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ID PMID Title PublicationDate abstract
21179534 Genetic variants in toll-like receptors are not associated with rheumatoid arthritis susce 2010 Dec 15 BACKGROUND: Several studies point to a role of Toll-like receptors (TLRs) in the development of rheumatoid arthritis (RA). We investigated if genetic variants in TLR genes are associated with RA and response to tumour necrosis factor blocking (anti-TNF) medication. METHODOLOGY AND PRINCIPAL FINDINGS: 22 single nucleotide polymorphisms (SNPs) in seven TLR genes were genotyped in a Dutch cohort consisting of 378 RA patients and 294 controls. Significantly associated variants were investigated in replication cohorts from The Netherlands, United Kingdom and Sweden (2877 RA patients and 2025 controls). 182 of the Dutch patients were treated with anti-TNF medication. Using these patients and a replication cohort (269 Swedish patients) we analysed if genetic variants in TLR genes were associated with anti-TNF outcome. In the discovery phase of the study we found a significant association of SNPs rs2072493 in TLR5 and rs3853839 in TLR7 with RA disease susceptibility. Meta-analysis of discovery and replication cohorts did not confirm these findings. SNP rs2072493 in TLR5 was associated with anti-TNF outcome in the Dutch but not in the Swedish population. CONCLUSION: We conclude that genetic variants in TLRs do not play a major role in susceptibility for developing RA nor in anti-TNF treatment outcome in a Caucasian population.
19714582 Rheumatoid arthritis does not share most of the newly identified systemic lupus erythemato 2009 Sep OBJECTIVE: Rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) share some genetic factors such as HLA, PTPN22, STAT4, and 6q23. The aim of this study was to determine whether 9 other SLE genetic factors are also implicated in RA susceptibility. METHODS: A characteristic single-nucleotide polymorphism (SNP) in each of 9 genetic factors, ITGAM (rs1143679), C8orf13-BLK (rs13277113), TYK2 (rs2304256), 1q25.1 (rs10798269), PXK (rs6445975), KIAA1542 (rs4963128), MECP2 (rs17435), BANK1 (rs17266594), and LY9 (rs509749), was studied in 1,635 patients with RA and 1,906 control subjects from Spain. The rs7574865 SNP in STAT4 was also included. Analyses were conducted globally and after stratification by sex and clinical features (anti-cyclic citrullinated peptide and rheumatoid factor, shared epitope, rheumatoid nodules, radiographic changes, sicca syndrome, and pneumonitis). RESULTS: No association was observed between RA and any of the 9 newly identified SLE genetic factors. A meta-analysis using previous data was consistent with these results. In addition, there were no significant differences between individuals with and those without each of the clinical features analyzed, except the frequency of the minor allele in the C8orf13-BLK locus that was decreased in patients with sicca syndrome (14.6% versus 22.4% in controls; P = 0.003). CONCLUSION: None of the 9 recently identified SLE risk factors showed association with RA. Therefore, common genetic factors affecting the pathogenesis of these 2 disorders seem to be limited, revealing that the genetic component contributes to the different expression of these diseases.
19856886 [Influence of genetic factors on development and severity of rheumatoid arthritis--part I] 2009 Aug Both genetic and environmental factors affect susceptibility, severity and probably drugs' efficacy in patients with rheumatoid arthritis (RA). After initial completion of the Human Genome Project on the 16th February 2001, significant progress has been made in identifying other than HLA genome regions linked to the increased RA susceptibility. As an effect several new genes have been recognized as an HLA-independent genetic risk factors of RA. PTPN22 gene polymorphism, C5/TRAF1 genes region polymorphism and TNFAIP3-OLIG3 genes region polymorphism(s) are among newly identified and already confirmed genetic risk factors, whereas STAT 4, CTLA4, PADI4 and IRF5 genes polymorphisms are listed among probable RA development genetic risk factors.
