Interleukin-17 Enhances Germinal Center Formation and Immunoglobulin G1 Production in Mice

OBJECTIVE: Interleukin (IL)-17 is a pro-inflammatory cytokine that has pleiotropic effects on multiple target cells and thereby contributes to the development of immune-mediated inflammatory disorders. However, the role of IL-17 in the humoral immune response has not been clearly elucidated. METHODS: Mice deficient in IL-17A (IL-17A knockout [KO] mice) and wild type (WT) C57BL/6 mice were compared. Distinct B cell (mature/precursor and marginal zone/follicular) and plasma cell populations were compared using fluorescence-activated cell sorting (FACS) and confocal immunostaining. Immunoglobulin production was assessed by enzyme-linked immunosorbent assay. RESULTS: There was no difference in B cell and plasma cell populations between IL-17A KO and WT mice. However, after T cell-dependent antigen challenge, IL-17A KO mice produced lower levels of immunoglobulin (Ig)G1 than wild-type animals. IL-17A KO mice also showed reduced germinal center (GC) formation and lower expression of activation-induced cytidine deaminase, the essential enzyme for class switch recombination (CSR). IL-17 had no effect on the proliferation or survival of naïve B cells in in vitro functional studies. However, IL-17 treatment promoted naïve B cell differentiation into plasma cells in synergy with IL-4, although IL-17 alone had no effect. CONCLUSION: Our findings suggest that IL-17 contributes to the humoral immune response by enhancing GC formation, CSR to IgG1, and plasma cell differentiation in synergy with IL-4.

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⁻ Sca1(int) Thy1(hi) 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 Sca1(int) Thy1(hi) 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.

Rhupus syndrome

No abstract available.

Iliopsoas Abscess Misconstrued as Aggravated Ankylosing Spondylitis / 대한내과학회지

An iliopsoas abscess is a collection of pus in the iliopsoas muscle caused by the direct spread of infection from adjacent internal organs or by hematogenous or lymphatic spread from distal sites. Its symptoms are vague back, hip, thigh or lower abdomen pain with insidious onset, similar to those of ankylosing spondylitis (AS). Therefore diagnosing an iliopsoas abscess in patients with AS is difficult. A forty-three year-old man was treated with adalimumab, a tumor necrosis factor inhibitor, and clinical symptoms were subsequently observed to improve. One year after voluntary discontinuation of adalimumab, the patient returned with a recurrence of right buttock pain and was diagnosed as having aggravated AS. Following re-initiation of adalimumab, symptoms did not improve and fever developed. On the basis of imaging studies, the patient was diagnosed as having an iliopsoas abscess and was successfully treated with intravenous antibiotics.

Advances in Systems Biology Approaches for Autoimmune Diseases

Because autoimmune diseases (AIDs) result from a complex combination of genetic and epigenetic factors, as well as an altered immune response to endogenous or exogenous antigens, systems biology approaches have been widely applied. The use of multi-omics approaches, including blood transcriptomics, genomics, epigenetics, proteomics, and metabolomics, not only allow for the discovery of a number of biomarkers but also will provide new directions for further translational AIDs applications. Systems biology approaches rely on high-throughput techniques with data analysis platforms that leverage the assessment of genes, proteins, metabolites, and network analysis of complex biologic or pathways implicated in specific AID conditions. To facilitate the discovery of validated and qualified biomarkers, better-coordinated multi-omics approaches and standardized translational research, in combination with the skills of biologists, clinicians, engineers, and bioinformaticians, are required.

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. Peyer's 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.

Pulmonary Cryptococcosis in a Patient with Ankylosing Spondylitis treated with Etanercept

Ankylosing spondylitis (AS) is a chronic inflammatory disorder, commonly characterized by inflammation of axial skeleton and development of enthesopathies. Tumor necrosis factor inhibitors (TNFi) shows good therapeutic responses in AS patients without good response to non-steroidal anti-inflammatory drugs. Although TNFi are relatively safe for AS patients, serious opportunistic infections, including tuberculosis and fungal infection, could develop. Here, according to our knowledge, we report a first Korean case of pulmonary cryptococcosis in a patient with AS treated with etanercept. A 64 year-old man with AS visited due to a newly appeared pulmonary nodule on a routine chest radiography. He had been administered etanercept for 5 months. Histologic findings of the lung nodule showed characteristic features of cryptococcosis. Etanercept was discontinued and oral fluconazole was administrated, as there was no evidence of central nervous system involvement. After 7 months of treatment, chest CT showed an improvement of the pulmonary lesion.

