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Experimental autoimmune encephalomyelitis (EAE) is the most common animal model of multiple sclerosis. In our previous works, two different age groups of mice (6 weeks; Y vs. 15 months; O) were used to compare the severity of EAE. Significant decreases of body weight and increases of clinical score were observed in O-EAE, indicating a more severe form of disease was induced at old age. With the purpose to identify genes that contribute to this pathology, we investigated gene expressions in brain using gene microarray. As a result, 32 genes including MHC class II molecules antigen, complement component and lysozyme in Y-EAE, and 4 genes including circulatory system, cell adhesion and migration functions in O-EAE were up-regulated compared to their controls. Expression of 44 genes was significantly different between O-EAE and Y-EAE. O-EAE showed 27 up-regulated genes with related pathways including response to stress and acute inflammatory responses, and 17 down-regulated genes with related pathways including immune development, hemopoiesis and homeostatic process, compared to Y-EAE. Over-expression of the stress response pathway-related genes in O-EAE such as argine vasopressin, cyclin-dependent kinase inhibitor 1A and hypoxia-induced factor 3α were validated by qRT-PCR. Our data suggest that the highly expressed genes related to stress responses in O-EAE affected serious disease process, and these genes may be prior targets for susceptibility of EAE.

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.

Department of Internal Medicine, Seoul St. Mary’s Hospital, Department of Internal Medicine, Seoul National University Hospital, Seoul, Department of Internal Medicine, Inha University Hospital, Incheon, Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine 5 , Department of Internal Medicine, Severance Hospital, Department of Medicine, Hanyang University Medical Center, Seoul, Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Department of Internal Medicine, Hallym University Sacred Heart Hospital, Pyeongchon, Department of Internal Medicine, Gachon Medical School Gil Medical Center, Incheon, Department of Biostatistics, Seo Kyeong University, Seoul, Korea

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 (ĸ = 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 ≤ 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.

Introduction Axial spondyloarthritis (SpA) is an inflammatory disease that predominantly affects vertebral and sacroiliac joint. Sarcoidosis is an inflammatory multi-system disease associated with the formation of non-caseating granulomas within involved systems (1). Both diseases can involve ocular manifestations of which anterior uveitis are common feature. Articular involvement has been reported in about 5% of cases with sarcoidosis (2). Therefore, it is sometimes difficult to distinguish one disease from the other. Sacroiliac joint involvement, in which the hallmark of axial SpA (3,4), is not a common feature of sarcoidosis. Here, we present a case with simultaneous onset of early axial SpA with ocular sarcoidosis.

Research has consistently showed that government has been held in low regard and the loss of confidence in government is mainly due to low productivity and inefficiency of government. The police are also confronted with low productivity. Citizens have more demands, but police have fewer resources. Increasing productivity is considered as an important task for government. Many politicians adopted “reinventing the government” as their slogan, and the coproduction effort has been recognized and promoted as “the law enforcement manifestation of reinventing movement”. This movement is apparently gaining tremendous support not only from law enforcement agencies but also from the general public. However, it has not been completely assured that collective citizen involvement in crime prevention is a sound and effective way to control crime, and thus reduce fear of crime. This research examines the effectiveness and problems associated with the coproduction effort such as Neighborhood Watch Program and Citizen Patrol.

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

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.

Antiphospholipid syndrome is characterized by recurrent episodes of arterial and venous thrombosis, spontaneous fetal losses, thrombocytopenia and persistently elevated levels of antiphospholipid antibodies. We experienced a case of Budd-Chiari syndrome in a 32-year old female lupus patient who was presented with left leg edema, ascites and esophageal varix. The clinical and laboratory findings were compatible with the cirteria for systemic lupus erythematosus (SLE) and she was found to have anticardiolipin antibody, thrombocytopenia and prolonged partial thromboplastin time. Initially, she was treated with intravenous heparin and uroki nase and she was followed up with warfarin, baby aspirin and steroids.

