAMP). Conclusions. The present study suggests that rebamipide would be useful as a novel agent for osteoporosis and rheumatoid arthritis

Ratio of Circulating IFNγ+ “Th17 Cells” in Memory Th Cells Is Inversely Correlated with the Titer of Anti-CCP Antibodies in Early-Onset Rheumatoid Arthritis Patients Based on Flow Cytometry Methods of the Human Immunology Project

Rheumatoid arthritis (RA) is a systemic autoimmune disease with chronic joint inflammation characterized by activated T cells. IL-17 and Th17 cells play important roles in the pathogenesis of RA. Recently, plasticity in helper T cells has been demonstrated; Th17 cells can convert to Th1 cells. However, it remains to be elucidated whether this conversion occurs in the early phase of RA. Here, we validated the methods of the Human Immunology Project using only the cell-surface marker through measuring the actual expression of IL-17 and IFNγ. We also evaluated the expression of CD161 in human Th17 cells. We then tried to identify Th17 cells, IL-17+Th17 cells, and IFNγ+Th17 cells in the peripheral blood of early-onset RA patients using the standardized method of the Human Immunology Project. Our findings validated the method and the expression of CD161. The ratio of IFNγ+Th17 cells in memory T cells was inversely correlated to the titers of anti-CCP antibodies in the early-onset RA patients. These findings suggest that Th17 cells play important roles in the early phase of RA and that anti-IL-17 antibodies should be administered to patients with early phase RA, especially those with high titers of CCP antibodies

Elevated Ratio of Th17 Cell-Derived Th1 Cells (CD161+Th1 Cells) to CD161+Th17 Cells in Peripheral Blood of Early-Onset Rheumatoid Arthritis Patients

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by the destruction of articular cartilage and bone with elevated levels of proinflammatory cytokines. It has been reported that IL-17 and Th17 cells play important roles in the pathogenesis of RA. Recently, plasticity in helper T cells has been demonstrated; Th17 cells can convert to Th1 cells. It remains to be elucidated whether this conversion occurs in the early phase of RA. Here, we tried to identify Th17 cells, Th1 cells, and Th17 cell-derived Th1 cells (CD161+Th1 cells) in the peripheral blood of early-onset RA patients. We also evaluated the effect of methotrexate on the ratio of Th17 cells in early-onset RA patients. The ratio of Th17 cell-derived Th1 cells to CD161+Th17 cells was elevated in the peripheral blood of early-onset RA patients. In addition, MTX reduced the ratio of Th17 cells but not Th1 cells. These findings suggest that IL-17 and Th17 play important roles in the early phase of RA; thus, anti-IL-17 antibodies should be administered to patients with RA in the early phase

IL-23 and Th17 Disease in Inflammatory Arthritis

IL-23, which is composed of p19 and p40 subunits, is a proinflammatory cytokine that contributes to the formation and maintenance of Th17 cells in inflammatory autoimmune diseases. IL-23 is a human osteoclastogenic cytokine and anti-IL-23 antibody attenuates paw volume and joint destruction in CIA rats. IL-23 levels in serum and synovial fluid are high in rheumatoid arthritis (RA) patients, and IL-23 may be a useful biomarker for the diagnosis of RA. In addition, IL-23 affects the pathogenesis of inflammation and bone destruction through interaction with other cytokines such as IL-17 and TNF-α. Furthermore, polymorphisms of IL23R are a risk factor for ankylosing spondylitis (AS) and psoriatic arthritis (PsA), which indicates that IL-23 is also involved in the pathogenesis of spondyloarthritis (SpA). Finally, IL-17 and IL-23 inhibitors reduce the clinical manifestations of SpA. Thus, the IL-23/Th17 pathway is a therapeutic target for the treatment of inflammatory arthritis

