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ID PMID Title PublicationDate abstract
16204374 Impaired endothelial function in patients with ankylosing spondylitis. 2006 Mar OBJECTIVE: In recent years, accelerated atherosclerosis and increased risk of cardiovascular events have been described in patients with rheumatic disease, particularly for rheumatoid arthritis and systemic lupus erythematosus. However, the link between inflammation, atherosclerosis and ankylosing spondylitis is controversial. We evaluated the degree of atherosclerosis and endothelial function of ankylosing spondylitis patients ultrasonographically. METHODS: Fifty-four patients with ankylosing spondylitis (37 +/- 11 yr, 29 males, 25 females) and 31 healthy controls (35 +/- 9 yr, 16 males, 15 females) were consecutively enrolled in the study. Serum lipids, creatinine, glucose, and acute-phase proteins were assessed. The Bath Ankylosing Spondylitis Metrology Index (BASMI), Bath Ankylosing Spondylitis Functional Index (BASFI) and Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) were also evaluated. Flow-mediated dilatation and endothelium-independent dilatation of the brachial artery and intima-media thickness of the common carotid artery were measured sonographically. RESULTS: Left, right and averaged intima-media thickness of the common carotid artery did not show a statistically significant difference between the ankylosing spondylitis and control groups. However, flow-mediated dilatation was significantly lower in the ankylosing spondylitis patients (14.1 +/- 6.7 vs 17.6 +/- 8%; P = 0.03). Likewise, nitroglycerin-induced dilatation was lower in the patient group, but the difference was not significant (16.4 +/- 6.8 vs 19.8 +/- 10%; P = 0.07). No correlation was detected between flow-mediated dilatation and age, sex, serum lipids, CRP, ESR, smoking habits and disease activity scores. Intima-media thickness of the common carotid artery was positively correlated with age and BASMI score (r = 0.55, P = 0.00; r = 0.22, P = 0.04, respectively). CONCLUSION: This study demonstrates impairment of endothelial function in ankylosing spondylitis.
18936772 Inflammatory caspases are critical for enhanced cell death in the target tissue of Sjögre 2009 Jan To date, little is known about why exocrine glands are subject to immune cell infiltrations in Sjögren's syndrome (SjS). Studies with SjS-prone C57BL/6.NOD-Aec1Aec2 mice showed altered glandular homeostasis in the submandibular glands (SMX) at 8 weeks before disease onset and suggested the potential involvement of inflammatory caspases (caspase-11 and -1). To determine whether inflammatory caspases are critical for the increased epithelial cell death before SjS-like disease, we investigated molecular events involving caspase-11/caspase-1 axis. Our results revealed concurrent upregulation of caspase-11 in macrophages, STAT-1 activity, caspase-1 activity and apoptotic epithelial cells in the SMX of C57BL/6.NOD-Aec1Aec2 at 8 weeks. Caspase-1, a critical factor for interleukin (IL)-1beta and IL-18 secretion, resulted in an elevated level of IL-18 in saliva. Interestingly, TUNEL-positive cells in the SMX of C57BL/6.NOD-Aec1Aec2 were not colocalized with caspase-11, indicating that caspase-11 functions in a noncell autonomous manner. Increased apoptosis of a human salivary gland (HSG) cell line occurred only in the presence of lipopolysaccharide (LPS-) and interferon (IFN)-gamma-stimulated human monocytic THP-1 cells, which was reversed when caspase-1 in THP-1 cells was targeted by siRNA. Taken together, our study discovered that inflammatory caspases are essential in promoting a pro-inflammatory microenvironment and influencing increased epithelial cell death in the target tissues of SjS before disease onset.
19209622 Novel homozygous AIRE mutation in a German patient with severe APECED. 2008 Oct Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare autosomal recessive disorder typically presenting with chronic mucocutaneous candidiasis, hypoparathyroidism, and adrenal failure variably accompanied by other symptoms. APECED is caused by a mutation in the autoimmune regulator gene (AIRE). Today over 60 different mutations are known world-wide, most of them localized in exons 2, 8, and 10. We report here a German girl with rheumatoid factor positive arthritis, chronic mucocutaneous candidiasis, autoimmune hepatitis, chronic diarrhea, vitiligo, hypothyroidism, hypoparathyroidism, and adrenal failure who is homozygous for a novel mutation at the end of exon 3 of the AIRE gene (c.462G>A), within the conserved splice donor sequence. This mutation probably introduces a frameshift after amino acid 154 (p.Pro154fs) by skipping exon 4. In addition, we analyzed five other family members out of three generations for the AIRE gene mutation and for polymorphisms in the cytotoxic T lymphocyte antigen 4 (CTLA4) gene region and lymphoid protein tyrosine phosphatase (PTPN22) gene, which are associated with the occurrence of sporadic autoimmune Addison's disease, type 1 diabetes mellitus, and generalized vitiligo.