Fibroblast-like synoviocytes (FLS) are major cell population of the pannus that invades adjacent cartilage and bone in rheumatoid arthritis (RA). The study was undertaken to determine the effect of interleukin-17 (IL-17) on the survival and/or proliferation of FLS from RA patients and to investigate whether signal tranducer and activator of transcription 3 (STAT3) is implicated in this process. The expressions of Bcl-2 and Bax in FLS were determined using real-time PCR and western blot analysis. The expression of CD55, Bcl-2, Bax, IL-17 and phosphoSTAT3 in synovial tissues were investigated by immunohistochemistry. Apoptosis of FLS was detected by Annexin V/propidium iodide staining and/or phase contrast microscopy. The proliferation of FLS was determined by CCK-8 ELISA assay. The pro-apoptotic Bax is decreased and anti-apoptotic Bcl-2 is increased in FLS from RA patients compared with in that from OA (Osteoarthritis) patients. IL-17 upregulates the expression of Bcl-2 in FLS from RA patients, not in FLS from OA patients. STAT3 was found to mediate IL-17-induced Bcl-2 upregulation in FLS from RA patients. In addition, IL-17 promotes the survival and proliferation of FLS from RA patients. Most importantly, treatment with STAT3 inhibitor reverses the protective effect of IL-17 on FLS apoptosis induced by SNP.

IL-17 producing Th17 has a key role in the pathogenesis of autoimmune inflammation. Among various cytokines which are interwoven with the IL-17 pathway, members of IL-1beta family including IL-18 have recently gained significance. In the present study, we stimulated synovial fibroblasts with the combination of IL-17 and IL-18, and quantified the cellular production of stromal cell-derived factor-1 (SDF-1) with ELISA and its mRNA with RT-PCR. Both IL-17 and IL-18 significantly increased the level of SDF-1, not only individually but also synergistically (p

Objective: We investigated whether the OSM was induced SOCS3 in Treg and Th17 generation in type II collagen induced arthritis (CIA) mice. Method: Isolated T cell of CIA mice was incubated with Th17 or Treg differentiation condition for 30min or 3day. The Th17 and Treg culture condition was incubated with or without OSM 5, 10, 20 and 50 ng/ml. The cell lysated was analyzed using western blot for phospho(p)-STAT3705, p-STAT3727 andp-STAT5 IL-17production was measured in 3day culture supernatant. IL-17 and SOCS3 mRNA levels were analysis by real-time PCR. Result: OSM was increased p-STAT3705 in Th17 and Treg culture condition, but not p-STAT5. However, production of IL-17 and IL-17 mRNA was decreased in Th17 and Treg culture condition. Inaddition, the OSM was increased SOCS3 mRNA in Th17 and Treg condition. Next we investigated expression of OSM and SOCS3 mRNA levels in Treg cell. P-STAT5, OSM and SOCS3 were activated inTreg, while p-STAT3 was decreased. Although OSM was induced activation of STAT3, that was suppressed differentiation from Treg to Th17. These result ssuggest that OSM was regulated expression of SOCS3, thereby tightly regulated plastically differentiation of Treg and Th17. Conclusion: SOCS3 induced by OSM is an acting negative feedback loop and since OSM-mediated signaling is suppression IL-17 production in mouse CD4 T cells, which is provide for feedback inhibition of inflammatory response in the CIA.

Introduction The study was undertaken to investigate the interrelation of toll-like receptor (TLR) and interleukin (IL)-17 in the salivary glands of patients with primary Sjogren's syndrome (pSS) and to determine the role of TLR and IL-17 in the pathophysiology of pSS. Methods The expressions of various TLRs, IL-17 and the cytokines involved in Th17 cell differentiation including IL-6, IL-23, tumor necrosis factor-alpha (TNF-α) and IL-1β were examined by immunohistochemistry in salivary glands of pSS patients. The IL-17 producing CD4+ T cells (Th17 cells) were examined by flow cytometry and confocal staining in peripheral mononuclear blood cells (PMBCs) and salivary glands of pSS patients. After PBMCs were treated with TLR specific ligands, the induction of IL-17 and IL-23 was determined using real-time PCR and ELISA. The signaling pathway that mediates the TLR2 stimulated production of IL-17 and IL-23 was investigated by using treatment with specific signaling inhibitors. Results We showed that TLR2, TLR4, TLR6, IL-17 and the cytokines associated with Th17 cells were highly expressed in salivary glands of pSS patients but not in controls. The expressions of TLR2, TLR4 and TLR6 were observed in the infiltrating mononuclear cells and ductal epithelial cells, whereas IL-17 was mainly observed in infiltrating CD4+ T cells. The number of IL-17 producing CD4+ T cells was significantly higher in pSS patients both in PBMCs and minor salivary glands. The stimulation of TLR2, TLR4 and TLR6 additively induced the production of IL-17 and IL-23 from the PBMCs of pSS patients especially in the presence of TLR2 stimulation. IL-6, signal transducer and activator of transcription 3 (STAT3) and nuclear factor-kappaB (NF-kB) pathways were implicated in the TLR2 stimulated IL-17 and IL-23. Conclusions Our data demonstrate that TLR2 ligation induces the production of IL-23/IL-17 via IL-6, STAT3 and NF-kB pathway in pSS. Therefore, therapeutic strategies that target TLR/IL-17 pathway might be strong candidates for treatment modalities of pSS.

