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ID PMID Title PublicationDate abstract
20737265 Ethnic differences in femur geometry in the women's health initiative observational study. 2011 May SUMMARY: Participants in the observational study of the Women's Health Initiative (WHI) were studied to determine if ethnic differences in femur geometry can help to explain differences in hip fracture rates. Structural differences in femurs of African and Mexican-American women appear to be consistent with lower rates of hip fractures vs. whites. INTRODUCTION: Ethnic origin has a major influence on hip fractures, but the underlying etiology is unknown. We evaluated ethnic differences in hip fracture rates among 159,579 postmenopausal participants in the WHI then compared femur bone mineral density (BMD) and geometry among a subset with dual X-ray absorptiometry (DXA) scans of the hip and total body. METHODS: The subset included 8,206 non-Hispanic whites, 1,476 African-American (AA), 704 Mexican-American (MA), and 130 Native Americans (NA). Femur geometry derived from hip DXA using hip-structure analysis (HSA) in whites was compared to minority groups after adjustment for age, height, weight, percent lean mass, neck-shaft angle and neck length, hormone use, chronic disease (e.g., diabetes, rheumatoid arthritis, cancer), bone active medications (e.g., corticosteroids, osteoporosis therapies), and clinical center. RESULTS: Both AA and MA women suffered hip fractures at half the rate of whites while NA appeared to be similar to whites. The structural advantage among AA appears to be due to a slightly narrower femur that requires more bone tissue to achieve similar or lower section moduli (SM) vs. whites. This also underlies their higher BMD (reduces region area) and lower buckling ratios (buckling susceptibility). Both MA and NA women had similar advantages vs. whites at the intertrochanter region where cross-sectional area and SM were higher but with no differences at the neck. NA and MA had smaller bending moments vs. whites acting in a fall on the hip (not significant in small NA sample). Buckling ratios of MA did not differ from whites at any region although NA had 4% lower values at the IT region. CONCLUSION: Differences in the geometry at the proximal femur are consistent with the lower hip fracture rates among AA and MA women compared to whites.
23000100 A novel small molecule, NecroX-7, inhibits osteoclast differentiation by suppressing NF-κ 2012 Nov 2 AIMS: Osteoclasts, the unique bone-resorbing polykaryons, are responsible for many bone-destructive diseases, such as osteoporosis and rheumatoid arthritis. Hence, the regulation of osteoclast formation is considered a potential therapeutic approach for these diseases. In this study, we investigated the effect of a novel small compound, C(25)H(32)N(4)O(4)S(2) (NecroX-7) on osteoclast formation. MAIN METHODS: We analyzed the effects of NecoX-7 on receptor activator of nuclear factor kappa B ligand (RANKL)-induced osteoclast differentiation in vitro and LPS-induced bone loss in vivo. KEY FINDINGS: We observed that NecroX-7 suppressed osteoclast formation from primary bone marrow macrophages (BMMs) in a dose-dependent manner. NecroX-7 significantly inhibited the NF-κB signaling pathway without affecting the activation of the mitogen-activated protein kinases (MAPKs) JNK, p38, and ERK in response to RANKL. In addition, NecroX-7 strongly attenuated the induction of c-Fos and nuclear factor of activated T cells c1 (NFATc1), which are crucial transcription factors for osteoclast differentiation. Mirroring the down-regulation of c-Fos and NFATc1, the expression of osteoclastogenic markers, such as tartrate-resistant acid phosphatase (TRAP) and cathepsin K, was also reduced by the addition of NecroX-7. Furthermore, confirming the in vitro anti-osteoclastogenic effect, NecroX-7 inhibited lipopolysaccharide (LPS)-induced bone loss in vivo. SIGNIFICANCE: Our data imply that NecroX-7 is useful as a therapeutic drug for the treatment of bone resorption-associated diseases.
22952725 Biochemical and functional studies of lymphoid-specific tyrosine phosphatase (Lyp) variant 2012 The Lymphoid specific tyrosine phosphatase (Lyp) has elicited tremendous research interest due to the high risk of its missense mutation R620W in a wide spectrum of autoimmune diseases. While initially characterized as a gain-of-function mutant, R620W was thought to lead to autoimmune diseases through loss-of-function in T cell signaling by a recent study. Here we investigate the biochemical characters and T cell signaling functions of two uncharacterized Lyp variants S201F and R266W, together with a previously characterized Lyp variant R263Q, which had reduced risk in several autoimmune diseases, including systemic lupus erythematosus (SLE), ulcerative colitis (UC) and rheumatoid arthritis (RA). Our kinetic and functional studies of R263Q polymorphism basically reproduced previous findings that it was a loss-of-function mutant. The other variant S201F reduced Lyp phosphatase activity moderately and decreased Lyp function in T cell slightly, while R266W severely impaired phosphatase activity and was a loss-of-function variant in T cell signaling. A combined kinetic and structure analysis suggests that the R266W variant may decrease its phosphatase activity through perturbing either the Q-loop or the WPD loop of Lyp. As both R266W and R263Q significantly change their phosphatase activity and T cell functions, future work could be considered to evaluate these mutants in a broader spectrum of autoimmune diseases.