19110153 Immediate weight bearing following first metatarsophalangeal joint fusion with Kirschner w 2009 Jan The general consensus regarding the postoperative management of patients who have undergone first metatarsophalangeal joint arthrodesis is to maintain non-weight bearing for 4 to 6 weeks. However, a number of studies indicate that immediate postoperative weight bearing does not result in a higher rate of nonunion. A retrospective case series investigation was performed to evaluate the fusion rate of first metatarsophalangeal joint arthrodesis using various forms of pin and wire fixation, and a postoperative protocol that involved immediate weight bearing with a padded surgical shoe. The impetus behind allowing immediate postoperative weight bearing stems from the desire to avoid difficult non-weight-bearing forms of ambulation in patients at risk for falling, and to enhance postoperative rehabilitation in patients at risk for other joint maladies, as in those suffering with rheumatoid and other polyarticular forms of arthritis. A total of 22 fusions (20 patients) were reviewed. Nonunion developed in 2 feet (9.1%), and a delayed union occurred in 1 additional foot (4.55%), for a total complication rate of 13.64% (3/22 cases) and a fusion rate of 86.36%. The remaining patients demonstrated radiographic consolidation of the arthrodesis. A crude rough comparison to previously published reports, wherein weight bearing was initiated anywhere from immediately to up to 2 weeks postoperative, showed that the rate of fusion observed in the patients described in this report was similar. This study demonstrated that immediate ambulation following first metatarsophalangeal joint fusion with wire fixation was safe and effective. LEVEL OF CLINICAL EVIDENCE: 4.
17304626 Murine dendritic cell transdifferentiation into osteoclasts is differentially regulated by 2007 Mar Dendritic cells (DC) are the mononuclear cells that initiate adaptive immune responses. Osteoclasts (OC) are the multinucleated giant cells that resorb bone. As previously described for human conventional DC (cDC), we demonstrate that murine cDC, either in vitro generated from Fms-like tyrosine kinase 3 (Flt3)+ bone marrow progenitors or ex vivo purified from spleen, are able to develop into OC in response to M-CSF and receptor activator of NF-kappaB ligand (RANKL) in vitro. This transdifferentiation is driven by the immune environment that controls cDC maturation, cell fusion, tartrate-resistant acid phosphatase (TRAP) and bone resorption activities. Only immature cDC have the capacity to become OC since mature cDC or plasmacytoid DC do not. Additions of the pro-inflammatory cytokines, such as IL-1beta and TNF-alpha, or human rheumatoid synovial fluid, increase murine cDC transdifferentiation into OC, whereas IFN-alpha inhibits it. The adaptive cytokine, IFN-gamma, inhibits cDC fusion while IL-4 increases it. IL-2, IFN-gamma and IL-4 inhibit TRAP and bone resorption activities contrary to IL-10, which enhances both activities. A putative new "immune multinucleated giant cell" unable to resorb bone, which is formed owing to IL-4, is underlined. The future analysis of cDC transdifferentiation into OC in murine models of inflammatory arthritis will give us the quantitative importance of this phenomenon in vivo.
18073511 NOD mice exocrinopathy: towards a neuroimmune link. 2007 Sjogren's syndrome (SS) is a chronic autoimmune disorder of exocrine glands characterized as an autoimmune exocrinopathy and more specifically as an autoimmune epithelitis. An impaired balance of neuroimmune interactions mediated by vasoactive intestinal peptide (VIP) in the target organ at early stages of disease is explored by means of the nonobese diabetic (NOD) mouse model of SS. We have previously described a reduced salivary secretion and signaling upon VIP stimulation. The effect reflected a differential regulation of the neural isoform of nitric oxide synthase by calcium calmodulin kinase II and occurred prior to the appearance of detectable levels of cytokines in NOD glands. VIP acting on NOD macrophages treated with lipopolysaccharide promoted anti-inflammatory effects by inhibiting nitric oxide synthase induction as well as IL-12 and TNF-alpha production, while stimulating IL-10. Here we present evidence on the ability of apoptotic acinar cells from submandibular glands of NOD mice to stimulate nitric oxide in both peritoneal and glandular macrophage pools to a similar extent as lipopolysaccharide + IFN-gamma. VIP was not effective to prevent nitrite accumulation and modestly increased IL-10 levels in macrophages coincubated with acinar cells. An enhanced nitrite response of NOD glandular macrophages in basal and stimulated conditions compared to peritoneal cells is also shown.