Division of Rheumatology, Department of Internal Medicine, School of Medicine, The Catholic University of Korea, Seoul, Wonkwang University, Iksan 2 , The Chosun University College of Medicine, Gwangju 3 , Chungbuk National University Hospital, Cheongju, Konkuk University School of Medicine, Seoul, Hallym University Sacred Heart Hospital, Anyang, Chung-Ang University School of Medicine, Seoul, Kangnam CHA Hospital, CHA University, Seoul 8 , Inha University College of Medicine, Incheon 9 , Korea

Secondary amyloidosis is one of the most serious complications in chronic inflammatory diseases such as rheumatoid arthritis. The extracellular deposit of aggregates of amyloid leads to target organ dysfunction. The mainstay treatment of secondary amyloidosis is the control of underlying disease activity. Many reports have reported that TNF-α inhibitors improve clinical outcomes. Here, we encountered a 34-year-old patient with juvenile rheumatoid arthritis who developed secondary amyloidosis despite treatment with TNF-α inhibitors. We present this case and include a review of the literature.

IL-17-producing CD4+ T cells (Th17) play important functions in autoimmune diseases and allograft rejection of solid organs. We examined the effects of IL 17 and its mechanism of action on arthritis in a murine collagen-induced arthritis (CIA) model using bone marrow transplantation (BMT) system. DBA/1J mice were administered a lethal radiation dose and then rescued with bone marrow derived from either wild-type (WT) or IL-17-/- mice on C57BL/6 background mice. CIA was induced after the bone marrow transplant, and disease progression was characterized. DBA/1J mice with CIA that received IL-17-/- donor bone marrow showed potently inhibited development and severity of clinical arthritis as compared with CIA mice that received WT bone marrow. Reduced secretion of the pro-inflammatory cytokines tumor necrosis factor-α, IL-1β, and IL-6, and collagen-specific T cell responses were observed in mice that received IL-17-/- bone marrow. IL-17 blockade also inhibited effector T cell proliferation by reciprocally regulating the Treg/Th17 ratio. IL-17 blockade prevented joint destruction in mice with CIA. These findings suggest that CIA with BMT is a viable method of immunological manipulation and that IL-17 deficiency suppresses severe joint destruction and inflammation in CIA mice. There may be clinical benefits in blocking IL-17 and BMT in the treatment of rheumatoid arthritis.

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.

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-α. 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.

Osteoarthritis (OA) is an age-related joint disease that is characterized by degeneration of articular cartilage and chronic pain. Oxidative stress is considered one of the pathophysiological factors in the progression of OA. We investigated the effects of grape seed proanthocyanidin extract (GSPE), which is an antioxidant, on monosodium iodoacetate (MIA)-induced arthritis of the knee joint of rat, which is an animal model of human OA. GSPE (100 mg/kg or 300 mg/kg) or saline was given orally three times per week for 4 weeks after the MIA injection. Pain was measured using the paw withdrawal latency (PWL), the paw withdrawal threshold (PWT) and the hind limb weight bearing ability. Joint damage was assessed using histological and microscopic analysis and microcomputerized tomography. Matrix metalloproteinase-13 (MMP13) and nitrotyrosine were detected using immunohistochemistry. Administration of GSPE to the MIA-treated rats significantly increased the PWL and PWT and this resulted in recovery of hind paw weight distribution (P < 0.05). GSPE reduced the loss of chondrocytes and proteoglycan, the production of MMP13, nitrotyrosine and IL-1β and the formation of osteophytes, and it reduced the number of subchondral bone fractures in the MIA-treated rats. These results indicate that GSPE is antinociceptive and it is protective against joint damage in the MIA-treated rat model of OA. GSPE could open up novel avenues for the treatment of OA.

