Ho-Youn Kim

Increased Th17 differentiation in aged mice is significantly associated with high IL-1β level and low IL-2 expression☆☆☆

OBJECTIVEnAging has been reported to be associated with changes in immune function. Although frequent infection and the development of malignancy suggest the decline of immune function with aging, changes toward proinflammatory conditions also develop at the same time. Th17 cells are well known CD4(+) T cell subpopulation closely linked to chronic inflammation and autoimmunity. In this study, changes in the Th17 population were investigated to elucidate a possible mechanism for this response with aging.nnnMETHODSnSplenocytes were isolated from 2-month-old (young) and 20-month-old (aged) mice. CD4(+)CD44(+) memory T cells and CD4(+)CD62L(+) naïve T cells were isolated and sorted using magnetic beads and flow cytometry. The frequency of IL-17-producing cells was measured using flow cytometry. The expression of IL-17 and Th17-related factors at the mRNA level was measured with RT-PCR. IL-17 and Il-1β expression in spleen tissues was additionally assessed using confocal microscopy.nnnRESULTSnThe proportion of IL-17-producing CD4(+) T cells was higher in the splenocytes among the old mice than those of the young mice. When splenocytes were cultured in Th17 polarizing conditions, the proportion of IL-17 producing CD4(+) T cells was higher in aged mice as well. This was consistently observed when naïve and memory cells were isolated and differentiated into Th17 respectively. In addition, the expression of retinoic acid receptor-related orphan nuclear receptor gamma t (RORγt) and other Th17-related factors (AhR, CCR6, and CCL20) increased in the splenocytes of aged mice compared to the young mice. The expression of IL-1β, showing to promote Th17 differentiation, was higher in the aged mice. Likewise, CD4(+) T cell expression of IL-1R was higher in the aged mice, suggesting that the CD4(+) T cells of the aged mice are readily prepared to differentiate into Th17 cells in response to IL-1β. Confocal microscopy showed that cells positive for IL-1R or IL-1β were more frequent in the spleens of the aged mice. When an anti-IL-2 antibody was applied, the proportion of IL-17-producing cells increased more prominently in the young mice. We observed that IL-2 production and IL-2R expression were reduced in the aged mice, respectively, explaining the blunted response to the anti-IL-2 antibody treatment and the consequent minimal change in the Th17 population.nnnCONCLUSIONnWe demonstrated that the proportion of Th17 cells increased in the aged mice both in naïve and memory cell populations. Elevation of IL-1R and IL-1β expression and the reduction in IL-2 and IL-2R expression in aged mice seemed to promote Th17 differentiation. Our results suggest that enhanced Th17 differentiation in aging may have a pathogenic role in the development of Th17-mediated autoimmune diseases.

Experimental autoimmune encephalomyelitis and age-related correlations of NADPH oxidase, MMP-9, and cell adhesion molecules: The increased disease severity and blood–brain barrier permeability in middle-aged mice

The aim of the present study was to investigate effect of two different ages (6 weeks [6 W] vs. 6 months [6 M]) on blood-brain barrier (BBB) disruption in EAE and evaluate the expression and correlations of NADPH oxidase, MMP-9, ICAM-1, and VCAM-1 following increased age and EAE induction. Higher disease severity was observed in 6 M-EAE than 6 W-EAE. The four factors were significantly elevated and correlated in 6 M-EAE. BBB permeability increased with statistically significant interaction between age and EAE effects. We suggest strong correlations between NADPH oxidase and the other factors play important roles in increased BBB disruption and EAE susceptibility in middle-aged mice.

Immunogenicity of anti-tumour necrosis factor therapy in Korean patients with rheumatoid arthritis and ankylosing spondylitis

The aim of this study was to investigate the prevalence of antidrug antibodies (ADAs) against tumour necrosis factor (TNF) inhibitors in patients with rheumatoid arthritis (RA) and ankylosing spondylitis (AS). ADAs were detected in 18 (9.8%) patients with RA and in 18 (10.2%) patients with AS of the 360 patients. Development of ADAs was significantly associated with treatment failure in RA patients (P=0.003). When classified by drugs, the prevalence of immunogenicity in descending order was 17 (28.8%) patients treated with infliximab, 17 (10.4%) with adalimumab, and 2 (1.4%) with etanercept. After adjustment for disease and duration of anti-TNF therapy, the odds ratio as a reference of adalimumab-treated patients was 9.159 (95% confidence interval [CI] 2.005-41.845) for infliximab and 0.280 (95% CI 0.128-0.611) for etanercept. The immunogenicity of anti-TNF therapy was highest in the infliximab-treated group and significantly lower in the etanercept-treated group.

Treatment of IL-21R-Fc control autoimmune arthritis via suppression of STAT3 signal pathway mediated regulation of the Th17/Treg balance and plasma B cells

Interleukin-21 (IL-21) is a T cell-derived cytokine modulating T cell, B cell, and natural killer cell responses. To determine whether IL-21 contributes to pathologic processes, recombinant IL-21 receptor (R) fusion protein (rhIL-21R-Fc) was examined in mice models of autoimmune arthritis (collagen-induced arthritis). DBA/1J mice were immunized with chicken type II collagen and then treated intraperitoneally with rhIL-21R-Fc, which was initiated after the onset of arthritis symptoms in 20% of the cohort. The mice were assessed 3 times per week for signs of arthritis and histologic features as well as serum immunoglobulin. Cytokine messenger RNA levels in the spleen were also examined. STAT3 phosphorylation is dose dependently activated by IL-21 and inhibited by rhIL-21R-Fc in vitro using T cells. Treatment of DBA/1J mice with rhIL-21R-Fc reduced the clinical and histologic signs of CIA. The IL-17 and STAT3-expressing CD4(+) splenocytes dramatically decreased in the rhIL-21R-Fc treated mice. IL-21R-Fc treated mice also decreased the production of IgG, STAT3 phosphorylation, and plasma cell transcription factor (Blimp1). These findings demonstrate a pathogenic role of IL-21 in animal models of RA, suggesting IL-21 as a promising therapeutic target among human RA.

