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ID PMID Title PublicationDate abstract
20863903 Atherosclerosis and macrovascular involvement in systemic sclerosis: myth or reality. 2011 Mar Systemic sclerosis (SSc) is a chronic disease of unknown etiology, characterized by enhanced fibrosis, and microvascular abnormalities. During the past several decades, the death rates due to cardiovascular disease or cerebrovascular disease in SSc patients substantially increased and are currently responsible for 20-30% of mortality. Various autoimmune rheumatic diseases such as rheumatoid arthritis and systemic lupus erythematosus accelerate atherosclerosis. Although microvascular disease is a hallmark of SSc, an ongoing debate exists regarding the presence and extent of macrovascular diseases and the presence of accelerated atherosclerosis in SSc patients. Despite conflicting results as to intima-media thickness (IMT) in SSc patients, the most recent and largest study has found no difference in either plaque occurrence or IMT. Additionally, abnormal coronary flow reserve in SSc patients appears to be due to microvascular involvement rather than atherosclerosis of the epicardial coronary arteries. Angiographic findings as well as computed tomography studies have generated conflicting reports as to coronary atherosclerosis in SSc. Herein, we review the current knowledge of macrovascular involvement and atherosclerosis in SSc. The differences between SSc and other autoimmune rheumatic diseases in the presence and extent of atherosclerosis need to be further investigated.
20595267 The patient activity scale-II is a generic indicator of active disease in patients with rh 2010 Sep OBJECTIVE: To determine whether the Patient Activity Scale-II (PAS-II) is a generic measure of disease activity by assessing whether the relationship of PAS-II with treatment decision (indicating disease activity) is invariant across disease. METHODS: The Health Assessment Questionnaire-II (HAQ-II), a 10 cm visual analog scale for "pain," and another for "patient global assessment" were recorded from 1000 consecutive patients attending rheumatology outpatient clinics. Active disease was defined as treatment intensity increased and inactive disease was defined as treatment intensity unchanged or decreased. A logistic regression analysis was conducted with active disease as the dependent variable and the predictor variables were PAS-II, diagnostic category, and the interaction between diagnostic category and PAS-II. RESULTS: PAS-II had a weak but statistically significant association with active disease that was independent of diagnosis. An increase of 1 point in PAS-II increased the odds of being in the active disease state by 1.19 (95% CI 1.10 to 1.37). The relationship between active disease state and PAS was not affected by diagnostic category. CONCLUSION: PAS-II can be used as a generic self-report indicator of active disease across different rheumatic disorders, and not just in rheumatoid arthritis. The strength of the relationship with disease activity is weak and physician-derived indicators remain very important.
20583029 IL-6: regulator of Treg/Th17 balance. 2010 Jul IL-6 is a pleiotropic cytokine involved in the physiology of virtually every organ system. Recent studies have demonstrated that IL-6 has a very important role in regulating the balance between IL-17-producing Th17 cells and regulatory T cells (Treg). The two T-cell subsets play prominent roles in immune functions: Th17 cell is a key player in the pathogenesis of autoimmune diseases and protection against bacterial infections, while Treg functions to restrain excessive effector T-cell responses. IL-6 induces the development of Th17 cells from naïve T cells together with TGF-beta; in contrast, IL-6 inhibits TGF-beta-induced Treg differentiation. Dysregulation or overproduction of IL-6 leads to autoimmune diseases such as multiple sclerosis (MS) and rheumatoid arthritis (RA), in which Th17 cells are considered to be the primary cause of pathology. Given the critical role of IL-6 in altering the balance between Treg and Th17 cells, controlling IL-6 activities is potentially an effective approach in the treatment of various autoimmune and inflammatory diseases. Here, we review the role of IL-6 in regulating Th17/Treg balance and describe the critical functions of IL-6 and Th17 in immunity and immune-pathology.