22903665 Naturally occurring antibodies as therapeutics for neurologic disease: can human monoclona 2012 Naturally occurring autoantibodies (NAbs) are common in normal humans. The majority of NAbs are IgMs, but a small proportion are IgGs. Therefore a certain portion of pooled whole human IgG (IVIG) can be considered NAbs. While the applications of IVIG to modulate human disease have increased dramatically, the use of IgMs as drugs has lagged. In fact, much of the contaminating IgM component of IVIG is disposed of as waste. However, a number of model studies, including those targeting Alzheimer and multiple sclerosis (MS) suggest that IgMs may better modulate disease at much lower doses than IVIG. Our own studies in a model of MS show that polyclonal human IgM promotes better remyelination than IVIG and that monoclonal IgMs promote greater remyelination than monoclonal IgGs containing identical variable region sequences. We propose that this difference is due to the ability of IgM to cross link cell surface antigens better than IgGs and induce signals in nervous system cells. Monoclonal antibodies (mAbs) that promote remyelination induce a transient Ca(2+) influx in myelin forming cells, whereas IgGs with identical variable sequences do not. MAbs that promote remyelination were identified in human serum and in EBV-immortalized human B-cell lines obtained from normal adults, fetal cord blood, and rheumatoid arthritis and MS patients. Therefore therapeutic mAbs are present and common in normal circulation. All therapeutic mAbs were IgMs and bound to nervous system cells, however, the tissue binding patterns suggest that binding any one of multiple antigens induces repair. An expression vector was constructed that can manufacture gram quantities of recombinant monoclonal human IgM. Therefore the technology exists to determine whether human monoclonal NAbs can modulate human disease. IVIG can modulate neurologic disease, but using IVIG to treat these chronic diseases is unsustainable. A long-term solution is to identify the functional component of IVIG and test whether a recombinant human monoclonal can replicate its efficacy.
22830400 Large granular lymphocyte leukemia: from dysregulated pathways to therapeutic targets. 2012 Jul Large granular lymphocyte (LGL) leukemia is a clonal lymphoproliferative disorder of cytotoxic lymphocytes characterized by an expansion of CD3(+) cytotoxic T lymphocytes or CD3(-) natural killer cells. Patients present with various cytopenias including neutropenia, anemia and thrombocytopenia. In addition, there is an association of T-cell large granular lymphocytic leukemia with rheumatoid arthritis. It is believed that LGL leukemia begins as an antigen-driven immune response with subsequent constitutive activation of cytotoxic T lymphocytes or natural killer cells through PDGF and IL-15 contributing to their survival. Consequently, this leads to a dysregulation of apoptosis and dysfunction of the activation-induced cell death pathway. Treatment of LGL leukemia is based on a low-dose immunosuppressive regimen using methotrexate or cyclophosphamide. However, no standard of therapy has been established, as large prospective trials have not been conducted. In addition, some patients are refractory to treatment. The lack of a curative therapy for LGL leukemia means that new treatment options are needed. Insight into the various dysregulated signaling pathways in LGL leukemia may provide novel therapeutic treatment modalities.