18793756 Characterization of YM-58483/BTP2, a novel store-operated Ca2+ entry blocker, on T cell-me 2008 Dec 20 YM-58483/BTP2 is a blocker of store-operated Ca2+ entry (SOCE), which regulates the activation of non-excitable cells such as lymphocytes. YM-58483 has been reported to inhibit cytokine production and proliferation in T cells, and to be useful as a probable medicinal candidate for treatment of bronchial asthma. The present study investigated the pharmacological profile and therapeutic potential of YM-58483 in relation to cell-mediated immune responses. In the mouse graft-versus-host disease (GVHD) model, YM-58483 (1-30 mg/kg, p.o.) and cyclosporine A (1-30 mg/kg, p.o.) inhibited donor anti-host cytotoxic T lymphocyte (CTL) activity and IFN-gamma production, and also reduced the number of donor T cells, especially donor CD8+ T cells, in the spleen. YM-58483 and cyclosporine A inhibited T cell proliferation in a one-way mixed lymphocyte reaction (MLR) with IC50 values of 330 and 12.7 nM, respectively. Additionally, YM-58483 (1-10 mg/kg, p.o.) and cyclosporine A (2, 10 mg/kg, p.o.) inhibited the sheep red blood cell (SRBC)-induced delayed type hypersensitivity (DTH) response. These results suggest that the inhibition of SOCE leads to the prevention of antigen-induced T cell responses, which participate in autoimmune diseases such as autoimmune hepatitis and rheumatoid arthritis.
17430113 Pharmacological targeting of IDO-mediated tolerance for treating autoimmune disease. 2007 Apr Cells at the maternal-fetal interface express indoleamine 2,3 dioxygenase (IDO) to consume all local tryptophan for the express purpose of starving adjacent maternal T cells of this most limiting and essential amino acid. This stops local T cell proliferation to ultimately result in the most dramatic example of immune tolerance, acceptance of the fetus. By contrast, inhibition of IDO using 1-methyl-tryptophan causes a sudden catastrophic rejection of the mammalian fetus. Immunomodulatory factors including IFNgamma, TNFalpha, IL-1, and LPS use IDO induction in responsive antigen presenting cells (APCs) also to transmit tolerogenic signals to T cells. Thus it makes sense to consider IDO induction towards tolerance for autoimmune diseases in general. Approaches to cell specific therapeutic IDO induction with NAD precursor supplementation to prevent the collateral non-T cell pathogenesis due to chronic TNFalpha-IDO activated tryptophan depletion in autoimmune diseases are reviewed. Tryptophan is an essential amino acid most immediately because it is the only precursor for the endogenous biosynthesis of nicotinamide adenine dinucleotide (NAD). Both autoimmune disease and the NAD deficiency disease pellagra occur in women at greater than twice the frequency of occurrence in men. The importance of IDO dysregulation manifest as autoimmune pellagric dementia is genetically illustrated for Nasu-Hakola Disease (or PLOSL), which is caused by a mutation in the IDO antagonizing genes TYROBP/DAP12 or TREM2. Loss of function leads to psychotic symptoms rapidly progressing to presenile dementia likely due to unchecked increases in microglial IDO expression, which depletes neurons of tryptophan causing neurodegeneration. Administration of NAD precursors rescued entire mental hospitals of dementia patients literally overnight in the 1930's and NAD precursors should help Nasu-Hakola patients as well. NAD depletion mediated by peroxynitrate PARP1 activation is one of the few established mechanisms of necrosis. Chronic elevation of TNFalpha leading to necrotic events by NAD depletion in autoimmune disease likely occurs via combination of persistent IDO activation and iNOS-peroxynitrate activation of PARP1 both of which deplete NAD. Pharmacological doses of NAD precursors repeatedly provide dramatic therapeutic benefit for rheumatoid arthritis, type 1 diabetes, multiple sclerosis, colitis, other autoimmune diseases, and schizophrenia in either the clinic or animal models. Collectively these observations support the idea that autoimmune disease may in part be considered as localized pellagra manifesting symptoms particular to the inflamed target tissues. Thus pharmacological doses of NAD precursors (nicotinic acid/niacin, nicotinamide/niacinamide, or nicotinamide riboside) should be considered as potentially essential to the therapeutic success of any IDO-inducing regimen for treating autoimmune diseases. Distinct among the NAD precursors, nicotinic acid specifically activates the g-protein coupled receptor (GPCR) GPR109a to produce the IDO-inducing tolerogenic prostaglandins PGE(2) and PGD(2). Next, PGD(2) is converted to the anti-inflammatory prostaglandin, 15d-PGJ(2). These prostaglandins exert potent anti-inflammatory activities through endogenous signaling mechanisms involving the GPCRs EP2, EP4, and DP1 along with PPARgamma respectively. Nicotinamide prevents type 1 diabetes and ameliorates multiple sclerosis in animal models, while nothing is known about the therapeutic potential of nicotinamide riboside. Alternatively the direct targeting of the non-redox NAD-dependent proteins using resveratrol to activate SIRT1 or PJ34 in order to inhibit PARP1 and prevent autoimmune pathogenesis are also given consideration.