A randomised, double-blind, parallel design, multi-institutional, non-inferiority phase IV trial of imidafenacin versus fesoterodine for overactive bladder.

Our objective was to compare the efficacy and safety of imidafenacin over fesoterodine in patients with overactive bladder (OAB).

Gut-residing Microbes Alter the Host Susceptibility to Autoantibody-mediated Arthritis

K/BxN serum can transfer arthritis to normal mice owing to the abundant autoantibodies it contains, which trigger innate inflammatory cascades in joints. Little is known about whether gut-residing microbes affect host susceptibility to autoantibody-mediated arthritis. To address this, we fed C57BL/6 mice with water containing a mixture of antibiotics (ampicillin, vancomycin, neomycin, and metronidazol) for 2 weeks and then injected them with K/BxN serum. Antibiotic treatment significantly reduced the amount of bacterial genomic DNA isolated from fecal samples, in particular a gene encoding 16S ribosomal RNA derived from segmented filamentous bacteria. Arthritic signs, as indicated by the arthritic index and ankle thickness, were significantly attenuated in antibiotic-treated mice compared with untreated controls. Peyers patches and mesenteric lymph nodes from antibiotic-treated mice contained fewer IL-17-expressing cells than those from untreated mice. Antibiotic treatment reduced serum C3 deposition in vitro via the alternative complement pathway. IL-17-/- congenic C57BL/6 mice were less susceptible to K/BxN serum-transferred arthritis than their wild-type littermates, but were still responsive to treatment with antibiotics. These results suggest that gut-residing microbes, including segmented filamentous bacteria, induce IL-17 production in GALT and complement activation via the alternative complement pathway, which cause the host to be more susceptible to autoantibody-mediated arthritis.

Interleukin 17-expressing Innate Synovial Cells Drive K/Bxn Serum-induced Arthritis

K/BxN serum can induce arthritis in normal mice because of abundant autoantibodies that trigger an innate inflammatory response in joints. To determine whether IL-17 is involved in the pathogenesis of serum-induced arthritis, we injected wild-type and IL-17−/− mice with K/BxN serum and evaluated them for signs of arthritis. Unlike wild-type mice, IL-17−/− mice did not show any signs of arthritis. IL-17 was produced predominantly by CD3− CD4− γδTCR− NK1.1− Sca1int Thy1hi cells residing in the inflamed synovial tissue. When synovial cells extracted from normal joints were stimulated with IL-23 or autoantibody-containing immune complexes, a substantial fraction of Sca1int Thy1hi cells produced IL-17. Thus, we have identified a novel population of IL-17-producing innate synovial cells that play a crucial role in the development of K/BxN serum-induced arthritis.

Pulmonary thromboembolism in patient with coexistence of Behçet's disease and antiphospholipid syndrome

Pulmonary thromboembolism (PTE) is rarely reported in Behçets disease (BD) due to its distinctive thrombus‐forming mechanism. In BD, the inflammation on vessel walls causes venous thrombosis. The thrombi are considered to be tethered to the inflamed walls making embolization less frequent. Thus, immunosuppressive agents are the mainstay of treatment. However, the necessity of anticoagulation therapy is controversial because of its uncertain efficacy of resolving thrombi and the possibility of fatal side effects of hemorrhage. A 25‐year‐old man with recurrent oral aphthae visited with abrupt onset of dyspnea and chest pain. Based on history, imaging studies and laboratory results, he was diagnosed with BD with vascular involvement and antiphospholipid syndrome (APS), causing PTE from deep vein thrombosis. The co‐existing APS may have further promoted the thrombosis, shifting his blood profile toward the hypercoagulable state. Immunosuppressive therapy with glucocorticoid and azathioprine, and concomitant anticoagulation with warfarin were achieved successfully without any fatal complications. When atypical features of vascular involvement in BD develop, other coexisting diseases should be considered to design an optimal therapeutic plan.

Corrigendum to “Experimental autoimmune encephalomyelitis and age-related correlations of NADPH oxidase, MMP-9, and cell adhesion molecules: The increased disease severity and blood–brain barrier permeability in middle-aged mice” [J. Neuroimmunol. 287 (2015) 43–53]

a Toxicology Laboratory, Doping Control Center, Korea Institute of Science and Technology, Seoul 136 791, Republic of Korea b Molecular Recognition Research Center, Korea Institute of Science and Technology, Seoul 136 791, Republic of Korea c Department of Biological Chemistry, University of Science and Technology, Daejeon 305 350, Republic of Korea d Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, Seoul 130 701, Republic of Korea e Division of Rheumatology, Department of Internal Medicine, College of Medicine, Catholic University of Korea, Seoul 137 701, Republic of Korea f Division of Rheumatology, Department of Internal Medicine, Konkuk University Medical Center, Seoul 143 729, Republic of Korea