22660804 Screening for cognitive impairment in systemic lupus erythematosus. 2012 Jul OBJECTIVE: We examined the association between responses on a screening questionnaire and objective performance on a computer-administered test of cognitive abilities in systemic lupus erythematosus (SLE). METHODS: The Cognitive Symptom Inventory (CSI) and Hospital Anxiety and Depression Scales (HADS) questionnaires were compared in patients with SLE or rheumatoid arthritis (RA). The Automated Neuropsychological Assessment Metrics (ANAM) was used to evaluate cognitive performance in patients with SLE. Efficiency of performance was measured by "throughput" (number of correct responses per minute) and "inverse efficiency" (response speed/proportion of correct responses). Linear regression was applied to log-transformed CSI scores to examine their associations with ANAM scores and other factors. RESULTS: Patients with SLE (n = 68) or RA (n = 33) were similar in age, sex, ethnicity, and education status (p > 0.05). Patients with SLE had higher total CSI scores (33.6 ± 10.5 vs 29.4 ± 6.8, respectively; p = 0.041) and attention/concentration subscale CSI scores (15.7 ± 5.3 vs 13.3 ± 3.4; p = 0.016) compared to patients with RA. In patients with SLE there was a positive association between CSI scores and neuropsychiatric (NP) events at the time of testing (p = 0.0006), HADS anxiety (p < 0.0001), and depression (p < 0.0001) scores. After adjustment for age, education, disease duration, and NP events at the time of testing, there was no significant association (p > 0.05) between ANAM and CSI scores in patients with SLE. The results were similar using either "throughput" or "inverse efficiency" or the number of impaired ANAM subscales after adjustment for simple reaction time. CONCLUSION: The CSI self-report questionnaire of cognitive symptoms does not reliably screen for efficiency of cognitive processing in patients with SLE. Rather, cognitive complaints reported in the CSI are influenced by the presence of anxiety and depression.
22442269 Gender-dependent skeletal effects of vitamin D deficiency in a younger generation. 2012 Jun CONTEXT: The major health threats caused by vitamin D deficiency in the young generation have not been fully elucidated. OBJECTIVE: The aim of this study was to investigate skeletal and nonskeletal effects of vitamin D deficiency and to study the optimal level of serum 25-hydroxyvitamin D [25(OH)D] in young people. DESIGN AND SETTING: The Fourth Korea National Health and Nutrition Examination Surveys (KNHANES IV) was conducted in 2008-2009. PARTICIPANTS: A total of 4276 people (1926 men and 2350 women) aged 10-40 yr were selected from 16 administrative districts of South Korea. MAIN OUTCOME MEASURES: We measured age-specific changes in bone mineral density (BMD) according to serum 25(OH)D. RESULTS: Serum 25(OH)D was less than 25 nmol/liter in 18.8% of participants, 25 to less than 50 nmol/liter in 50.0%, 50 to less than 75 nmol/liter in 27.0%, and 75 nmol/liter or greater in 4.2%. Vitamin D deficiency was more frequent in women than in men. There were gender differences in the skeletal effects of vitamin D deficiency. In men between 10 and 22 yr old, BMD was significantly higher in the vitamin D-sufficient group, and in men between 23 and 40 yr old, a positive correlation between serum 25(OH)D and BMD was observed. However, in women, we could not find significant differences in BMD according to vitamin D status. Vitamin D deficiency in younger generations had no remarkable effects on most nonskeletal parameters or on the prevalence of concomitant diseases except for rheumatoid arthritis. CONCLUSIONS: Vitamin D plays an essential role in skeletal health of young people. Moreover, the presence of gender-dependent skeletal effects was an important observation of this study. Reassurance of serum 25(OH)D up to 20-30 ng/ml or higher is necessary, especially during the modeling phase in men.
22350497 Non-steroidal anti-inflammatory drugs and gastroprotection with proton pump inhibitors: a 2012 Apr 1 Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most commonly prescribed agents for rheumatic disorders such as osteoarthritis (OA), rheumatoid arthritis (RA) and ankylosing spondylitis (AS). Despite the known association between NSAID use and gastropathy, however, only around one-third of patients at risk of NSAID-induced gastrointestinal toxicity receive adequate gastroprotection, and as many as 44% of these patients are non-adherent. We review the co-prescription of proton pump inhibitors (PPIs) for the prevention of NSAID-induced gastropathy, with a particular focus on the first fixed-dose NSAID/PPI formulation: ketoprofen/omeprazole modified-release capsules. The ketoprofen/omeprazole fixed-dose combination is available in doses of 100 mg/20 mg, 150 mg/20 mg or 200 mg/20 mg as a single capsule for once-daily administration. Ketoprofen monotherapy has been shown to be generally equivalent to other NSAIDs when used in the treatment of OA. In RA, ketoprofen has demonstrated equivalent efficacy to diclofenac, indometacin, piroxicam, aceclofenac, phenylbutazone, naproxen and flurbiprofen. Studies comparing ketoprofen with ibuprofen and sulindac in patients with RA have, in general, favoured ketoprofen. Studies in AS have generally reported similar efficacy between ketoprofen and phenylbutazone and pirprofen. Prophylaxis with omeprazole is effective for the prevention of gastroduodenal ulcers, maintenance of remission and alleviation of dyspeptic symptoms in NSAID recipients. Omeprazole is well tolerated, and adverse events are generally gastrointestinal in nature. The fixed-dose combination of ketoprofen and omeprazole has demonstrated bioequivalence to the respective monotherapies. The incidence of digestive symptoms and the need for dose reduction was reported to be lower with the combination than with its components. Ketoprofen/omeprazole modified-release capsules are the first fixed-dose NSAID/PPI formulation to be approved. This formulation ensures compliance with the gastroprotective prophylaxis, as whenever the NSAID is taken, the PPI is co-administered. Additionally, the once-daily formulation has the potential to improve adherence to anti-inflammatory therapy.