20392164 The lysosome among targets of metformin: new anti-inflammatory uses for an old drug? 2010 May BACKGROUND: Rheumatoid arthritis and type-2 diabetes exhibit progressive co-morbidity. Chloroquine (CQ) reportedly improves both. CQ inhibits lysosomal function in cultured cells at supra-therapeutic concentration; however, this is doubted as target mechanism. Some anti-diabetic biguanides are metal-interactive lysosomal inhibitors; and all bind Zn(2+). OBJECTIVES: i) To bioassay the potency of CQ using (3)H-leucine release from perfused myocardial tissue. ii) To determine whether metformin (MET) is CQ-mimetic, and interactive with Zn(2+). RESULTS: Therapeutic CQ concentration (0.1 - 0.5 microM) clearly does cause lysosomal inhibition although delayed and submaximal. MET alone (10 microM) caused sub-maximal inhibition. Supra-physiological extracellular Zn(2+) (5 - 50 microM) alone increased tissue Zn(2+) content, and inhibited lysosomal proteolysis. Physiological equivalent Zn(2+) (approximately 1 microM) had no effect. MET (
20375986 The Th17 immune response in renal inflammation. 2010 Jun The discovery of interleukin (IL)-17-producing CD4(+) T (Th17) cells as a unique T-helper cell lineage has revised our understanding of T-cell-mediated tissue injury. Recent data from studies in humans and mice indicate that autoimmune diseases such as multiple sclerosis and rheumatoid arthritis, classically believed to be Th1-mediated, are predominantly driven by a Th17 immune response. IL-17 (IL-17A), IL-17F, IL-21, IL-22, and possibly also IL-9 produced by Th17 cells promote inflammation by directly causing tissue injury and enhancing secretion of pro-inflammatory cytokines and chemokines by resident cells. This results in augmented infiltration of leukocytes, in particular neutrophils, to the affected tissue where they induce organ inflammation and injury. Recent studies have highlighted the potential importance of the Th17 immune response also in renal inflammatory disease. This includes the identification and characterization of IL-17-producing T cells in nephritic kidneys of mice and humans, as well as evidence for the contribution of IL-17 and the IL-23/Th17 axis to renal tissue injury in glomerulonephritis. In this review, we will briefly summarize general characteristics of Th17 cells and discuss in detail the potential role of the Th17 immune response in human and experimental renal inflammation with a special focus on glomerulonephritis.
20207526 Conjugated linoleic acid and inflammatory cell signalling. 2010 Apr Conjugated linoleic acids (CLA) are a family of polyunsaturated fatty acids (PUFA), some isomers occurring naturally in beef and dairy products and others being formed as a result of bihydrogenation of vegetable oils to form margarine. Synthetic and natural sources of CLA may have beneficial effects in a range of inflammatory conditions including colitis, atherosclerosis, metabolic syndrome and rheumatoid arthritis. Most of the biological effects have been attributed to the cis9, trans11- (c9, t11-) and the trans10, cis12- (t10, c12-) isomers. Evidence suggests that c9, t11-CLA is responsible for the anti-inflammatory effect attributed to CLA while t10, t12-CLA appears to be responsible for anti-adipogenic effects. This review will focus on the effects of CLA on the inflammatory components associated with insulin resistance, atherosclerosis and Th1 mediated inflammatory disease, at a cellular, systemic and clinical level. Whist CLA may ameliorate certain aspects of the inflammatory response, particularly within cellular and animal models, the relevance of this has yet to be clarified within the context of human health.