経尿道的前立腺切除術後の感染症に対する経口抗菌剤Levofloxacin予防的投与の効果の検討

われわれは前立腺肥大症患者98例を,リスク群(術前尿路感染症を有する患者および糖尿病患者)と非リスク群とに分け,経尿道的前立腺切除術(TURP)後感染症に対する経口剤の予防的効果を検討した.術後急性期(手術日を含め7日以内)の化学療法は,リスク経口群(Ia群)ではlevofloxacin(LVFX)600mg/日を7日間,非リスク経口群(IIa群)ではLVFX400mg/日を2日間およびLVFX200mg/日を5日間投与した.対照として,リスク点滴静注群(Ib群)および非リスク点滴静注群(IIb群)では2日間のみ抗生剤の点滴静注を行い,3日から7日までは経口群(IaおよびIIa群)と同様とした.また創傷治癒期(術後7日目以降)には,4群ともにLVFX100mgを就寝前に1回服用させ,膿尿が白血球10コ/high power field以下になるまで継続した,感染症については,38.0℃以上の発熱および尿路性器感染症の有無を検討した.急性期感染症を示した症例は,Ia群(n=11):9.1%,Ib群(n=16):18.8%,IIa群(n=39):15.4%,IIb群(n=32):12.5%であった.創傷治癒期感染症は,検討できた63例のうち,リスク群(Ia+Ib群,n=15):20.0%,非リスク群(IIa+IIb群,n=48):16.7%であった.術後急性期における経口抗菌剤LVFXによる化学療法は,リスク症例,非リスク症例ともに,注射用抗生物質を併用した群に比べ感染症発症頻度に有意差を認めず,有用であった.また創傷治癒期においても,LVFXの少量就寝前1回投与法は,安全で有用であると考えられた.Recently, oral antibiotics have been evaluated in place of parenteral antibiotics for prophylactic chemotherapy against infections after transurethral resection of the prostate (TURP). We studied the prophylactic effect of levofloxacin (LVFX) on infections following TURP in 98 patients with prostatic hypertrophy. The subjects were divided into a high-risk group (patients with preoperative urinary tract infection and/or diabetes mellitus) and a low-risk group. For postoperative acute-phase prophylaxis (within 7 days of surgery), 600 mg/day of LVFX was administered orally in the high-risk oral group (Group Ia) and 200～400 mg/day was given in the low-risk oral group (Group IIa). A parenteral antibacterial agent was initially administered for 2 days in the high-risk intravenous group (Group Ib) and the low-risk intravenous group (Group IIb), after which they subsequently received the oral LVFX regimens mentioned above. In the healing phase (from postoperative day 8 onwards), 100 mg of LVFX was administered orally before bedtime until the disappearance of pyuria (less than 10 WBC/HPF) in all groups. The percentage of patients with acute phase infection was 9.1% in Group Ia (n=11), 18.8% in Group Ib (n=16), 15.4% in Group IIa (n=39), and 12.5% in Group IIb (n=32). The percentage of patients with healing phase infections was 20.0% in the high-risk group (Ia+Ib, n=15) and 16.7% in the low-risk group (IIa+IIb, n=48). Oral LVFX therapy was useful for the prevention of acute phase infections in both the high-risk group and the low-risk group. In addition, administration of a low dose of LVFX once before bedtime was safe and useful for prophylaxis in the healing phase after TURP

経尿道的前立腺切除術後の感染症に対する経口抗菌剤Levofloxacin予防的投与の効果の検討

われわれは前立腺肥大症患者98例を,リスク群(術前尿路感染症を有する患者および糖尿病患者)と非リスク群とに分け,経尿道的前立腺切除術(TURP)後感染症に対する経口剤の予防的効果を検討した.術後急性期(手術日を含め7日以内)の化学療法は,リスク経口群(Ia群)ではlevofloxacin(LVFX)600mg/日を7日間,非リスク経口群(IIa群)ではLVFX400mg/日を2日間およびLVFX200mg/日を5日間投与した.対照として,リスク点滴静注群(Ib群)および非リスク点滴静注群(IIb群)では2日間のみ抗生剤の点滴静注を行い,3日から7日までは経口群(IaおよびIIa群)と同様とした.また創傷治癒期(術後7日目以降)には,4群ともにLVFX100mgを就寝前に1回服用させ,膿尿が白血球10コ/high power field以下になるまで継続した,感染症については,38.0℃以上の発熱および尿路性器感染症の有無を検討した.急性期感染症を示した症例は,Ia群(n=11):9.1%,Ib群(n=16):18.8%,IIa群(n=39):15.4%,IIb群(n=32):12.5%であった.創傷治癒期感染症は,検討できた63例のうち,リスク群(Ia+Ib群,n=15):20.0%,非リスク群(IIa+IIb群,n=48):16.7%であった.術後急性期における経口抗菌剤LVFXによる化学療法は,リスク症例,非リスク症例ともに,注射用抗生物質を併用した群に比べ感染症発症頻度に有意差を認めず,有用であった.また創傷治癒期においても,LVFXの少量就寝前1回投与法は,安全で有用であると考えられた.Recently, oral antibiotics have been evaluated in place of parenteral antibiotics for prophylactic chemotherapy against infections after transurethral resection of the prostate (TURP). We studied the prophylactic effect of levofloxacin (LVFX) on infections following TURP in 98 patients with prostatic hypertrophy. The subjects were divided into a high-risk group (patients with preoperative urinary tract infection and/or diabetes mellitus) and a low-risk group. For postoperative acute-phase prophylaxis (within 7 days of surgery), 600 mg/day of LVFX was administered orally in the high-risk oral group (Group Ia) and 200～400 mg/day was given in the low-risk oral group (Group IIa). A parenteral antibacterial agent was initially administered for 2 days in the high-risk intravenous group (Group Ib) and the low-risk intravenous group (Group IIb), after which they subsequently received the oral LVFX regimens mentioned above. In the healing phase (from postoperative day 8 onwards), 100 mg of LVFX was administered orally before bedtime until the disappearance of pyuria (less than 10 WBC/HPF) in all groups. The percentage of patients with acute phase infection was 9.1% in Group Ia (n=11), 18.8% in Group Ib (n=16), 15.4% in Group IIa (n=39), and 12.5% in Group IIb (n=32). The percentage of patients with healing phase infections was 20.0% in the high-risk group (Ia+Ib, n=15) and 16.7% in the low-risk group (IIa+IIb, n=48). Oral LVFX therapy was useful for the prevention of acute phase infections in both the high-risk group and the low-risk group. In addition, administration of a low dose of LVFX once before bedtime was safe and useful for prophylaxis in the healing phase after TURP