19186969 Aggressive periodontitis and chronic arthritis: blood mononuclear cell gene expression and 2009 Feb BACKGROUND: Cytokines and cytokine inhibitors have been associated with many immunoinflammatory diseases. In the present study, we examined whether peripheral blood mononuclear cell (PBMC) gene expression mirrors the corresponding plasma levels of clinically important pro- and anti-inflammatory cytokines and cytokine receptors in patients with periodontitis and patients with arthritis representing two examples of chronic inflammatory diseases, such as periodontitis and arthritis. To identify possible disease-specific characteristics of subjects with periodontitis relative to subjects with chronic inflammation in general, patients with arthritis (juvenile idiopathic arthritis [JIA] and rheumatoid arthritis [RA]) were included. METHODS: The study population consisted of white adults <35 years of age diagnosed with localized aggressive periodontitis (LAgP; n = 18), generalized aggressive periodontitis (GAgP; n = 27), JIA (n = 10), and RA (n = 23) and healthy controls (n = 25). PBMC transcripts of interleukin (IL) 1 alpha (IL1A), IL 1 beta (IL1B), IL 1 receptor antagonist (IL1RN), IL6, IL10, tumor necrosis factor alpha (TNFA), TNF alpha receptor I (TNFRI), and TNFRII were measured using real-time reverse transcription-polymerase chain reaction and compared to the corresponding plasma protein levels measured by enzyme-linked immunosorbent assay and a multiplex antibody bead assay. RESULTS: Compared to controls, soluble (s) TNF-RII levels were significantly elevated in patients with GAgP (P = 0.001) or JIA (P = 0.002), and PBMC TNFA transcript levels were lower in patients with JIA (P = 0.001). A negative correlation was found between IL6 expression and IL-6 plasma levels in patients with JIA versus controls, and a positive correlation/association was found between TNFRI expression and sTNF-RI plasma levels in patients with LAgP and RA. CONCLUSIONS: The study demonstrated only a few changes in the PBMC expression of various cytokine and cytokine inhibitor genes in aggressive periodontitis and chronic arthritis compared to controls. There were a few similarities among disease groups, and no direct and simple correlation between cellular transcripts and proteins was found.
20494752 Postoperative infections: prevention and management. 2010 May Postoperative infections continue to be a challenging problem. The incidence of bacterial antibiotic resistance such as methicillin-resistant Staphylococcus aureus is rising. There are numerous intrinsic patient factors that should be optimized before surgery to minimize the risk of surgical site infections. When postoperative infections develop, treatment must be individualized. This article outlines the principles that can help guide treatment.
19602638 Instrumenting the health care enterprise for discovery research in the genomic era. 2009 Sep Tens of thousands of subjects may be required to obtain reliable evidence relating disease characteristics to the weak effects typically reported from common genetic variants. The costs of assembling, phenotyping, and studying these large populations are substantial, recently estimated at three billion dollars for 500,000 individuals. They are also decade-long efforts. We hypothesized that automation and analytic tools can repurpose the informational byproducts of routine clinical care, bringing sample acquisition and phenotyping to the same high-throughput pace and commodity price-point as is currently true of genome-wide genotyping. Described here is a demonstration of the capability to acquire samples and data from densely phenotyped and genotyped individuals in the tens of thousands for common diseases (e.g., in a 1-yr period: N = 15,798 for rheumatoid arthritis; N = 42,238 for asthma; N = 34,535 for major depressive disorder) in one academic health center at an order of magnitude lower cost. Even for rare diseases caused by rare, highly penetrant mutations such as Huntington disease (N = 102) and autism (N = 756), these capabilities are also of interest.