20196720 Osteopontin; as a target molecule for the treatment of inflammatory diseases. 2010 Apr It has been well recognized that inflammatory responses are part of pathogenesis for various disorders such as autoimmune diseases. For example, multiple sclerosis (MS) is an inflammatory demyelinating disease of central nervous system that is presumably caused by activated T cells specific for myelin antigens. Rheumatoid arthritis (RA) is also a chronic inflammatory disease characterized by synovial inflammation in which several inflammatory cytokines are involved. On the other hand, Osteopontin (Opn) is a pleiotropic cytokine expressed by activated T cells, dendritic cells (DCs) and macrophages and its expression is up-regulated during inflammation. Secreted form of Opn (s-Opn), which is modified by phosphorylation, glycosylation and proteolytic cleavage with thrombin, has activities as a T helper type 1 (Th1) cytokine and as a chemoattractant for many types of cells through integrin receptors and CD44. Recently, it has been uncovered that intracellular form of Opn (i-Opn) is a critical regulator for Toll like receptor-9 (TLR-9), TLR-7-dependent interferon-alpha (IFN-alpha) expression by plasmacytoid DCs and Th17 development. In this review, we have summarized recent progress in understanding of Opn's role in variety of inflammatory disorders.
20055719 Dickkopf-1 as a potential therapeutic target in Paget's disease of bone. 2010 Feb IMPORTANCE OF THE FIELD: Wnt signalling plays a role in maintaining healthy bone mass. Dickkopf-1 (DKK-1) is a soluble inhibitor of Wnt signalling and its excessive expression contributes to bone loss in rheumatoid arthritis and multiple myeloma. New therapeutics have been developed for treatment of these conditions that target DKK-1 expression. DKK-1 is elevated in serum of patients with Paget's disease of the bone (PDB) and evidence is accumulating for a role of DKK-1 in PDB. AREAS COVERED IN THIS REVIEW: The role of Wnt signalling and DKK-1 in bone health and disease and the aetiology of PDB in the light of recent advances in understanding of Wnt signalling. WHAT THE READER WILL GAIN: PDB is a disorder of unknown aetiology characterised by localised increase in unregulated bone remodelling resulting in osteolytic and osteosclerotic lesions. Evidence is adduced for the involvement of Wnt signalling, DKK-1 and osteoblasts in PDB pathogenesis. TAKE HOME MESSAGE: At present there is no cure for PDB and the current treatment of choice are bisphosphonates. These treat the resorptive phase of PDB but do not prevent its return. We present a new perspective on the aetiology of PDB and speculate on DKK-1 as a therapeutic target.
20018064 Single versus multiple imputation for genotypic data. 2009 Dec 15 Due to the growing need to combine data across multiple studies and to impute untyped markers based on a reference sample, several analytical tools for imputation and analysis of missing genotypes have been developed. Current imputation methods rely on single imputation, which ignores the variation in estimation due to imputation. An alternative to single imputation is multiple imputation. In this paper, we assess the variation in imputation by completing both single and multiple imputations of genotypic data using MACH, a commonly used hidden Markov model imputation method. Using data from the North American Rheumatoid Arthritis Consortium genome-wide study, the use of single and multiple imputation was assessed in four regions of chromosome 1 with varying levels of linkage disequilibrium and association signals. Two scenarios for missing genotypic data were assessed: imputation of untyped markers and combination of genotypic data from two studies. This limited study involving four regions indicates that, contrary to expectations, multiple imputations may not be necessary.
19960866 The molecular basis of lactose intolerance. 2009 A staggering 4000 million people cannot digest lactose, the sugar in milk, properly. All mammals, apart from white Northern Europeans and few tribes in Africa and Asia, lose most of their lactase, the enzyme that cleaves lactose into galactose and glucose, after weaning. Lactose intolerance causes gut and a range of systemic symptoms, though the threshold to lactose varies considerably between ethnic groups and individuals within a group. The molecular basis of inherited hypolactasia has yet to be identified, though two polymorphisms in the introns of a helicase upstream from the lactase gene correlate closely with hypolactasia, and thus lactose intolerance. The symptoms of lactose intolerance are caused by gases and toxins produced by anaerobic bacteria in the large intestine. Bacterial toxins may play a key role in several other diseases, such as diabetes, rheumatoid arthritis, multiple sclerosis and some cancers. The problem of lactose intolerance has been exacerbated because of the addition of products containing lactose to various foods and drinks without being on the label. Lactose intolerance fits exactly the illness that Charles Darwin suffered from for over 40 years, and yet was never diagnosed. Darwin missed something else--the key to our own evolution--the Rubicon some 300 million years ago that produced lactose and lactase in sufficient amounts to be susceptible to natural selection.