Intra-familial Infection due to Trichophyton tonsurans in Korean General Population / 대한의진균학회지

Trichophyton (T.) tonsurans is a common anthropophilic species, which causes tinea capitis and tinea corporis particularily in Europe and America, but has not been prevalent in Korea. One case with mycoses infection of the scalp and the other with tinea corporis due to T. tonsurans were observed in Korean general population. We confirmed T. tonsurans infection on the basis of the direct microscopic examination and culture from scales and infected hairs of skin lesions. Systemic itraconazole and terbinafine therapy with topical ketoconazole cream led to clinical and mycological recovery in our cases. Infection of T. tonsurans appears to have spread gradually among the general population in Korea. Therefore, athletic and medical associations should make constant observation and take close consideration about T. tonsurans infection.

Periarticular Osteoporosis Is a Prominent Feature in Early Rheumatoid Arthritis: Estimation Using Shaft to Periarticular Bone Mineral Density Ratio

We aimed to quantify periarticular osteoporosis and investigate its significance in 45 patients with rheumatoid arthritis (RA) and 106 controls. Dual-energy X-ray absorptiometry (DXA) was used to determine the ratio of shaft to periarticular bone mineral density (BMD) as an index of periarticular demineralization. Periarticular osteoporosis was measured by conventional radiography. The BMDs of shaft and periarticular regions in eight designated areas on proximal phalanges were quantified. Clinical variables were examined to identify risk factors for periarticular osteoporosis. The assessment of periarticular osteoporosis on X-ray images reached a moderate degree of interobserver agreement among four physicians (k = 0.47). For BMD quantification, we designed three types of mathematical formulae: the ratio of shaft to periarticular BMD, the mean of the ratios, and the ratio of the sums. These ratios were significantly higher in the patients with early RA (disease duration < or = 3 yr) than in controls (P < 0.01). The findings were not as distinctive in patients with established RA. Body mass index, cumulative dose of corticosteroid, and C-terminal telopeptide were correlated with BMD ratios. Conclusively, DXA-assisted localized quantification and BMD ratio calculations are feasible for assessing periarticular demineralization. Periarticular osteoporosis is a relatively distinctive feature of early RA.

The Urate-lowering Efficacy and Safety of Febuxostat in Korean Patients with Gout

OBJECTIVE: To compare the urate-lowering efficacy and the safety of febuxostat, allopurinol and placebo in Korean patients with gout for 4 weeks. METHODS: Subjects (n=182) with gout were randomized to febuxostat (40, 80, 120 mg), allopurinol 300 mg, or placebo group. The primary end point was the proportion of subjects whose serum urate concentration fell to less than 6.0 mg/dL after the 4-week treatment. RESULTS: The primary end point was reached at 25.7%, 80.0% and 83.3% of patients receiving 40, 80 and 120 mg of febuxostat, respectively, 58.3% of those receiving 300 mg of allopurinol and none of the placebo (p<0.001: each febuxostat dose or allopurinol group versus placebo group, p=0.0484 and p=0.0196: febuxostat 80 and 120 mg compared with allopurinol, respectively). The number and proportion of subjects who developed adverse events (AEs) were 13 subjects (37%), 14 (39%) and 18 (50%) in the febuxostat of 40, 80 and 120 mg group, respectively, 21 (57%) in the allopurinol 300 mg group and 17 (46%) in the placebo group. No statistically significant differences in the incidence rates of adverse events were observed between the groups. There was no significant difference in gout flare-up incidence. CONCLUSION: Febuxostat, 80 mg or 120 mg, was more effective than allopurinol (300 mg) or placebo, when lowering the serum urate. The safety of febuxostat and allopurinol was comparable.