Basal cell carcinoma (BCC), which frequently occurs in sun-exposed areas of the head and neck region, is the most common cutaneous malignancy. The nipple-areola complex (NAC) is an uncommon site for BCC to develop. BCCs in this region display more aggressive behavior and a greater potential to spread than when found in other anatomical sites. This paper outlines the case of 67-year-old female with a solitary asymptomatic black plaque on the right areola. The lesion was initially recognized as Paget's disease of the nipple by a general surgeon. However, the histopathological features showed a tumor mass of basaloid cells, a peripheral palisading arrangement and scattered pigment granules. Finally, the patient was diagnosed with pigmented BCC of the NAC and was referred to the department of dermatology. Positron emission tomography-computed tomography revealed the absence of distant metastasis. A wide excision was done. The lesion resolved without recurrence or metastasis during 14 months of follow-up.

Parry-Romberg syndrome (PRS) is a relatively rare degenerative disorder that is poorly understood. PRS is characterized by slowly progressing atrophy affecting one side of the face, and is frequently associated with localized scleroderma, especially linear scleroderma, which is known as en coup de sabre. This is a report of the author's experiences with PRS accompanying en coup de sabre, and a review of the ongoing considerable debate associated with these two entities. Case 1 was a 37-year-old woman who had right hemifacial atrophy with unilateral en coup de sabre for seven years. Fat grafting to her atrophic lip had been conducted, and steroid injection had been performed on the indurated plaque of the forehead. Case 2 was a 29-year-old woman who had suffered from right hemifacial atrophy and bilateral en coup de sabre for 18 years. Surgical corrections such as scapular osteocutaneous flap and mandible/maxilla distraction showed unsatisfying results.

B cells play an important role in the pathogenesis of rheumatoid arthritis (RA). High levels of B cell activating factor (BAFF) are detected in autoimmune diseases. BAFF and BAFF receptor (BAFF-R) are expressed in B and T cells of RA synovium. The study was undertaken to identify the NF-κB signal pathway involved in the induction of BAFF-R in human B cells. Immunohistochemical staining of NF-κB p65, NF-κB p50, BAFF, and BAFF-R was performed on sections of synovium from severe and mild RA and osteoarthritis (OA) patients. Peripheral blood mononuclear cells (PBMCs) were isolated from control and RA patients and B cells were isolated from controls. BAFF-R was analyzed by flow cytometry, realtime PCR and confocal staining after treatment with NF-κB inhibitors. NF-κB p65, NF-κB p50, BAFF, and BAFF-R were highly expressed in severe RA synovium relative to mild RA synovium or OA synovium. BAFF-R expression was reduced by NF-κB inhibitors in PBMCs and B cells from normal controls. We also showed reduction in expression of BAFF-R via inhibition of the NF-κB pathway in PBMCs of RA patients. BAFF/BAFF-R signaling is an important mechanism of pathogenesis in RA and that BAFF-R reduction by NF-κB blocking therapy is another choice for controlling B cells in autoimmune diseases such as RA.

Background: Epidermal growth factor receptor (EGFR) inhibitors are being used to treat malignancies originating from epithelia. Unfortunately, blocking the EGFR pathway leads to various side effects, most frequently acneiform eruptions. Objective: To probe the mechanism underlying this side effect, we investigated the effect of EGFR inhibitors on cultured sebocytes. Methods: To examine the effects of an EGFR inhibitor (cetuximab, Erbitux(R) 10 ng/ml) and the effects of EGFR ligands, such as epidermal growth factor (EGF, 10 ng/ml) and transforming growth factor-α (TGF-α, 5 ng/ml), on the production of inflammatory cytokines in cultured sebocytes, we used reverse transcriptase-polymerase chain reaction, immunocytofluorescence and Western blots. Outcomes included the expression of interleukin (IL)-1, IL-6, tumor necrosis factor-α (TNF-α), peroxisome proliferator-activated receptor-γ (PPAR-γ) and EGFR. Results: There were no significant differences in the expression of IL-1, IL-6, TNF-α, PPAR-γ and EGFR between (a) groups treated with an EGFR inhibitor or an EGFR ligand and (b) the control group, except for a significant increase in the expression of IL-1 in the EGF-treated group. Conclusion: EGFR inhibitors and EGFR ligands do not provoke the expression of inflammatory biomarkers in cultured sebocytes. The role of the sebaceous glands in EGFR inhibitor-induced acneiform eruption should be investigated more thoroughly. (Ann Dermatol 23(1) 12~18, 2011)