19855968 Dermatomyositis and HIV infection: case report and review of the literature. 2011 May Since the 1980s, a host of autoimmune phenomena and rheumatologic illnesses have been linked to infection with the human immunodeficiency virus (HIV). Given the broad effects of this virus on both the humoral and cell-mediated arms of the immune system, illnesses such as polymyositis and Reiter's syndrome appear to be more prevalent in HIV-infected individuals and occur in the absence of well-described predispositions. The activities of some rheumatologic illnesses exhibit an inverse relationship with the course of HIV infection, such as rheumatoid arthritis, which becomes more quiescent with advancing disease. Dermatomyositis is a rheumatologic illness that very infrequently occurs and during our review of literature only three other cases were reported. We present the case of a Caucasian male in his mid-20s who presented with acquired immunodeficiency syndrome and subsequently developed dermatomyositis. In this review, we highlight the current relationship between HIV infection and autoimmunity, the possible ways HIV infection may foster an environment favorable for the development of dermatomyositis, and review the previously reported cases of individuals with HIV infection who developed dermatomyositis. The complex issues of how to treat individuals with HIV and dermatomyositis is also discussed.
19768575 TIM-3 as a new therapeutic target in systemic lupus erythematosus. 2010 Jan T-cell immunoglobulin- and mucin-domain-containing molecule-3 (TIM-3) was the first surface molecule that specifically identifies Th1 cells in both mice and human. Recently, identification of Galectin-9 as a ligand for TIM-3 has established the TIM-3-Galectin-9 pathway as an important regulator of Th1 immunity and tolerance induction. Many previous studies have demonstrated that TIM-3 influences chronic autoimmune diseases, such as multiple sclerosis and rheumatoid arthritis. In addition, association of TIM-3 polymorphisms with susceptibility to several autoimmune diseases has been identified. Recent work has explored the role of TIM-3 in systemic lupus erythematosus (SLE), and their results indicate that TIM-3 may represent a novel target for the treatment of SLE. In this review, we will discuss the TIM-3 pathway and the therapeutic potential of modulating the pathway in SLE.
19760074 Targeting CD30/CD30L in oncology and autoimmune and inflammatory diseases. 2009 The transmembrane receptor CD30 (TNFRSF8) and its ligand CD30L (CD153, TNFSF8) are members of the tumor necrosis factor (TNF) superfamily and display restricted expression in subpopulations of activated T-and B-cells in nonpathologic conditions. CD30 expression is upregulated in various hematological malignancies, including Reed-Sternberg cells in Hodgkin's disease (HD), anaplastic large cell lymphoma (ALCL) and subsets of Non-Hodgkin's lymphomas (NHLs). Increased CD30L expression was found on mast cells within HD tumors and preclinical and clinical studies with compounds targeting the CD30/ CD30L system in HD and ALCL demonstrated therapeutic benefit. Upregulation of CD30 and CD30L is also linked to leukocytes in patients with chronic inflammatory diseases, including lupus erythematosus, asthma, rheumatoid arthritis and atopic dermatitis (AD). Preclinical studies conducted with transgenic mice or biologic compounds suggested important regulatory functions of the CD30-CD30L system in various aspects of the immune system. Such key regulatory roles and their low expression in normal conditions combined with increased expression in malignant tissues provided a strong rationale to investigate CD30 and CD30L as therapeutic targets in hematologic malignancies, autoimmune and inflammatory diseases. In this report, we review the pharmacodynamic effects of specific therapeutic compounds targeting the CD30/CD30L system in preclinical- and clinical studies.