Epigenetic Modification in Systemic Rheumatic Diseases

Epigenetics is defined as an inheritable effect that influences gene activity, but does not involve a change in DNA sequence. Epigenetic gene regulation has an essential role in determining individual gene function and activity in each specific cell type. Epigenetics includes four predominant mechanisms: DNA methylation, histone modification, nucleosome positioning and microRNA (miRNA). These mechanisms influence gene expression, cell differentiation, proliferation, DNA repair and replication. Epigenetic modifications are far more sensitive to environmental stimuli than DNA sequence alterations. Candidate gene approaches have identified a small set of genes that undergo epigenetic changes, such as aberrant DNA demethylation, histone modification, as well as regulation by miRNA in rheumatic diseases. It is well known that T cells from patients with SLE or RA, as well as synovial fibroblasts from individuals with RA, have sequences undergoing DNA hypomethylation and/or histone modifications. In addition, miRNA regulates the gene expression by pairing with its target mRNAs and is often deregulated in systemic rheumatic diseases. High-throughput approaches are necessary for screening the epigenetic alterations, and it is essential to screen the specific tissue and cell types that are relevant to the disease pathogenesis. Identification of cell-specific targets of the epigenetic deregulation in rheumatic disorders will provide clinical markers for the diagnosis, disease progression and response to therapy. Our understanding of epigenetics is in its infancy. New generation of pharmaceuticals, which manipulate the epigenome to the switch targeted genes on or off are under investigation. The new field of repairing or optimizing the epigenome through epigenetic modifier and/or diet is wide open.

Simultaneous Presentation of Ocular Sarcoidosis and Early Axial Spondyloarthritis in a Young Woman

Axial spondyloarthritis and sarcoidosis are both inflammatory multi-system diseases. Having different pathophysiologies, they develop different typical lesions. The co-occurrence of both diseases is rare and nature of the association between the entities is unknown.

Serum Level of Interleukin-33 and Soluble ST2 and Their Association with Disease Activity in Patients with Behcet's Disease

Interleukin (IL)-33 is an important mediator of innate immunity. Behcet's disease (BD) is an autoinflammatory disorder characterized by hyperactivity of the innate immune response. We measured serum levels of IL-33 and its receptor soluble ST2 (sST2) in patients with BD to investigate their association with disease activity. Serum levels of both IL-33 and sST2 were higher in patients with BD compared with those in normal controls (IL-33: 594.48+/-175.04 pg/mL in BD and 224.23+/-56.64 pg/mL in normal controls [P=0.048], sST2: 99.01+/-15.92 pg/mL in BD and 23.56+/-3.25 pg/mL in normal controls [P<0.001]). IL-33 and sST2 expression in skin tissue, as shown by immunohistochemistry, was higher in patients with BD compared with that in the normal controls. Serum sST2 level correlated significantly with the BD currently active form (BDCAF), Iranian BD dynamic activity measure (IBDDAM), erythrocyte sedimentation rate and C-reactive protein. Multiple linear regression showed that serum sST2 was an independent factor associated with IBBDAM (regression coefficient, 0.374; P=0.004), and BDCAF (regression coefficient, 0.236; P=0.047). These results demonstrate that IL-33 and sST2 are highly expressed in patients with BD and that serum sST2 is an independent factor associated with IBDDAM and BDCAF, suggesting a potential role for sST2 as a surrogate marker of disease activity in patients with BD.

Partial Anomalous Pulmonary Venous Return (PAPVR) in a Patient with Sjogren's Syndrome

Pulmonary hypertension (PH) is a rare manifestation in patients with primary Sjogren's syndrome (pSS) and it can occur with or without interstitial lung disease (ILD). Patients with PH and ILD who show signs of exacerbation of dyspnea are commonly assessed for pure PH aggravation, ILD progression or pulmonary infection. However, the presence of congenital cardiac anomalies, such as partial anomalous pulmonary vein return (PAPVR), can also be a cause of dyspnea exacerbation. PAPVR is a rare congenital anomaly that involves drainage of 1 to 3 pulmonary veins into the right-sided heart circulation, resulting in a partial left-to-right shunt. Here we present a case of PAPVR as the cause of PH aggravation in a patient with pSS with accompanying PH.

The Effects of Antihypertensive Drugs on Bone Mineral Density in Ovariectomized Mice

The effects of several antihypertensive drugs on bone mineral density (BMD) and micro-architectural changes in ovariectomized (OVX) mice were investigated. Eight-week-old female C57/BL6 mice were used for this study. Three days after ovariectomy, mice were treated intraperitoneally with nifedipine (15 mg/kg), telmisartan (5 mg/kg), enalapril (20 mg/kg), propranolol (1 mg/kg) or hydrochlorothiazide (12.5 mg/kg) for 35 consecutive days. Uterine atrophy of all mice was confirmed to evaluate estrogen deficiency state. BMD and micro-architectural analyses were performed on tibial proximal ends by micro-computed tomography (micro-CT). When OVX mice with uterine atrophy were compared with mice without atrophy, BMD decreased (P < 0.001). There were significant differences in BMD loss between different antihypertensive drugs (P = 0.005). Enalapril and propranolol increased BMD loss in mice with atrophied uteri compared with control mice. By contrast, thiazide increased BMD in mice with uterine atrophy compared with vehicle-treated mice (P = 0.048). Thiazide (P = 0.032) and telmisartan (P = 0.051) reduced bone loss and bone fraction in mice with uterine atrophy compared with the control. Thiazide affects BMD in OVX mice positively. The reduction in bone loss by thiazide and telmisartan suggest that these drugs may benefit menopausal women with hypertension and osteoporosis.