22233204 Lack of effect of tofacitinib (CP-690,550) on the pharmacokinetics of the CYP3A4 substrate 2012 Jul WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: • Tofacitinib (CP-690,550) is a novel, oral Janus kinase inhibitor being investigated as a targeted immunomodulator and disease-modifying therapy in rheumatoid arthritis. • Non-renal elimination accounts for 70% of the total clearance of tofacitinib and the metabolism is primarily mediated by cytochrome P450 (CYP) 3A4. • This study was required to determine the effect of tofacitinib on the in vivo pharmacokinetics of a sensitive CYP3A4 substrate. WHAT THIS STUDY ADDS: • The pharmacokinetics of midazolam, a sensitive CYP3A4 substrate, are not altered when co-administered with tofacitinib in healthy subjects. • Tofacitinib is unlikely to affect the clearance of drugs metabolized by CYP enzymes. • There is no need for dose adjustments of CYP substrates when co-administered with tofacitinib. AIMS: To investigate inhibitive and inductive effects of tofacitinib (CP-690,550), a Janus kinase inhibitor, on CYP3A4 function via in vitro and in vivo studies. METHODS: In vitro experiments were conducted to assess the inhibition and induction potential of tofacitinib for major drug metabolizing enzymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4). A phase 1, randomized, open-label, two-way crossover study (NCT00902460) was conducted to confirm the lack of inhibitive/inductive effect on a sensitive CYP3A4 substrate, midazolam, in healthy subjects. Midazolam pharmacokinetics were assessed over 24 h following single dose 2 mg administration prior to administering tofacitinib and after twice daily dosing of tofacitinib 30 mg for 6 days. The primary endpoint was midazolam area under the concentration-time profile, from time 0 to infinity (AUC(0,∞)). RESULTS: In vitro studies demonstrated low potential for CYP inhibition (IC(50) estimates tofacitinib > 30 µm), CYP3A4 mRNA induction (observed at tofacitinib concentrations ≥ 25 µm) and no effect on enzymatic activity of CYP substrates. In the human study, AUC(0,∞) adjusted geometric mean ratio for midazolam plus tofacitinib to midazolam alone was 103.97% [90% confidence interval (CI) 95.57, 113.12], wholly within the pre-specified acceptance region (80, 125). The 90% CI for the ratio of adjusted geometric means of maximum plasma concentration (C(max) ) (95.98, 108.87) was also wholly within this acceptance region. CONCLUSIONS: These data confirm a lack of an inhibitive or inductive effect of tofacitinib on CYP3A activity in humans and, in conjunction with in vitro data, support the conclusion that tofacitinib is unlikely to influence the CYP enzyme system as a whole.
23885314 Gastrointestinal-associated autoantibodies in different autoimmune diseases. 2012 BACKGROUND: Gastrointestinal (GI)-related autoantibodies (Abs) are rarely evaluated in autoimmune diseases (AID) other than inflammatory bowel disease, autoimmune hepatitis and celiac disease. Our aim was to determine the prevalence of these antibodies in a wide spectrum of AID. METHODS: We examined 923 serum samples representing 18 AID and compared them with 338 samples from healthy subjects. We used the BioPlex 2200-immunoassay (Bio-Rad, USA) to test samples for the presence of IgA and IgG directed at gliadin (AGA), tissue-transglutaminase (tTG), and Saccharomyces cerevisiae (ASCA). RESULTS: Prevalence of IgA AGA was significantly higher in antiphospholipid syndrome (APS) (7.1 %, P=0.012) and in pemphigus vulgaris (25%, P =0.008) patients, as compared with healthy controls. Presence of IgG-AGA was more common among Crohn's disease (20.5%, P = 0.023) and rheumatoid arthritis (6.5%, P=0.027) patients. IgG anti tTG were frequently observed in APS (6.1%, P=0.012), in giant cell arteritis (11.5%, P=0.013) and in ulcerative colitis (11.1%, P=0.018) patients, and as expected, higher prevalence of ASCA (IgA 19.3% and IgG 27.7%) was found in Crohn's disease. IgG ASCA were also found in systemic lupus erythematosus (SLE) (4.5%, P=0.01), in Graves' disease (5.7%, P=0.018), in cryoglobulinemia (7.1%, P=0.006), and in patients with vasculitides (6.5%, P=0.002). In contrast, lower prevalence of IgG type AGA was found in SLE (P=0.034), cryoglobulinemia (P=0.019) and vasculitides (P=0.013) patients. CONCLUSIONS: Our findings suggest an association between GI-related- Abs and a wide spectrum of AID. The clinical implication of these findings is yet to be determined.