19603540 Treating MS: getting to know the two birds in the bush. 2009 Jul Current therapies for immune-mediated diseases, such as rheumatoid arthritis and MS, could represent the proverbial bird in the hand - a known entity, yet limited in potential. Emerging biologic therapeutics for these diseases carry with them the potential for known as well as unknown adverse effects. Alemtuzumab, a biologic that depletes leukocytes, shows great promise for the treatment of MS. However, a significant number of patients develop autoimmunity after treatment, raising the level of caution for the use of this drug. In this issue of the JCI, Jones et al. describe a link between IL-21 levels and alemtuzumab-associated autoimmunity (see the related article beginning on page 2052). They show that proliferation of lymphocytes in those patients with autoimmunity is higher than in those without autoimmunity and suggest that the lymphopenia-driven proliferation of T cells, in combination with higher IL-21 levels, results in autoimmunity. This study helps inspire new enthusiasm for making a grab for the proverbial two birds in the bush - representing undiscovered therapies - with greater confidence.
19500629 STAT4 gene polymorphism is associated with psoriasis in the genetically homogeneous popula 2009 Sep Recent genome-wide association studies (GWAS) of many complex diseases have successfully identified novel susceptibility loci, with many of them being associated with more than one condition. Taking into consideration that different autoimmune diseases may share some common pathogenetic pathways, we hypothesized that STAT4, a susceptibility gene found to be associated with increased risk for systemic lupus erythematosus, rheumatoid arthritis, type 1 diabetes, Sjögren's syndrome, Wegener's granulomatosis, Crohn's disease, and ulcerative colitis may also have a role in psoriasis. Psoriasis is an autoimmune, chronic inflammatory skin disease. Here we performed a case-control study in the population of island of Crete and demonstrated for the first time the association of a STAT4 single nucleotide polymorphism (SNP) with susceptibility to psoriasis, thus suggesting a putative key role of STAT4 in multiple autoimmune diseases. We found that mutated allele T of the STAT4 rs7574865 SNP, which previously was implicated in the predisposition to many autoimmune diseases, were more common in individuals with psoriasis than in controls (p = 0.045, odds ratio = 1.42, 95% confidence interval 1.01-2.00), thus concluding that the polymorphism examined is associated with the development of psoriasis in our population.
19426249 Innate immunity and toll-like receptor antagonists: a potential role in the treatment of c 2009 Summer Toll-like receptors (TLRs) are germline-encoded receptors that recognize various pathogen-associated molecular patterns (PAMPs). They are key components of the innate immunity which are activated in response to pathogens as well as non-pathogenic components of damaged tissues. TLR agonists have been developed to treat allergies, cancers, and chronic infections by upregulating the innate immune system. TLR antagonists may be used to treat a number of inflammatory conditions, such as rheumatoid arthritis and systemic lupus erythematosus. Recent research also has shown that TLRs are involved in the pathogenesis of atherosclerosis, thrombosis, myocardial remodeling, ischemic/reperfusion injury, and valvular disease. This article reviews the current experimental and clinical evidence for the role of TLRs in the cardiovascular system, and examines the mechanisms by which TLR antagonists could potentially be used in targeted therapy.
19426230 The clinical utility of inhibiting CD28-mediated costimulation. 2009 May This volume covers many topics in the field of T-cell costimulation. The need for such a volume is testament to the growth of the field. From its beginning as a concept in the 1980s, we have now progressed to the point where many molecules now have functionally defined roles in T-cell costimulation. In addition, the field has progressed 'from bench to bedside'. Abatacept [cytotoxic T-lymphocyte antigen-4 (CTLA-4)-immunoglobulin (Ig) (CTLA-4-Ig)], an inhibitor of CD28-mediated T-cell costimulation, was approved for the treatment of moderate-to-severe rheumatoid arthritis in 2006 by the Food and Drug Administration and in 2007 by the European Medicines Agency. This chapter first presents a personal historical perspective on the early basic studies on the elucidation of the CD28/B7 T-cell costimulatory pathway and the discovery of CTLA-4-Ig. We next present an overview of studies of CTLA-4-Ig in preclinical animal studies. The material discussed in these first two sections is selective rather than exhaustive; their purpose is to provide context for the final section, a summary of human clinical studies performed with abatacept.