The Effects of Antihypertensive Drugs on Bone Mineral Density in Ovariectomized Mice

The effects of several antihypertensive drugs on bone mineral density (BMD) and micro-architectural changes in ovariectomized (OVX) mice were investigated. Eight-week-old female C57/BL6 mice were used for this study. Three days after ovariectomy, mice were treated intraperitoneally with nifedipine (15 mg/kg), telmisartan (5 mg/kg), enalapril (20 mg/kg), propranolol (1 mg/kg) or hydrochlorothiazide (12.5 mg/kg) for 35 consecutive days. Uterine atrophy of all mice was confirmed to evaluate estrogen deficiency state. BMD and micro-architectural analyses were performed on tibial proximal ends by micro-computed tomography (micro-CT). When OVX mice with uterine atrophy were compared with mice without atrophy, BMD decreased (P < 0.001). There were significant differences in BMD loss between different antihypertensive drugs (P = 0.005). Enalapril and propranolol increased BMD loss in mice with atrophied uteri compared with control mice. By contrast, thiazide increased BMD in mice with uterine atrophy compared with vehicle-treated mice (P = 0.048). Thiazide (P = 0.032) and telmisartan (P = 0.051) reduced bone loss and bone fraction in mice with uterine atrophy compared with the control. Thiazide affects BMD in OVX mice positively. The reduction in bone loss by thiazide and telmisartan suggest that these drugs may benefit menopausal women with hypertension and osteoporosis.

In vivo action of IL-27: reciprocal regulation of Th17 and Treg cells in collagen-induced arthritis

Interleukin (IL)-27 is a novel cytokine of the IL-6/IL-12 family that has been reported to be involved in the pathogenesis of autoimmune diseases and has a pivotal role as both a pro- and anti-inflammatory cytokine. We investigated the in vivo effects of IL-27 on arthritis severity in a murine collagen-induced arthritis (CIA) model and its mechanism of action regarding control of regulatory T (Tregs) and IL-17-producing T helper 17 (Th17) cells. IL-27-Fc-treated CIA mice showed a lower severity of arthritis. IL-17 expression in the spleens was significantly decreased in IL-27-Fc-treated CIA mice compared with that in the CIA model. The Th17 population was decreased in the spleens of IL-27-Fc-treated CIA mice, whereas the CD4+CD25+Foxp3+ Treg population increased. In vitro studies revealed that IL-27 inhibited IL-17 production in murine CD4+ T cells, and the effect was associated with retinoic acid-related orphan receptor gammaT and signal transducer and activator of transcription 3 inhibition. In contrast, fluorescein isothiocyanate-labeled forkhead box P3 (Foxp3) and IL-10 were profoundly augmented by IL-27 treatment. Regarding the suppressive capacity of Treg cells, the proportions of CTLA-4+ (cytotoxic T-lymphocyte antigen 4), PD-1+ (programmed cell death protein 1) and GITR+ (glucocorticoid-induced tumor necrosis factor receptor) Tregs increased in the spleens of IL-27-Fc-treated CIA mice. Furthermore, in vitro differentiated Treg cells with IL-27 exerted a more suppressive capacity on T-cell proliferation. We found that IL-27 acts as a reciprocal regulator of the Th17 and Treg populations in CD4+ cells isolated from healthy human peripheral blood mononuclear cells (PBMCs), as well as from humans with rheumatoid arthritis (RA) PBMCs. Our study suggests that IL-27 has the potential to ameliorate overwhelming inflammation in patients with RA through a reciprocal regulation of Th17 and Treg cells.