20838745 Increased levels of citrullinated antithrombin in plasma of patients with rheumatoid arthr 2010 Dec Citrullination is a post-translational modification that plays essential roles in both physiological processes and disease. Recent studies have found increased levels of citrullinated antithrombin in patients with rheumatoid arthritis and in different malignant tumours. Antithrombin, the main haemostatic serpin, loses its anticoagulant function via citrullination, which might contribute to the pathogenesis or thrombotic side effects of these disorders. We have developed a specific monoclonal antibody against citrullinated antithrombin. We determined the levels of citrullinated antithrombin and anti-FXa activity in plasma from 66 donors, 17 patients with rheumatoid arthritis and 77 patients with colorectal adenocarcinoma (42 suffering from venous thrombosis). Healthy subjects had negligible amounts of citrullinated antithrombin in plasma (7.9 ± 22.1 ng/ml), while it significantly increased in patients with rheumatoid arthritis or adenocarcinoma (159.7 ± 237.6 ng/ml and 36.8 ± 66.1 ng/ml), levels that, however, did not modify the plasma anticoagulant activity. Moreover, we did not find association between citrullinated antithrombin and the thrombotic risk in patients with adenocarcinoma. In conclusion, we have developed an antibody specific for citrullinated antithrombin that allows its quantification in biological samples, offering a new tool for the analysis of citrullination in different diseases. We confirm increased levels of citrullinated antithrombin in plasma of patients with rheumatoid arthritis and adenocarcinoma. This modification, probably local, could have pathological consequences in both disorders, but only affects a minor fraction of plasma antithrombin, resulting in no significant reduction of global anticoagulant activity. This result explains the absence of association of this marker with an increased risk of thrombosis in patients with colorectal adenocarcinoma.
20673535 Aquagenic wrinkling of the palms: A case report and literature review. 2010 Jul 15 Aquagenic wrinkling of the palms (AWP) is a condition that results in pain and edema of the hands after exposure to water. We describe a 32-year-old woman who presented with a several-year history of AWP. She was unable to tolerate a 20 percent aluminum chloride solution because of irritation, but a gel formulation of 15 percent aluminum chloride controlled her symptoms without side effects.
19394279 Decreased DNA methyltransferase levels contribute to abnormal gene expression in "senescen 2009 Aug A senescent CD4(+)CD28(-) T cell subset develops with aging and in chronic inflammatory diseases like rheumatoid arthritis, and is implicated in plaque rupture and myocardial infarctions. This subset is pro-inflammatory, cytotoxic for endothelial cells, and aberrantly expresses genes like CD70, perforin and killer cell immunoglobulin-like receptor (KIR) genes. Why CD4(+)CD28(-) cells overexpress these genes is unclear. We found that the CD70, perforin and KIR2DL4 promoters are demethylated in CD4(+)CD28(-) T cells, and that DNA methyltransferase 1 (Dnmt1) and Dnmt3a levels are decreased in this subset. siRNA "knockdown" of Dnmt1, but not Dnmt3a, in CD4(+)CD28(+) T cells caused similar demethylation and overexpression of KIR2DL4, perforin and CD70, while simultaneous knockdown of Dnmt1 and Dnmt3a caused greater demethylation and overexpression of these genes than Dnmt1 alone. We conclude that decreased Dnmt1 and Dnmt3a cause demethylation and overexpression of these and perhaps other genes in CD4(+)CD28(-) cells, potentially contributing to pathologic functions by this subset.
20046130 Consequences of bed rest. 2009 Oct Bed rest is frequently prescribed for critically ill patients because it is assumed to be beneficial for preventing complications, for conserving scarce metabolic resources, and for providing patient comfort. Furthermore, higher levels of physical activity in critically ill patients have been assumed to be impractical or not feasible. Bed rest has been prescribed in the past for several other clinical conditions including acute flares of rheumatoid arthritis, cavitary tuberculosis, acute myocardial infarction, and acute low back pain. However, randomized, controlled, clinical trials failed to demonstrate beneficial effects of bed rest in most of these conditions. Bed rest can cause several complications that may delay or prevent recovery from critical illnesses including disuse muscle atrophy, joint contractures, thromboembolic disease, and insulin resistance. Recent studies demonstrated the feasibility and safety of physical medicine programs in critically ill patients including those with acute respiratory failure requiring mechanical ventilation. Other physical medicine tools, such as neuromuscular electrical stimulation and passive stretching of muscles, may also reduce some complications of bed rest.