19383496 Methotrexate induces apoptosis in CaSki and NRK cells and influences the organization of t 2009 Jun 24 Methotrexate is a widely used drug in treatments of various types of malignancies and in the therapy of rheumatoid arthritis. The goal of our study was to look at the effect of this dihydrofolate reductase inhibitor on the actin cytoskeleton, since actin plays an important role in cancer transformation and metastasis. For this reason we compared results obtained from experiments on CaSki (human uterine cervix cancer) and NRK (normal fibroblastic rat kidney) cells treated with methotrexate. It has been shown previously that methotrexate can induce apoptosis. Therefore we first examined whether methotrexate induces apoptosis in our model cells. For this aim we applied several assays like Caspase Glo 3/7, DNA fragmentation and binding of phosphatidylserine by annexin V-fluorescein. The data obtained indicated that methotrexate induces programmed cell death in CaSki and NRK cells. However, differences between CaSki and NRK cells were observed in the morphological alterations and dynamics of apoptosis induced by methotrexate. It seemed that cancer cells were more sensitive towards the cell death inducing activity at lower concentrations of methotrexate. Analysis by confocal microscopy of methotrexate-treated cells demonstrated that treatment with this folate antagonist affected the actin cytoskeleton, although the dis-organization of the actin cytoskeleton after treatment with methotrexate differed between cancer and normal cells.
19290474 For whom the bell tolls? DING proteins in health and disease. 2009 Jul DING proteins, identified mainly by their eponymous N-terminal sequences, are ubiquitous in living organisms. Amongst bacteria, they are common in pseudomonads, and have been characterised with respect to genetics and structure. They form part of a wider family of phosphate-binding proteins, with emerging roles in phosphate acquisition and pathogenicity. Many DING proteins have been isolated in eukaryotes, in which they have been associated with very diverse biological activities, often in the context of possible signalling roles. Disease states in which DING proteins have been implicated include rheumatoid arthritis, lithiasis, atherosclerosis, some tumours and tumour-associated cachexia, and bacterial and viral adherence. Complete genetic and structural characterisation of eukaryotic DING genes and proteins is still lacking, though the phosphate-binding site seems to be conserved. Whether as bacterial proteins related to bacterial pathogenicity, or as eukaryotic components of biochemical signalling systems, DING proteins require further study.
19010373 IL-6R distribution in normal human and cynomolgus monkey tissues. 2009 Feb Interleukin-6 (IL-6) is a pleiotropic cytokine and a contributing factor in many diseases such as rheumatoid arthritis, Castleman's disease, Crohn's disease, and multiple myeloma. Since the blockade of the signaling pathway of the IL-6/interleukin-6 receptor (IL-6R)/gp130 complex is considered to have therapeutic value in such diseases, we developed an IL-6R humanized antibody (tocilizumab). In the current report, distribution of IL-6R in both normal human and cynomolgus monkey tissues was assessed as fundamental data to support preclinical and clinical studies of tocilizumab. Human and cynomolgus monkey tissue panels were stained with commercially available anti-human IL-6R and a species- and isotype-matched negative antibody, as well as assay control slides. The detection system applied used an Envision immunoperoxidase staining procedure with DAB reaction. Positive reactions were observed in the tissue elements of lymphatic, hematopoietic, digestive, reproductive, exocrine, endocrine, neural, muscular, epidermal, respiratory, and urinary systems of the human and cynomolgus monkey tissue panels. The current report is inclusive of a wide variety of tissues and shows the distribution of IL-6R to be similar for both human and monkey tissues. We consider this information fundamental for the support and interpretation of preclinical and clinical studies of anti-IL-6R antibody therapy.