Gender Differences in Clinical Features and Anti-TNF Agent Use in Korean Ankylosing Spondylitis Patients

OBJECTIVE: The aim of this study was to assess the gender differences in the clinical presentation and treatment patterns between Korean women and men with ankylosing spondylitis (AS). METHODS: We retrospectively analyzed the data from extensive clinical assessments of 721 patients (162 women and 559 men) with AS, who were diagnosed at Seoul St. Mary's Hospital, between January 2000 and September 2009. Clinical data, regarding the disease onset, disease duration, clinical presentations, status of human leukocyte antigen (HLA)-B27, and bone mineral density, were determined using a dual-energy X-ray absorptiometry (DEXA). Finally, we analyzed the medical treatments prescribed for these patients. RESULTS: The ratio of men to women was 3.45:1. Compared to men, women were older at the time of diagnosis, had shorter disease durations, and were diagnosed in earlier stages of the disease. More women had a history of uveitis at diagnosis than men. Back pain was the main presenting symptom, and its prevalence was the same in both genders. Fewer women showed cervical and thoracic axial involvement than men. Initially, more women had wrist and hand pain than men; however, at some point, peripheral arthritis development was equally likely in both genders. Women experienced shoulder pain, during the disease course, more often thanmen. On the other hand, men presented with knee and hip pain more often than women. Sulfasalazine and anti-TNF agents were more often prescribed to women. CONCLUSION: The presentation and progression of AS showed a difference between women and men. Because of these differences, AS should be considered when a women presents with peripheral arthritis or uveitis in the early stage of the disease.

Usefulness and Limitation of 2010 ACR/EULAR Classification Criteria in Korean Patients with Early RA

OBJECTIVE: The 2010 New American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) criteria for rheumatoid arthritis (RA) was raised to identify patients with early RA and replaced the 1987 ACR classification criteria. The aims of this study are to assess the availability of new classification criteria and to evaluate its potential limitation. METHODS: A total of 408 patients with newly diagnosed RA were included from 13 secondary or tertiary hospitals in South Korea. The symptom duration was less than 12 months before the diagnosis of RA. RA was defined as either 1987 ACR classification criteria or new 2010 ACR/EULAR criteria. We compared the full details of both classification criteria. RESULTS: The mean symptom duration was 5.1 months. The majority (76.2%) of the patients were female. Two hundred and seventy three patients (66.9%) fulfilled both of the 2010 and 1987 classification criteria. Forty-seven (14.7%) of the 320 patients fulfilling the 1987 criteria did not fulfill the new classification criteria. On the other hand, eighty-eight (24.4%) of the 361 patients fulfilling the 2010 ACR/EULAR classification criteria did not fulfill the 1987 ACR criteria. Thirty-six (55.4%) of the 65 patient with seronegative RA failed to meet the 2010 classification criteria. In case of seropositive RA (n=343), 85 additional patients (24.8%) could be diagnosed as RA using new classification criteria. CONCLUSION: The new 2010 ACR/EULAR classification criteria enable physicians to diagnose more patients with early RA via the help of serology. However, the sensitivity for the diagnosis of seronegative RA is projected to decrease.

Obesity aggravates the joint inflammation in a collagen-induced arthritis model through deviation to Th17 differentiation

White fat cells secrete adipokines that induce inflammation and obesity has been reported to be characterized by high serum levels of inflammatory cytokines such as IL-6 and TNF-alpha. Rheumatoid arthritis (RA) is a prototype of inflammatory arthritis, but the relationship between RA and obesity is controversial. We made an obese inflammatory arthritis model: obese collagen-induced arthritis (CIA). C57BL/6 mice were fed a 60-kcal high fat diet (HFD) from the age of 4 weeks and they were immunized twice with type II collagen (CII). After immunization, the obese CIA mice showed higher arthritis index scores and histology scores and a more increased incidence of developing arthritis than did the lean CIA mice. After treatment with CII, mixed lymphocyte reaction also showed CII-specific response more intensely in the obese CIA mice than lean CIA. The anti-CII IgG and anti-CII IgG2a levels in the sera of the obese CIA mice were higher than those of the lean CIA mice. The number of Th17 cells was higher and the IL-17 mRNA expression of the splenocytes in the obese CIA mice was higher than that of the lean CIA mice. Obese CIA mice also showed high IL-17 expression on synovium in immunohistochemistry. Although obesity may not play a pathogenic role in initiating arthritis, it could play an important role in amplifying the inflammation of arthritis through the Th1/Th17 response. The obese CIA murine model will be an important tool when we investigate the effect of several therapeutic target molecules to treat RA.