19397781 Integrin alpha1beta1 is involved in the differentiation into myofibroblasts in adult react 2009 Sep Connective tissue cell activation is of importance during reactive conditions such as solid tumour growth, wound healing and pannus formation in rheumatoid arthritis. Here, we have compared connective tissue cells of mesenchymal origin in human tissues from these conditions and their normal counterparts using a panel of cell-type-specific markers. In particular, we investigated variations of integrin expression among connective tissue cell phenotypes. Connective tissue cell populations were defined based on their association with the microvasculature and their expression of activation markers. The phenotype of these cells varied according to the type of pathological connective tissue examined. Our morphological data from human tissues suggested that the alpha(1)beta(1) integrin, a collagen/laminin receptor, is involved in the differentiation of precursor cells into myofibroblasts. To mechanistically investigate this hypothesis, we employed experimental models for carcinoma growth and wound healing utilizing alpha(1) integrin-deficient mice. The data confirmed that the alpha(1)beta(1) integrin is of importance not only for the differentiation of mesenchymal cells into myofibroblasts but also for the neovascularization and connective tissue organization and emphasize the importance of myofibroblasts in the pathophysiology of tissue repair, inflammation and tumour growth.
19535263 CCL20 produced in the cytokine network of rheumatoid arthritis recruits CCR6+ mononuclear 2009 Aug Although a notable amount of CCL20 is detectable in the synovial fluid of human rheumatoid arthritis (RA), its role in the pathogenesis of RA remains to be determined. IL-1beta vigorously induced the production of CCL20 from FLSs of human RA and the production of CCL20 induced by TNF-alpha was partially attributed to a trace amount of IL-1beta induced by TNF-alpha. Although IL-6 failed to induce CCL20, TNF-alpha-induced IL-6 enhanced the production of CCL20 in an autocrine/paracrine manner. To determine the role of CCL20 and its sole receptor CCR6 in the recruitment of mononuclear cells (MNCs) into the inflamed joint of RA, conditioned medium of IL-1beta-stimulated FLSs was used in migration assays. The conditioned medium significantly recruited CCR6(+) MNCs in a CCL20-dependent manner. The production of CCL20 induced by TNF-alpha and IL-1beta was modified by helper-T-cell-derived cytokines. Interestingly, CCL20 enhanced the production of IL-6 coordinately with the stimulation of IL-17 but not with that of IFN-gamma. These findings imply FLSs stimulated by proinflammatory cytokines recruit CCR6(+) MNCs including IL-17-producing-helper T cells into the inflamed joint, leading to the enhancement of the production of CCL20, which chemokine and IL-17 coordinately induce proinflammatory cytokines.
19740904 Effectiveness and retention rates of methotrexate in psoriatic arthritis in comparison wit 2010 Apr OBJECTIVE: To examine the effectiveness and 2-year retention rates of methotrexate (MTX) in MTX naïve patients with psoriatic arthritis (PsA). METHODS: Data on 430 patients with PsA participating in an ongoing longitudinal observational multicentre study in Norway were analysed. 1218 MTX naïve patients with rheumatoid arthritis (RA) from the same study served as a reference population. Assessments included measures of disease activity (28 joint counts, acute phase reactants), health status and utility scores. Six-month effectiveness data were compared both by crude analyses and with adjustments for age, sex and the respective baseline values. Two-year drug survival was compared by Kaplan-Meier and Cox regression analyses. RESULTS: After 6 months of MTX treatment, both patients with PsA and those with RA improved in most disease activity measures and patient reported outcomes. In the adjusted analysis, patients with PsA tended to have less improvement, but changes were in the same range as in patients with RA. Two-year retention rates of MTX therapy in patients with PsA and RA were 65% and 66%, respectively, with only minor differences in reported reasons for discontinuation. Lower age, longer disease duration and higher Modified Health Assessment Questionnaire (MHAQ) score and patient global assessment were independent predictors of MTX termination within the first 2 years of treatment. CONCLUSION: In this real-life study, MTX treatment was associated with improvement in disease activity and health-related quality of life in patients with PsA after 6 months of treatment. Retention rates of MTX were similar in PsA and RA.