18317568 High Mobility Group Box Protein-1 correlates with renal function in chronic kidney disease 2008 Mar Chronic kidney disease (CKD) is associated with inflammation and malnutrition and carries a markedly increased risk of cardiovascular disease (CVD). High Mobility Group Box Protein-1 (HMGB-1) is a 30-kDa nuclear and cytosolic protein known as a transcription and growth factor, recently identified as a proinflammatory mediator of tissue injury. Recent data implicates HMGB-1 in endotoxin lethality, rheumatoid arthritis, and atherosclerosis. The aim of this post-hoc, cross-sectional study was to determine whether HMGB-1 serum levels are elevated in CKD patients. The study groups were categorized as follows: 110 patients starting dialysis defined as CKD 5; 67 patients with moderately to severely reduced renal function or CKD 3-4; and 48 healthy controls. High-sensitivity C-reactive-protein (hs-CRP), interleukin-6 (IL-6), tumor necrosis factor (TNF), serum-albumin (S-albumin), hemoglobin A(1c) (HbA(1c)), hemoglobin, subjective global nutritional assessment (SGA), and glomerular filtration rate (GFR) were analyzed. Kruskal-Wallis test was used to compare groups and Spearman's rank correlation test was used for continuous variables. HMGB-1, measured by Western blot, was significantly (P < 0.001) elevated in CKD 5 (146.7 +/- 58.6 ng/mL) and CKD 3-4 (85.6 +/- 31.8) compared with controls (10.9 +/- 10.5). HMGB-1 levels were correlated positively with TNF (Rho = 0.52; P < 0.001), hs-CRP (Rho = 0.38; P < 0.001), IL-6 (Rho = 0.30; P < 0.001), HbA(1c) (Rho = 0.14; P = 0.02) and SGA (Rho = 0.21; P = 0.002) and negatively correlated with GFR (Rho = -0.69; P = 0.0001), Hb (Rho = -0.60; P < 0.001), S-albumin (Rho = -0.31; P < 0.001). The current study has revealed that HMGB-1 is elevated significantly in CKD patients and correlates with GFR as well as markers of inflammation and malnutrition. Future studies may delineate whether HMGB-1 is also a marker of disease activity and severity as well as a predictor of outcome in CKD.
25966834 Recommendations for the diagnosis and treatment of latent and active tuberculosis in infla 2008 Mar The Portuguese Society of Rheumatology and the Portuguese Society of Pulmonology have updated the guidelines for the diagnosis and treatment of latent tuberculosis infection (LTBI) and active tuberculosis (ATB) in patients with inflammatory joint diseases (IJD) that are candidates to therapy with tumour necrosis factor alpha (TNFα) antagonists. In order to reduce the risk of tuberculosis (TB) reactivation and the incidence of new infections, TB screening is recommended to be done as soon as possible, ideally at the moment of IJD diagnosis, and patient assessment repeated before starting anti-TNFα therapy. Treatment for ATB and LTBI must be done under the care of a TB specialist. When TB treatment is indicated, it should be completed prior to starting anti-TNFα therapy. If the IJD activity justifies the need for immediate treatment, anti-TNFα therapy can be started two months after antituberculous therapy has been initiated, in the case of ATB, and one month after in the case of LTBI. Chest X-ray is mandatory for all patients. If Gohn's complex is present, the patient should be treated for LTBI; healed lesions require the exclusion of ATB. In cases of suspected active lesions, ATB should be excluded/confirmed and adequate therapy initiated. Tuberculin skin test, with two units of RT23, should be performed in all patients. If the induration is <5 mm, the test should be repeated within 1 to 2 weeks, on the opposite forearm, and will be considered negative only if the result is again <5 mm. Positive TST implicates LTBI treatment, unless previous proper treatment was provided. If TST is performed in immunossuppressed IJD patients, LTBI treatment should be offered to the patient before starting anti-TNF-α therapy, even in the presence of a negative test, after risk / benefit assessment. Rev Port Pneumol 2007; XIV (2): 271-283.