The functional role of IL-12 in rheumatoid arthritis is controversial. Moreover, whether IL-12 contributes to regulation of antibody-induced joint inflammation remains unclear. To address these issues, we explored the functional roles of IL-12 in the K/BxN serum transfer model. IL-12p35-/- and IL-12R2-/- mice were resistant to the development of arthritis. Injection of K/BxN serum into IL-12p40 reporter (yet40) mice induced CD11b+,CD11c+ cells and Gr-1+ granulocytes to produce IL-12p40 in the joints. The levels of IFN-γ, IL-4, and IL-6 production were lower in joint tissues of IL-12p35-/- and IL-12Rβ2-/- mice than B6 mice, whereas that of TGF-β expression was higher. Administering IL-12p35-/- mice recombinant IL-12 or IFN-γ restored joint inflammation and suppressed TGF-β production in joint tissues. Moreover, administering neutralizing αTGF-β mAb enhanced joint inflammation. Among the immune cells that infiltrated joint tissues during antibody-induced arthritis, NKT cells expressed IL-12Rβ2 receptors. Furthermore, the adoptive transfer of splenocytes from B6 or Gr-1+ granulocyte-depleted mice restored joint inflammation in IL-12Rβ2-/- mice as much as in B6 mice, whereas splenocytes from Jα18-/- mice did not. These findings indicate that signals via IL-12 receptors on NKT cells play a critical role in the development of antibody-induced arthritis. In conclusion, the IL-12p35/IFN-γ axis promotes antibody-induced joint inflammation by activating NKT cells and suppressing TGF-β.

To examine the effects of NF-κB inhibition on the secretion of macrophage migration inhibitory factor (MIF) in CD4+ T cells. Isolated human CD4+ T cells were cultured with NF-κB inhibitors for 24 hrs. MIF levels were evaluated by intracellular FACs, ELISA, and real time PCR. The levels of intracellular O2-, H2O2, and glutathione were evaluated by intracellular FACs. The amounts of phosphorylated Akt and c-Jun were measured by Western blotting. Treatment of CD4+ T cells with NF-κB inhibitors resulted in a significant increase of MIF concentration in culture supernatants, MIF gene expression and O2- production and decrease of intracellular MIF, H2O2, and GSH. Treatment with LY294002, and SP600125 suppressed NF-κB inhibitors induced MIF mRNA expression and MIF secretion and inhibited parthenolide induced phosphorylation of Akt and c-Jun. Treatment with H2O2 also decreased the amounts of intracellular MIF protein and increased MIF level in the culture supernatant. NAC, an antioxidant precursor of GSH, inhibited parthenolide or H2O2 induced secretion of MIF. These results indicate inhibition of NF-κB leads to release of MIF through de novo synthesis of MIF and secretion of preformed MIF in CD4+ T cells through reactive oxygen species production. .

Objective: Mature B cells in the spleen of mouse can be divide into two main subsets: the follicular (FO) B cells and the marginal zone (MZ) B cells. In this study, we investigated which subtype of B cells is involved in the production of costimulatory molecules, cytokine and antibody during the induction of autoimmune arthritis. Methods: The MZB and FOB cells isolated from DBA/1J induced- and collagen-induced arthritis (CIA) mice were stimulated with LPS or CpG. The costimulatory molecules were measured by flow cytometry (FACs). The cytokines were measured by ELISA. Production of antibodies by the MZB cells or FOB cells was measured by ELISA and the results were observed by confocal microscopy. Results: The expression of co-stimulatory molecules was stronger in the MZB cells than that in the FOB cells. The production of cytokines (IL-10, IL-6) and antibodies was higher in the MZB cells. The IgG expression of the MZB cells, which is known to be associated with the acceleration of autoimmunity, was higher in the CIA mice than that in the DBA/1J mice. Conclusion: We observed that the MZB cells were increased in the CIA mice. The