22188392 Anti-TNF drugs in patients with hepatitis B or C virus infection: safety and clinical mana 2012 Feb INTRODUCTION: Drugs targeting TNF-α biological activity are increasingly used for the treatment of immune-mediated diseases, like rheumatoid arthritis, inflammatory bowel diseases and psoriasis. Since TNF-α is a mediator of the immune response against viral infections, use of TNF-α inhibitors in patients with concurrent HBV or HCV infection can promote viral reactivation and potentially fatal liver failure. AREAS COVERED: This paper reviews TNF mechanisms of action in viral hepatitis B and C, recommendations for managing HBV and HCV-infected patients receiving treatment with anti-TNF drugs, safety and anti-TNF hepatotoxicity. EXPERT OPINION: In hepatitis B surface antigen (HBsAg) carriers undergoing anti-TNF therapy, either anti-HBV treatment or prophylaxis is mandatory to prevent hepatitis reactivation, whereas HBsAg-negative antibody to hepatitis B core antigen (anti-HBc) seropositive patients require watchful monitoring, only. Conversely, in HCV-infected patients, TNF-α inhibition by specific drugs is safe and could be even beneficial, as TNF-α pathways are involved in perpetuating liver inflammation and fibrosis progression in HCV. HBV- or HCV-infected patients should be referred to a hepatologist for expert clinical management whenever antiviral therapy is deemed necessary or hepatitis reactivation occurs.
22060256 Depressive symptoms and health-related quality of life in breast cancer survivors. 2012 Mar BACKGROUND: Breast cancer diagnosis and treatment can have a profound influence on a woman's physical, psychosocial, and overall well-being. We examined the prevalence of depressive symptoms and its association with health-related quality of life (HRQOL) in women who are survivors of breast cancer. We also assessed if factors, including metastasis, cancer recurrence, diagnosis of new primary cancers, and comorbid conditions, are associated with depressive symptoms. METHODS: The Patient Health Questionnaire (PHQ-8) and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 were mailed to assess depressive symptoms and HRQOL, respectively, in breast cancer patients who received cancer treatment in a large tertiary cancer center. RESULTS: Two hundred forty patients participated (56% response rate and 6-13 years since treatment). The mean score on the PHQ-8 scale was 4 points (standard deviation [SD] 4.8, median 2.0). Sixteen percent had PHQ-8 score ≥10 and were categorized as depressed. Depression was inversely associated with HRQOL subscales for functioning, financial, and global health and positively associated with symptoms. Logistic regression showed that younger age (odds ratio [OR] age in years 0.92, 95% confidence interval [CI] 0.86- 0.99, p<0.02), rheumatoid arthritis (OR 8.4, 95%CI 1.3-57.4, p<0.03), and years from treatment (OR 0.70, 95% CI 0.46-0.99, p<0.05) were significant correlates of depression. CONCLUSIONS: Depression is a significant health concern for breast cancer survivors and is associated with lower HRQOL. The results suggest the need to monitor women with breast cancer for depression and provide resources for treating depression during the survival period.