17900737 Sustained delivery of IL-1 Ra from biodegradable microspheres reduces the number of murine 2007 Nov 6 The interleukin-1 receptor antagonist (IL-1Ra) is approved for treating rheumatoid arthritis and has the potential to treat metastatic cancers involving excess amounts of the pro-inflammatory cytokine, interleukin-1 beta (IL-1). To maintain sustained delivery and improve its therapeutic efficacy, IL-1Ra was encapsulated with stabilizers in biodegradable poly-(lactic/glycolic acid) (PLGA) microspheres. In vitro cytokine release and bioactivity studies in cultured melanoma B16 cells revealed the microspheres to be capable of sustained IL-1Ra release on a daily level that could inhibit cell proliferation for at least 7 days. The level of IL-1Ra released from the microspheres was revealed in rat serum. Significant amounts of IL-1Ra were released over the course of 2 weeks, at levels sufficient for the inhibition of exogenously-administered IL-1 beta. In mice injected with B16 melanoma cells, the sustained IL-1Ra delivery from biodegradable microspheres inhibited tumor growth and significantly prolonged mice survival. Furthermore, the tumors were less vascularized and after amputation of the primary tumor, the number of lung metastases was reduced by 70%, as compared to the control groups. Thus, we show that biodegradable microspheres represent an efficient system for sustaining IL-1Ra delivery and improving its therapeutic efficacy. As such, the system can be integrated into therapeutic protocols for treating metastatic cancers.
17849265 Interleukin-6 and cyclic AMP stimulate release of cathepsin B in human osteoblasts. 2007 Previous studies have suggested that cathepsin B participates in the joint destruction associated with rheumatoid arthritis (RA). This study examined the activity of cathepsin B (a lysosomal cysteine protease) in human osteoblasts along with its regulation by cyclic AMP and Interleukin-6 (IL-6). Cyclic AMP elevating agents activate cathepsin B and stimulate the secretion of cathepsin B via the secretion of IL-6, a potent mediator of RA. This study investigated the induction of cathepsin B using the proinflammatory cytokine in human osteoblasts (MG-63) in relation to p38 mitogen-activated protein kinase (MAPK) and nuclear factor (NF)-kappa B transcription factor. When added to MG-63 cells, IL-6 stimulated the production of cathepsin B, which was reduced significantly by the addition of SB203580, a specific p38 MAPK inhibitor. In addition, the release of IL-6 was also inhibited by either pyrrolidine dithiocarbamate (PDTC) or NF-kappaB SN50, which are potent NF-kappaB inhibitors. Both NF-kappaB inhibitors had a larger inhibitory effect on the activity of cathepsin B in the presence of SB203580. IL-6 stimulated the NF-kappaB binding affinity as well as the activation of p38 MAP kinase, leading to the release of cathepsin B. However, SB203580 had no effect on the IL-6-induced activation of NF-kappaB, and neither of the NF-kappaB inhibitors decreased the level of p38 MAPK activation in the IL-6-stimulated osteoblasts. Moreover, IL-6 increased the activity of urokinase type plasminogen activator (uPA) in MG-63 cells, which was inhibited by SB203580, PDTC and NF-kappaB SN50. This strongly suggests that p38 MAPK and NF-kappaB are essential to the IL-6-induced activation of cathepsin B or uPA and that these two IL-6-activated pathways can act independently.
17679548 In vivo and in vitro anti-inflammatory activities of alpha-linolenic acid isolated from Ac 2007 Jun The fruit of Actinidia polygama (AP) has long been used as a folk medicine in Korea for the treatment of pain, rheumatoid arthritis and inflammation. In the present study, bioassay-guided fractionation of AP led to the separation and identification of a polyunsaturated fatty acid, alpha-linolenic acid (ALA), which was found to show anti-inflammatory activity. The anti-inflammatory effects of ALA, using acetic acid or carrageenan-induced inflammation models, were investi gated in mice or rats, respectively. ALA significantly inhibited the acetic acid-induced vascular permeability in a dose dependent manner (34.2 and 37.7% inhibition at doses of 5 and 10 mg/ kg, respectively). ALA also significantly reduced a rat paw edema induced by a single treatment of carrageenan. To investigate the mechanism of the anti-inflammatory action of ALA, the effects of ALA on lipopolysaccharide (LPS)-induced responses in the murine mac rophages cell line, RAW 264.7, were examined. Exposure of LPS-stimulated cells to ALA inhibited the accumulation of nitrite and prostaglandin E2 (PGE2) in the culture medium. Consistent with these observations, the protein and mRNA expression levels of iNOS and COX-2 enzyme were markedly inhibited by ALA in a dose dependent manner. These results suggest that the anti-inflammatory activity of ALA might be due to the suppression of the expressions of iNOS and COX-2 mRNA.