Infection still remains a major cause of morbidity and mortality in systemic lupus erythematosus (SLE). Patients with SLE are well known to have an increased risk of various opportunistic infections, which can be fatal. Central nervous system (CNS) infections such as meningitis are rare complications to SLE. On occasion, nonspecific neurologic manifestations of infectious meningitis in SLE patients can be confused with neuropsychiatric lupus. Listeria monocytogenes is a less-commonly identified organism causing meningitis in SLE patients. Here, we describe a case of Listeria monocytogenes meningitis presenting with bilateral abducens nerve (sixth cranial nerve) palsy in a patient with SLE, who was successfully treated with systemic antibiotics.

Interstitial lung disease (ILD) is one of the common extra-articular manifestations of rheumatoid arthritis (RA). Bronchiolitis obliterans with organizing pneumonia (BOOP) is one type of ILD, and this is characterized by the proliferation of granulation tissue in the bronchioles, alveolar ducts and some alveoli and interstitial infiltration by chronic inflammatory cells. It develops as a manifestation of RA or as a side effect of anti-rheumatic drugs in patients with RA. We experienced a 41-year-old female patient with RA who developed BOOP during the treatment with methotrexate and bucillamine. She presented with cough and sputum for several months and pleuritic chest pain for one week. The chest radiograph showed bilateral multifocal consolidations. She received thoracoscopic biopsy and her pulmonary infiltrations resolved after the treatment with corticosteroid.

Objective: Interleukin (IL)-10 has been demonstrated to have anti-inflammatory and anti-tumour activity. Because aberrant angiogenesis is a significant pathogenic component of tumor growth and chronic inflammation, we investigated the effect of IL-10 on the production of vascular endothelial growth factor (VEGF) by the synovial fibroblasts derived from the patients with rheumatoid arthritis (RA). Methods: Fibroblast-like synoviocytes (FLS) were cultured with transforming growth factor (TGF-β) alone or with IL-10. The level of VEGF was measured by RT-PCR and enzyme-linked immunosorbent assay (using the 24, 48 and 72 h culture supernatants). The FLSs were cultured with TGF-b for 48 hr in the presence of PD98059 (an ERK inhibitor), curcumin and SP600125 (a JNK and Ap-1 inhibitor, respectively). The level of VEGF in the supernatants was measured by ELISA. Cell viability was assessed using MTT assay. The expressions of VEGF, ERK, AP-1 and IL-10 in the synovial tissue were quantified by immunohistochemistry. Results: IL-10 exhibited the inhibitory effect on VEGF production when the FLSs were stimulated with TGF-β. ERK and AP-1 inhibitors inhibited the TGF-β induced VEGF production.

BACKGROUND/AIMS: The bone marrow functions not only as the primary B-lymphocyte-producing organ but also as a secondary lymphoid organ for CD4 and CD8 cell responses and a site of preferential homing and persistence for memory T cells. Bone marrow T (BM-T) cells are distinguished from peripheral blood T cells by surface phenotype, cytokine secretion profile, and immune functions. In this study, we evaluated the alloreactive potential of donor lymphocyte infusion (DLI) using BM-T cells in mixed chimerism compared to that using spleen T (SP-T) cells. METHODS: Cells were prepared using established procedures. BM-T cells were obtained as a by-product of T-cell depletion in BM grafting and then cryopreserved for subsequent DLI. We performed DLI using BM-T cells in allogeneic mixed chimera mice on post-BMT day 21. RESULTS: When the same dose of T cells, 5-10x10(5) (Thy1.2+), fractionated from BM and spleen were administered into mixed chimeras, the BM-T group showed complete chimeric conversion, with self-limited graft-versus-host disease (GVHD) and no pathological changes. However, the SP-T group showed persistent mixed chimerism, with pathological signs of GVHD in the liver and intestine. CONCLUSIONS: Our results suggest that DLI using BM-T cells, even in small numbers, is more potent at inducing chimeric conversion in mixed chimerism than DLI using SP-T cells. Further study is needed to determine whether cryopreserved BM-T cells are an effective cell source for DLI to consolidate donor-dominant chimerism in clinical practice without concerns about GVHD.