20604932 Effects of inflammatory cytokine IL-27 on the activation of fibroblast-like synoviocytes i 2010 INTRODUCTION: Interleukin (IL)-27 is a novel member of the IL-6/IL-12 family cytokines that are produced early by antigen-presenting cells in T helper (Th)1-mediated inflammation. Elevated expression of IL-27 has been detected in the synovial membranes and fluid of rheumatoid arthritis (RA). METHODS: We investigated the in vitro effects of IL-27, alone or in combination with inflammatory cytokine tumor necrosis factor (TNF)-α or IL-1 β on the pro-inflammatory activation of human primary fibroblast-like synoviocytes (FLS) from RA patients and normal control subjects, and the underlying intracellular signaling molecules were determined by intracellular staining using flow cytometry. RESULTS: Significantly higher plasma concentration of IL-27 was found in RA patients (n = 112) than control subjects (n = 46). Both control and RA-FLS constitutively express functional IL-27 receptor heterodimer, gp130 and WSX-1, with more potent IL-27-mediated activation of signal transducers and activators of transcription (STAT)1 in RA-FLS. IL-27 was found to induce significantly higher cell surface expression of intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1 and release of inflammatory chemokine IL-6, CCL2, CXCL9, CXCL10 and matrix metalloproteinase-1 of RA-FLS than that of control FLS (all P < 0.05). Moreover, an additive or synergistic effect was observed in the combined treatment of IL-27 and TNF-α or IL-1 β on the surface expression of ICAM-1 and VCAM-1 and the release of CXCL9 and CXCL10 of RA-FLS. Further investigations showed that the expression of ICAM-1, VCAM-1 and chemokines stimulated by IL-27 was differentially regulated by intracellular activation of phosphatidylinositol 3-OH kinase-AKT, c-Jun amino-terminal kinase and Janus kinase pathways. CONCLUSIONS: Our results therefore provide a new insight into the IL-27-activated immunopathological mechanisms mediated by distinct intracellular signal transductions in joint inflammation of RA.
19579151 Immune-mediated skin lesions in patients treated with anti-tumour necrosis factor alpha in 2009 OBJECTIVE: To describe immune-mediated skin lesion (IMSL) development in patients during anti-tumour necrosis factor (TNF) therapy. METHODS: Two hundred and fifty-two patients with rheumatoid arthritis (RA) and 183 with spondyloarthropathies (SpA) treated with anti-TNF inhibitors were analysed to identify IMSLs. RESULTS: Of the 252 patients with RA (146 treated with infliximab, 72 with adalimumab, and 34 with etanercept), 32 developed IMSLs. Eleven patients developed psoriatic skin lesions, 10 presented with granuloma annulare (GA), five had skin vasculitis, two alopecia areata, two discoid lupus erythematosus, one lichenoid eruption (lichen planus), and one vitiligo. Of the 183 patients with SpA (138 treated with infliximab, 37 with etanercept, and eight with adalimumab), 10 cases with IMSLs were identified. All were treated with infliximab. More specifically, six patients with ankylosing spondylitis (AS) developed psoriatic skin lesions, one developed GA, one lichen planus, and one alopecia areata. In addition, one patient with psoriatic arthritis (PsA) developed skin vasculitis. The occurrence of these IMSLs ranged from 3 to 36 months with a median of 20 months. Of all the patients with IMSL development, two with psoriatic skin lesions, two with GA, and one with vasculitis stopped anti-TNF therapy because of the extent and severity of the skin lesions. CONCLUSIONS: Our results on patients treated with TNF antagonists strongly support a link between TNF inhibition and IMSL development. Although these clinical complications are rare, clinicians should be aware of their occurrence and should recognize them.