17157117 Clinical assessment of pain, tolerability, and preference of an autoinjection pen versus a 2006 Oct BACKGROUND: Adalimumab is a therapeutic monoclonal antibody for SC administration by 2 single-use injection devices providing bioequivalent amounts of adalimumab: a ready-to-use, prefilled syringe and an integrated, disposable delivery system, the autoinjection Pen. Although pens have been shown to be preferred over syringes by patients requiring long-term SC administration of medications, there are no data on preference and pain in the use of biologics in patients with chronic inflammatory diseases. OBJECTIVE: The aim of this study was to assess injection-site pain, tolerability, and patient preference of 2 delivery systems of adalimumab. METHODS: Patients with rheumatoid arthritis were enrolled in a Phase II, multicenter, open-label, single-arm, sequential trial. Patients self-administered a standard dose of adalimumab 40 mg SC every other week at each of 3 monitored clinical visits: visit 1 (syringe), visits 2 and 3 (Pen). At each visit, patients rated their pain on an 11-point scale (0 = none to 10 = pain as bad as it could be) immediately after injection and 15-30 minutes after injection and provided their impressions of and preferences for each delivery system. Safety events were recorded throughout the study and 70 days after final study dose. RESULTS: Fifty-two patients were enrolled in the trial and completed all 3 visits (32 women, 20 men; mean [SD] age, 53.8 [12.1] years). Forty (76.9%) patients reported that the Pen was less painful than the syringe, 4 (7.7%) patients found the syringe to be less painful, and 8 (15.4%) patients had no preference. Patients had statistically significant reductions in injection-pain scores from visit 1 to visit 2 and from visit 1 to visit 3. No new safety signals or apparent differences regarding tolerability between the syringe and Pen were observed. In addition, 46 (88.5%) patients preferred the Pen, 3 (5.8%) preferred the syringe, and 3 (5.8%) had no preference. Overall, patients evaluated the Pen as easier to use (94.2%), more convenient (92.3%), requiring less time to inject (82.7%), and safer (88.5%). CONCLUSIONS: Patients experienced less pain self-administering adalimumab via the Pen and preferred it versus the syringe. Further, patients perceived the Pen to be easier to use and more convenient. Both delivery systems were generally well tolerated.
16938648 Comparative analysis of serum proteomes: discovery of proteins associated with osteonecros 2006 Sep No means exist to evaluate the activity status, turnover, and prognosis of idiopathic osteonecrosis of the femoral head (IONFH) except for X-ray evidence of segmental collapse as a very good marker for prognosis. Moreover, the only current method for diagnosis of this disease is through physical examination and diagnostic imaging results, and no serum biochemical markers exist. A comparative analysis of serum proteomes was performed to discover proteins associated with osteonecrosis of the femoral head. Two-dimensional electrophoresis (2-DE) patterns of human sera from 10 patients with IONFH and 10 normal subjects were analyzed. The differentially expressed spots were identified by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS), and 7 proteins were found. The expression levels of tissue-type plasminogen activator (t-PA), bone-carboxyglutamate protein (BGP), c-sis, and an unknown protein were downregulated in the sera of patients with IONFH, whereas the other 3 proteins, including plasminogen activator inhibitor type 1 (PAI-1), crosslaps, and anti-p53 antibody, were upregulated. To examine their applicability as diagnostic markers, levels of the 6 identified proteins in serum were validated from patients with IONFH, osteoarthritis (OA), rheumatoid arthritis (RA), and fracture using the enzyme-linked immunosorbent assay (ELISA) method. It was found that only serum levels of t-PA, PAI-1, crosslaps, and anti-p53 antibody in patients with IONFH were always significantly different from those in patients with OA, RA, and fracture. These results suggest that serum levels of t-PA, PAI-1, crosslaps, and anti-p53 antibody could be used as noninvasive diagnostic biomarkers for IONFH.