23127799 Characterization of fibrinogen-like protein 2 (FGL2): monomeric FGL2 has enhanced immunosu 2013 Feb Fibrinogen-like protein 2 (FGL2), a novel effector molecule of CD4(+)CD25(+)Foxp3(+) regulatory T cells (Treg), mediates its suppressive activity through binding to low affinity Fcγ receptors expressed on antigen presenting cells (APCs). FGL2 has been implicated in the pathogenesis of viral hepatitis, xeno- and allotransplant rejection, and rheumatoid arthritis. Here we fully analyzed the structure-function relationships of recombinant murine FGL2 generated in COS-7 cells and identified the receptor binding domains. Native FGL2 exists as an oligomer with a molecular weight of approximately 260 kDa, while under reducing conditions, FGL2 has a molecular weight of 65 kDa suggesting that native FGL2 is composed of four monomers. By site-directed mutation, cysteines at positions 94, 97, 184 and 187, found in the coiled-coil domain were shown to be crucial for FGL2 oligomerization. Monomeric FGL2 had a lower affinity binding to APCs, but increased immunosuppressive activity compared to oligomeric FGL2. Deglycosylation demonstrated that sugar moieties are critical for maintaining solubility of FGL2. SWISS-MODEL analysis suggested that FGL2 has a similar tertiary structure with other members of the fibrinogen family such as fibrinogen and tachylectin. Mutational analysis of cysteine residues and Western blots suggested an asymmetric bouquet-shaped quaternary structure for oligomeric FGL2, resembling many pattern-recognition molecules in the lectin pathway of innate immunity. The functional motifs of FGL2 were mapped to the C terminal globular domain, using a peptide blockade assay. These results collectively define the biochemical and immunological determinants of FGL2, an important immunosuppressive molecule of Treg providing important insights for designing FGL2-related therapeutics.
23000338 Crosstalk between VEGF and novel angiogenic protein regulates tumor angiogenesis and contr 2013 Jan We have identified and characterized a novel proangiogenic glycoprotein (NAP) with molecular weight of 67 kDa from synovial fluid of rheumatoid arthritis patients. Proteomic analysis of the protein revealed 29% sequence coverage with maximum identity for human retinoblastoma binding protein 2. N-terminal amino acid sequence showed no identity to recently discovered protein sequences. NAP was also identified in both normal and tumor cell lines by Western blotting. NAP is a permeability factor as verified by miles permeability assay. The proangiogenic potential of NAP was identified using shell less CAM, rat cornea and tumor on CAM assays. NAP induces expression of VEGF and Flt-1 gene as verified by promoter reporter gene analysis. Further NAP induces proliferation of endothelial cells and formation of tube like structures. NAP is also involved in migration and invasion of tumor cells. Clinical data revealed the presence of NAP in breast cancer biopsies. We have developed monoclonal antibody (mAb), and specific ELISA, which confirmed the presence of NAP in the cytosol of tumor cells. The mAb effect was evaluated with established angiogenic assays. Further, we investigated the detailed mechanism by which NAP induces angiogenesis. NAP is phosphorylated by VEGF induced activation of MAPK and JNK pathways through VEGFR2 phosphorylation. NAP involves JNK pathway predominantly with further activation of NFκB in downstream processing of VEGF activation. Together these findings establish that NAP displays angiogenic properties and promotes efficient neovascularization both in vitro and in vivo models. These observations suggest that anti-NAP-mAb can be targeted for antiangiogenic therapy of cancer.
22980031 Recombinant IL-6 treatment protects mice from organ specific autoimmune disease by IL-6 cl 2013 Feb Cytokines are key regulators of physiological inflammatory responses, while aberrant cytokine expression contributes to pathogenesis of autoimmune diseases. We noted increased IL-6 levels in human and murine epidermolysis bullosa acquisita (EBA), a prototypic organ-specific autoimmune bullous dermatoses (AIBD) induced by autoantibodies to type VII collagen (COL7). In contrast to rheumatoid arthritis, blockade of IL-6 led to strikingly enhanced experimental EBA, while treatment with recombinant IL-6 was protective. This was due to classical IL-6 signalling and independent of IL-6 trans-signalling, as treatment of mice with sgp130Fc had no impact on EBA manifestation. Induction of EBA in mice led to increased IL-1ra levels in skin and serum, while blockade of IL-6 completely inhibited IL-1ra expression induced by autoantibodies to COL7. In line, treatment of mice with EBA with recombinant IL-6 induced IL-1ra concentrations exceeding those of untreated animals with EBA, and IL-1ra (anakinra) administration significantly impaired experimental EBA induction. We here identified a novel anti-inflammatory pathway in an organ-specific autoimmune disease. Modulation of this IL-1ra pathway by classical IL-6 signalling demonstrates anti-inflammatory and protective activities of IL-6 in vivo.