19300490 An African ancestry-specific allele of CTLA4 confers protection against rheumatoid arthrit 2009 Mar Cytotoxic T-lymphocyte associated protein 4 (CTLA4) is a negative regulator of T-cell proliferation. Polymorphisms in CTLA4 have been inconsistently associated with susceptibility to rheumatoid arthritis (RA) in populations of European ancestry but have not been examined in African Americans. The prevalence of RA in most populations of European and Asian ancestry is approximately 1.0%; RA is purportedly less common in black Africans, with little known about its prevalence in African Americans. We sought to determine if CTLA4 polymorphisms are associated with RA in African Americans. We performed a 2-stage analysis of 12 haplotype tagging single nucleotide polymorphisms (SNPs) across CTLA4 in a total of 505 African American RA patients and 712 African American controls using Illumina and TaqMan platforms. The minor allele (G) of the rs231778 SNP was 0.054 in RA patients, compared to 0.209 in controls (4.462 x 10(-26), Fisher's exact). The presence of the G allele was associated with a substantially reduced odds ratio (OR) of having RA (AG+GG genotypes vs. AA genotype, OR 0.19, 95% CI: 0.13-0.26, p = 2.4 x 10(-28), Fisher's exact), suggesting a protective effect. This SNP is polymorphic in the African population (minor allele frequency [MAF] 0.09 in the Yoruba population), but is very rare in other groups (MAF = 0.002 in 530 Caucasians genotyped for this study). Markers associated with RA in populations of European ancestry (rs3087243 [+60C/T] and rs231775 [+49A/G]) were not replicated in African Americans. We found no confounding of association for rs231778 after stratifying for the HLA-DRB1 shared epitope, presence of anti-cyclic citrullinated peptide antibody, or degree of admixture from the European population. An African ancestry-specific genetic variant of CTLA4 appears to be associated with protection from RA in African Americans. This finding may explain, in part, the relatively low prevalence of RA in black African populations.
20022460 Randomized controlled trial of radiographic and patient-assessed outcomes following fixed 2010 Dec This prospectively blinded randomized controlled study evaluated the difference in the functional and radiological outcomes in patients who received a press-fit condylar Sigma cemented cruciate-substituting total knee arthroplasty with either a rotating platform (RP) or a fixed bearing (FB). There were 51 joints in 49 patients: 24 joints in the RP group (mean follow-up, 43 months) and 27 joints in the FB group (mean follow-up, 40 months). At baseline, there was no significant difference in age, body mass index, preoperative diagnosis, Charnley class, range of motion, clinical and functional scores, between the RP and FB groups. At mid-term follow up both the RP and FB give equivalent results, but patients with the RP tended to have a higher activity level score.
19959227 Differential calcium signaling and Kv1.3 trafficking to the immunological synapse in syste 2010 Jan Systemic lupus erythematosus (SLE) T cells exhibit several activation signaling anomalies including defective Ca(2+) response and increased NF-AT nuclear translocation. The duration of the Ca(2+) signal is critical in the activation of specific transcription factors and a sustained Ca(2+) response activates NF-AT. Yet, the distribution of Ca(2+) responses in SLE T cells is not known. Furthermore, the mechanisms responsible for Ca(2+) alterations are not fully understood. Kv1.3 channels control Ca(2+) homeostasis in T cells. We reported a defect in Kv1.3 trafficking to the immunological synapse (IS) of SLE T cells that might contribute to the Ca(2+) defect. The present study compares single T cell quantitative Ca(2+) responses upon formation of the IS in SLE, normal, and rheumatoid arthritis (RA) donors. Also, we correlated cytosolic Ca(2+) concentrations and Kv1.3 trafficking in the IS by two-photon microscopy. We found that sustained [Ca(2+)](i) elevations constitute the predominant response to antigen stimulation of SLE T cells. This defect is selective to SLE as it was not observed in RA T cells. Further, we observed that in normal T cells termination of Ca(2+) influx is accompanied by Kv1.3 permanence in the IS, while Kv1.3 premature exit from the IS correlates with sustained Ca(2+) responses in SLE T cells. Thus, we propose that Kv1.3 trafficking abnormalities contribute to the altered distribution in Ca(2+) signaling in SLE T cells. Overall these defects may explain in part the T cell hyperactivity and dysfunction documented in SLE patients.