Cytomegalovirus (CMV) infection commonly affects patients who are in an immunocompromised state, such as acquired immune deficiency syndrome (AIDS) and during organ transplantation. Although cytomegalovirus infection does not occur frequently, it is a major cause of morbidity and mortality in patients suffering with connective tissue diseases, including dermatomyositis. Cytomegalovirus pneumonitis and retinitis has been rarely reported in patients with dermatomyositis. We report here on an usual case involving the simultaneous occurrence of cytomegalovirus pneumonitis and retinitis in a 39-year-old female with dermatomyositis, and this woman had been treated with steroids and immunosuppressive agents for the previous 5 months.

Background & Objectives: Recently, T cells in BM have attracted renewed interest because they are now known to have different surface phenotypes, subsets, and activation states from those in the periphery. Memory T cells undergo extensive migration from the blood to the BM and vice versa. The BM plays an important role in preferential homing and extensive proliferation of memory T cells, and contributes considerably to the longlived memory T cell pool. BM T cells are more activated than their splenic counterparts and have a higher rate of local proliferation. Although BM-T (NK1.1– CD4+ or CD8+) cells did not induce lethal GVH disease, even at high cell numbers, BM-T cells mediated vigorous graft-versus-tumor activity and facilitated engraftment of hematopoietic progenitor cells. These studies suggested that BM-T cells could be a useful cellular source for adoptive immunotherapy following ABMT, instead of peripheral T cells. Non-myeloablative bone marrow transplantation (NMT) and allogeneic mixed chimerism can provide an environment adequate for diminishing susceptibility to DLI-mediated GVHD and an immunological platform for DLI in both mouse and human models. In patients treated with DLI, a successful GVL effect is often associated with conversion to complete donor chimerism, supporting the concept of a graft-versus-host (GVH) response as part of the GVL effect. Thus, a quiet chimeric conversion following DLI is desirable to reach an optimal DLI-mediated GVL effect, without the occurrence of GVHD. Although in a mouse model, the administration of non-tolerant donor spleen cells to established mixed chimeras has been shown to convert mixed hematopoietic chimerism to full donor chimerism, without the concomitant development of GVHD, DLI in humans frequently results in serious GVHD and life-threatening complications. However, the use of BM-T cells, as compared with spleen T cells (SP-T), as the DLI source has not been investigated in allogeneic mixed chimerism prepared with NMT. In this study, we evaluated the beneficial alloreactivity of DLI using cryopreserved BM-T cells, a by-product obtained during the T cell depletion (TCD) procedure in BM grafting, to effectively induce chimeric conversion without the occurrence of GVHD in MHC-mismatched NMT. Methods: Cells were prepared using established procedures. During the T cell depletion (TCD) procedure in BM grafting, BM-T cells were obtained as a by-product and then cryopreserved for subsequent DLI using BM-T cells 21 days after the bone marrow transplant. Results: The administration of 5–10 × 105 BM-T (Thy1.2+) cells in mixed chimeras resulted in complete chimeric conversion, with self-limited graft-versus-host disease (GVHD) and no pathological changes. However, the administration of 5–10 × 105 SP-T (Thy1.2+) cells resulted in persistent mixed chimerism, with pathological GVHD signs in the liver and intestine. Conclusion: Our results suggest that DLI using BM-T cells, even in small numbers, could be more potent for inducing chimeric conversion in mixed chimerism than DLI using SP-T cells. Further study is needed to determine whether cryopreserved BM-T cells are an effective cell source for DLI to consolidate donor-dominant chimerism in clinical practice, without concerns about GVHD.

Cryptococcal meningitis is a rare complication of systemic lupus erythematosus (SLE). The nonspecific neurologic findings associated with this infection delays accurate diagnosis because initial neuropsychiatric manifestations of SLE are in instances indistinguishable from that of crytococcal meningitis. We report a case of cryptococcal meningitis presenting with unilateral sixth cranial nerve palsy in a male patient with SLE, which was successfully treated with antifungal agents.