22890824 Interleukin-15 plays an essential role in the pathogenesis of autoimmune diabetes in the N 2012 Nov AIMS/HYPOTHESIS: IL-15, induced by innate immune stimuli, promotes rheumatoid arthritis and inflammatory bowel disease. However, its role in autoimmune type 1 diabetes is unclear. Our aim is to define the role of IL-15 in the pathogenesis of diabetes in the NOD mouse model. METHODS: We generated NOD.Il15(-/-) mice expressing a polyclonal repertoire of T cell antigen receptor (TCR) or a transgenic TCR and monitored diabetes onset and insulitis. NOD Scid.Il15(-/-) (full name NOD.CB17-Prkdc (scid)/NCrCrl) and NOD Scid.gamma (full name NOD.Cg-Prkdc(scid) Il2rg ( tm1Wjl )/SzJ) mice were used to distinguish the requirement for IL-15 signalling in CD8(+) T cells and antigen-presenting cells (APCs) to induce disease. We examined the effect of blocking IL-15 signalling on diabetes onset in NOD mice. RESULTS: At 7 months of age, more than 75% of the NOD Il15(-/-) female mice remained diabetes free compared with only 30% in the control group. Diabetes incidence was also decreased in 8.3-NOD (full name NOD Cg-Tg[TcraTcrbNY8.3]-1Pesa/DvsJ).Il15(-/-) mice expressing a highly pathogenic transgenic TCR on CD8(+) T cells. Adoptive transfer of splenocytes from diabetic NOD and 8.3-NOD donors induced disease in NOD Scid recipients but not in NOD Scid.Il15(-/-) or NOD Scid.gamma mice. Transient blockade of IL-15 signalling at the onset of insulitis prevented diabetes in NOD mice. CONCLUSIONS/INTERPRETATION: Our results show that IL-15 is needed for the initial activation of diabetogenic CD8(+) T cells as well as for sustaining the diabetogenic potential of antigen-stimulated cells, acting on both CD8(+) T cells and on APCs. Our findings demonstrate a critical role for IL-15 in the pathogenesis of autoimmune diabetes and suggest that IL-15 is a promising therapeutic target.
22734797 Association between -174 interleukin-6 gene polymorphism and biological response to rituxi 2012 Sep Rituximab has become a pivotal treatment for systemic autoimmune diseases. The aim of this study was to determine whether the genetic variant -174 IL-6 contributes to differences in the response to rituximab in patients with systemic autoimmune diseases, including systemic lupus erythematosus (SLE), inflammatory myopathies, anti-neutrophil cytoplasmic antibody-mediated vasculitis, systemic sclerosis, Sjöegren's syndrome, rheumatoid arthritis, and autoimmune hemolytic anemia. DNA samples from 144 Spanish patients with different systemic autoimmune diseases receiving rituximab were genotyped for -174 IL-6 (rs1800795) gene polymorphism using the TaqMan(®) allelic discrimination technology. Six months after the first infusion with rituximab, we evaluated the response to the drug: 60.4% of the patients showed a complete response, partial 27.8%, and 11.8% did not respond to the treatment. The CC genotype frequency was significantly increased in nonresponders with respect to responders (23.5% vs. 7.1%, respectively; p=0.049; odds ratio (OR)=4.03, 95% confidence intervals (CI) 0.78-16.97). According to the genotype distribution, rituximab was effective in 69.2% of the CC carriers, 91.9% of the CG carriers, and 88.4% of the GG carriers. A similar trend was observed when SLE patients were analyzed separately (27.3% carried CC homozygosis in nonresponders and 6.9% in responders; p=0.066; OR=5.10, 95% CI 0.65-31.73). Rituximab was effective in 62.5% of the CC carriers, 88.9% of the GC carriers, and 90% of the GG carriers. These results suggest that -174 IL-6 (rs1800795) gene polymorphism plays a role in the response to rituximab in systemic autoimmune diseases. Validation of these findings in independent cohorts is warranted.
22659743 Sphingosine 1-phosphate receptor activation enhances BMP-2-induced osteoblast differentiat 2012 Jun 22 We previously demonstrated that sphingosine 1-phosphate (S1P) receptor-mediated signaling induced proliferation and prostaglandin productions by synovial cells from rheumatoid arthritis (RA) patients. In the present study we investigated the role of S1P receptor-mediated signaling for osteoblast differentiation. We investigated osteoblast differentiation using C2C12 myoblasts, a cell line derived from murine satellite cells. Osteoblast differentiation was induced by the treatment of bone morphogenic protein (BMP)-2 in the presence or absence of either S1P or FTY720 (FTY), a high-affinity agonist of S1P receptors. Osteoblast differentiation was determined by osteoblast-specific transcription factor, Runx2 mRNA expression, alkaline phosphatase (ALP) activity and osteocalcin production by the cells. Smad1/5/8 and extracellular signal-regulated kinase (ERK) 1/2 phosphorylation was examined by Western blotting. Osteocalcin production by C2C12 cells were determined by ELISA. Runx2 expression and ALP activity by BMP-2-stimulated C2C12 cells were enhanced by addition of either S1P or FTY. Both S1P and FTY enhanced BMP-2-induced ERK1/2 and Smad1/5/8 phosphorylation. The effect of FTY was stronger than that of S1P. S1P receptor-mediated signaling on osteoblast differentiation was inhibited by addition of mitogen-activated protein kinase/ERK kinase (MEK) 1/2 inhibitor, indicating that the S1P receptor-mediated MEK1/2-ERK1/2 signaling pathway enhanced BMP-2-Smad signaling. These results indicate that S1P receptor-mediated signaling plays a crucial role for osteoblast differentiation.