16792673 The association of CTLA-4 and HLA class II autoimmune risk genotype with regulatory T cell 2006 Jul Regulatory T cells (Treg) are involved in the maintenance of peripheral tolerance by suppression of autoreactive lymphocytes that have avoided thymic depletion. The defective function of Treg cells has recently attracted attention in autoimmune diseases such as type 1 diabetes (T1D), rheumatoid arthritis and multiple sclerosis. Susceptibility to these diseases is associated with specific human leucocyte antigen (HLA) class II and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) gene polymorphisms. This study aimed to investigate the relationship between HLA class II and CTLA +49 A/G polymorphisms associated with susceptibility to T1D and the number and characteristics of Treg cells in children. Samples from 47 5-year-old children who participated in the All Babies in South-east Sweden (ABIS) follow-up study were grouped according to the presence of the T1D risk-associated HLA genotype (DQA1*0501-DQB1*0201, DQA1*0301-DQB1*0302) or neutral HLA genotypes. Lower percentages of CD4+ T cells (P = 0.03) and CD4+ CD25high cells (P = 0.06) expressing intracellular CTLA-4 were detected in samples from children with CTLA-4 +49GG compared to children with the +49AA genotype. Similarly, lower percentages of CD4+ (P = 0.002) and CD4+ CD25high (P = 0.002) cells expressing CTLA-4 were observed in children positive for HLA DQA1*0501-DQB1*0201 and DQA1*0301-DQB1*0302 (P = 0.04 for CD4+ and P = 0.02 for CD4+ CD25high) risk haplotypes when compared to children without these alleles. The percentage of CD25high cells among CD4+ cells was correlated inversely with CTLA-4 mRNA expression in PBMC (r = -0.56, P = 0.03). Decreased levels of CTLA-4 in CD4+ and CD4+ CD25high cells in individuals with CTLA-4 and HLA class II alleles associated with T1D may contribute to the initiation and/or progression of autoimmune response.
16540526 Differential expression of CD126 and CD130 mediates different STAT-3 phosphorylation in CD 2006 Apr IL-6 is a pleiotropic cytokine involved in T-lymphocyte biology. Following IL-6 binding, the soluble IL-6R (CD126)-IL-6 complex can directly activate cells that express the signal-transducing gp130 (CD130) molecule, which mediates two distinct signals, mitogenesis by mitogen-activated protein kinase (MAPK) activation and anti-apoptosis by signal transducer and activator of transcription 3 (STAT-3) activation. This 'trans-signaling', also mediated by the soluble CD126/IL-6 fusion protein hyper-IL-6 (H-IL-6), contributes to the perpetuation of autoimmune diseases such as Morbus Crohn or rheumatoid arthritis. On the other hand, the homeostasis of cellular immune reactions and its failure leading to autoimmune diseases are critically controlled by regulatory T cells (Tregs). Here, we investigated the differential expression of CD126 and CD130 on subsets of human leukocytes in blood, tonsil and spleen. Among CD4+ T cells, differential expression of CD126 and CD130 was observed on the basis of CD25 expression. CD4+CD25- T cells were strongly CD126+ and CD130+, whereas CD25(high) Tregs expressed CD126 but little CD130. Both CD126 and CD130 were down-modulated on CD4+CD25- T cells following ligand binding, whereas only marginal modulation was observed on Tregs. Interestingly, we observed a correlation between CD126 and CD130 expression with STAT-3 phosphorylation in CD4+CD25- T cells compared with Tregs after stimulation with IL-6 or H-IL-6, whereas the MAPK extracellular signal-regulated kinase 1/2 were not activated by CD130 dimerization. The differential expression of CD126 and CD130 and subsequent STAT-3 phosphorylation might be relevant for the recently described role of IL-6 in the control of Treg activity.
19103878 Functional anergy in a subpopulation of naive B cells from healthy humans that express aut 2009 Jan 16 Self-reactive B cells not controlled by receptor editing or clonal deletion may become anergic. We report that fully mature human B cells negative for surface IgM and retaining only IgD are autoreactive and functionally attenuated (referred to as naive IgD(+)IgM(-) B cells [B(ND)]). These B(ND) cells typically make up 2.5% of B cells in the peripheral blood, have antibody variable region genes in germline (unmutated) configuration, and, by all current measures, are fully mature. Analysis of 95 recombinant antibodies expressed from the variable genes of single B(ND) cells demonstrated that they are predominantly autoreactive, binding to HEp-2 cell antigens and DNA. Upon B cell receptor cross-linkage, B(ND) cells have a reduced capacity to mobilize intracellular calcium or phosphorylate tyrosines, demonstrating that they are anergic. However, intense stimulation causes B(ND) cells to fully respond, suggesting that these cells could be the precursors of autoantibody secreting plasma cells in autoimmune diseases such as systemic lupus erythematosus or rheumatoid arthritis. This is the first identification of a distinct mature human B cell subset that is naturally autoreactive and controlled by the tolerizing mechanism of functional anergy.