19560569 T-cell leukemia translocation-associated gene (TCTA) protein is required for human osteocl 2009 Oct Synovial tissues of patients with rheumatoid arthritis (RA) include factors regulating bone resorption, such as receptor activator NF-kappaB ligand (RANKL), TNFalpha, IL-6, IL-17 and IFNgamma. However, in addition to these cytokines, other factors expressed in synovial tissues may play a role in resorbing bone. Here, our objective was to identify novel proteins expressed in synovial tissues of RA that regulate human osteoclastogenesis. Proteins were purified from synovial tissues of patients with RA, using gel filtration chromatography, ion-exchange chromatography, reverse-aspect HPLC, and mass spectrometry. We evaluated the effects of the purified fractions on human osteoclastogenesis induced by RANKL and M-CSF. We determined the amino acid sequences showing inhibitory activity on human osteoclastogenesis. In addition, we synthesized novel peptides from the molecule including the amino acid sequences. Then, we evaluated the effects of the peptides and antibodies against the molecule on human osteoclastogenesis from monocytes and mature osteoclasts, and on pit formation by mature osteoclasts using Osteologic discs. We examined the effect of the peptide on the expression of both mRNA and protein of NFATc1. We also examined the effect of RANKL on the expression of mRNA of the molecule on osteoclasts and macrophages. We identified a small peptide including Gly-Gln-Asn (GQN) with inhibitory activity on human osteoclastogenesis. We then found that GQN is included in the amino acid sequence of the extra-cellular domain of TCTA protein, which is expressed ubiquitously in normal human tissues, but whose function has not been clarified. We designed novel peptides, including GQN, from the sequence of TCTA protein. One of these peptides (29-mer), but not a scrambled peptide for the 29-mer peptide, potently inhibited RANKL-induced human osteoclastogenesis. The peptide also inhibited pit formation of mature human osteoclasts and suppressed the formation of large osteoclasts in the culture of mature osteoclasts. Furthermore, polyclonal antibodies against TCTA protein suppressed the formation of large osteoclasts in the cultures of both monocytes and mature osteoclasts, supporting our hypothesis. Peptide A did not significantly inhibit the expression of both mRNA and protein of NFATc1 in osteoclasts. Our novel peptide and polyclonal antibodies against the peptide inhibited human osteoclastogenesis and the function of mature osteoclasts, preventing cellular fusion by TCTA protein and a putative counterpart molecule.
20050823 Clinically validated approaches to the treatment of autoimmune diseases. 2010 Feb IMPORTANCE OF THE FIELD: Autoimmune diseases are pathological conditions in which "self-tolerance" has been broken, and an immune response has been mounted against the body's own tissues. More than seventy autoimmune diseases have been described, some of which are systemic and others of which are organ-specific. Although many of these diseases are rare, the collective prevalence of autoimmune diseases in the United States alone is between 5 and 8%, and is increasing. AREAS COVERED IN THIS REVIEW: Herein, we review the exciting advances made during the past decade (1999 - 2009) in the development of clinically-validated agents for the treatment of autoimmune disease. We focus on five of the most prevalent conditions: rheumatoid arthritis, psoriasis, multiple sclerosis, Crohn's disease, and systemic lupus erythematosus. The discussion is largely restricted to agents - both small molecules and macromolecules - that have advanced through randomized, controlled clinical trials. WHAT THE READER WILL GAIN: An overview of the pathogenesis of each disease is provided, along with a description of the therapies. Results from pivotal clinical trials are tabulated for four of the disease areas. We also provide summaries of experiences with both failed clinical trials and side effects observed during the course of clinical investigations. We conclude the review with thoughts on current challenges in the field and the prospect for future innovations. TAKE HOME MESSAGE: During the past decade, some of the largest advances in the treatment of autoimmune disease have arisen from highly potent and selective macromolecule-based therapies (e.g. antibodies, recombinant proteins and fusion proteins). Together, these clinical experiences have provided insight into the critical mechanisms in autoimmune pathogenesis, including inflammatory cytokine release, T-cell migration and co-stimulation, and B-cell function.