22658256 META060 attenuates TNF-α-activated inflammation, endothelial-monocyte interactions, and m 2012 Jul BACKGROUND: Cytokine-induced monocyte-endothelial interaction and vascular inflammation play a critical role in atherogenesis. A modified hop extract, META060, was identified as an inhibitor of inflammatory mediators in human rheumatoid arthritis synovial fibroblasts. OBJECTIVE: To determine how META060 may impact the initial stages of atherosclerosis, we investigated the effects of META060 in endothelial and monocyte cell models. METHODS: and results: TNF-α (10 ng/mL)-activated human monocytic THP-1 cells adhered to human aortic endothelial cells (HAECs); pre-treatment of cells with META060 (10 μg/mL) significantly inhibited cell adhesion. META060 (1-20 μg/mL) inhibited TNF-α-induced expression of inflammatory mediators including IL-1β, MCP-1 and RANTES in HAECs and THP-1 cells. TNF-α- or LPS-mediated MMP-9 protein levels (measured by an immunoassay) and enzyme activity (determined by zymography) were inhibited by META060 in a dose-dependent manner. Data from transcription factor screening assays showed that META060 selectively inhibited NF-κB and AP-1 in THP-1 cells, suggesting that META060 regulated inflammatory markers through gene regulation. CONCLUSION: META060 inhibited monocyte-endothelial cell interactions and suppressed multiple biomarkers of inflammation in both a monocytic cell line and an endothelial cell line. MMP-9 expression and activity also were inhibited. These effects resulted in part from META060's inhibition of transcription factors NF-κB and AP-1. META060 may have beneficial effects for prevention or treatment of cardiovascular diseases by ameliorating inflammation and plaque destabilization, which are hallmarks of atherosclerosis.
22337239 In vivo peripheral blood proinflammatory T cells in patients with ankylosing spondylitis. 2012 Apr OBJECTIVE: Previous reports have shown an increase in peripheral blood mononuclear cells' (PBMC) Th17 cell subpopulation and tumor necrosis factor-α (TNF-α) secretion after in vitro stimulation with anti-CD3/CD28 or phorbol myristate acetate/ionomycin in ankylosing spondylitis (AS). The aim of our study was to determine whether there is a Th17 polarization not subjected to in vitro stimulation in patients with AS. METHODS: Nonstimulated PBMC were analyzed from 46 patients with AS, including 7 (15.2%) receiving tumor necrosis factor-α (TNF-α) inhibitors, 20 patients with rheumatoid arthritis, and 25 healthy controls. The surface phenotype of freshly isolated PBMC was determined by flow cytometry. Th1, Th2, Th17, and Treg subsets were defined as CD3+CD4+IFN-γ+, CD3+CD4+IL-4+, CD3+CD4+IL-17A+, and CD3+CD4+FoxP3+, respectively. Serum cytokines and interleukin 8 (IL-8) levels were quantified by Luminex technology. RESULTS: The percentages of Th17 and Th1 cells in AS were higher than in healthy controls (7.4% ± 1.8% vs 0.7% ± 0.2% and 4.0% ± 1.3% vs 1.1% ± 0.3%, respectively; p < 0.0001). Th17 and Th1 cell subsets in patients taking TNF-α inhibitors were lower than in those naive to such therapeutics and similar to healthy controls. Serum levels of IL-6, IL-17A, TNF-α, and IL-8 were significantly higher in patients with AS compared to controls. CONCLUSION: The percentages of Th17 and Th1 cells in PBMC without in vitro stimulation, as well as cytokine and IL-8 levels, were significantly increased in patients with AS compared with healthy controls. These T cell subsets and cytokine profiles of patients with AS taking TNF-α inhibitors were similar to those of healthy controls.