20641919 [(18)F]Fluorobenzyl-bombesin[7-14]-c(RGDyK). 2004 The amphibian bombesin (BBN or BN, a peptide of 14 amino acids) is an analog of human gastrin-releasing peptide (GRP, a peptide of 27 amino acids) that binds to GRP receptors (GRPR) with high affinity and specificity (1, 2). Both GRP and BBN share an amidated C-terminus sequence homology of seven amino acids, Trp-Ala-Val-Gly-His-Leu-Met-NH(2). BBN-Like peptides have been shown to induce various biological responses in diverse tissues, including the central nervous system (CNS) and the gastrointestinal (GI) system. They also act as potential growth factors for both normal and neoplastic tissues (3). Specific BBN receptors (BBN-R) have been identified on CNS and GI tissues and on a number of tumor cell lines (4). The BBN-R superfamily includes at least four different subtypes, namely the GRPR subtype (BB2), the neuromedin B (NMB) receptor subtype (BB1), the BB3 subtype, and the BB4 subtype. The findings of GRPR overexpression in various human tumors, such as breast, prostate, lung, colon, ovarian, and pancreatic cancers, provide opportunities for tumor imaging by designing specific molecular imaging agents to target the GRPR (5, 6). Integrins are a family of heterodimeric glycoproteins on cell surfaces that mediate diverse biological events involving cell–cell and cell–matrix interactions (7). Integrins consist of an α and a β subunit and are important for cell adhesion and signal transduction. The α(v)β(3) integrin is the most prominent receptor affecting tumor growth, tumor invasiveness, metastasis, tumor-induced angiogenesis, inflammation, osteoporosis, and rheumatoid arthritis (8-13). Expression of the α(v)β(3) integrin is strong on tumor cells and activated endothelial cells, whereas expression is weak on resting endothelial cells and most normal tissues. Antagonists of α(v)β(3) are being studied as antitumor and antiangiogenic agents, and agonists of α(v)β(3) are being studied as angiogenic agents for coronary angiogenesis (12, 14, 15). A peptide sequence consisting of Arg-Gly-Asp (RGD) has been identified as a recognition motif used by extracellular matrix proteins (vitronectin, fibrinogen, laminin, and collagen) to bind to a variety of integrins, including α(v)β(3). Various ligands have been introduced for imaging of tumors and tumor angiogenesis (16). Because prostate cancer expresses both GRPR and α(v)β(3), Li et al. (17) designed a BBN-RGD heterodimer in which BBN[7-14] and c(RGDyK) were connected with a glutamate linker. N-Succinimidyl-4-[(18)F]fluorobenzoate ([(18)F]SFB) was used to synthesize [(18)F]FB-BBN-RGD for tumor targeting.
16490784 cGMP-dependent protein kinase phosphorylates p21-activated kinase (Pak) 1, inhibiting Pak/ 2006 Apr 28 Endothelial cells are normally non-motile and quiescent; however, endothelial cells will become permeable and invade and proliferate to form new blood vessels (angiogenesis) in response to wounding, cancer, diabetic retinopathy, age-related macular degeneration, or rheumatoid arthritis. p21-activated kinase (Pak), an effector for the Rho GTPases Rac and Cdc42, is required for angiogenesis and regulates endothelial cell permeability and motility. Although Pak is primarily activated by Rac and Cdc42, there are additional proteins that regulate Pak activity and localization, including three AGC protein kinase family members, Akt-1, PDK-1, and cAMP-dependent protein kinase. We describe phosphorylation and regulation of Pak localization by a fourth AGC kinase family member, cGMP-dependent protein kinase (PKG). Using in vitro mapping, a phosphospecific antibody, co-transfection assays, and untransfected bovine aortic endothelial cells we determined that PKG phosphorylates Pak at serine 21. Phosphorylation was accompanied by changes in proteins associated with Pak. The adaptor protein Nck was released, whereas a novel complex with vasodilator-stimulated phosphoprotein was stimulated. Furthermore Ser-21 phosphorylation of Pak appears to be important for regulation of cell morphology. In both human umbilical vein endothelial cells and HeLa cells, activation of PKG in the presence of Pak stimulated tail retraction and cell polarization. However, in cells expressing S21A mutant Pak1, PKG activation or treatment with a peptide that blocks Nck/Pak binding caused aberrant cell morphology, blocked cell retraction, and mislocalized Pak, producing uropod (tail-like) structures. These data suggest that PKG regulates Pak and that the interaction plays a role in tail retraction.