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ABSTRACT: BACKGROUND/PURPOSE: Patients with rheumatoid arthritis (RA) are at increased risk for cardiovascular disease, an observation not explained by traditional cardiac risk factors and generally limited to those with RA-associated autoantibodies such as rheumatoid factor and anti-citrullinated protein antibodies (ACPA). We hypothesized that citrullinated proteins within the atherosclerotic plaque can be targeted by ACPA, forming stimulatory immune complexes which propagate the progression of atherosclerosis. METHODS AND RESULTS: Protein lysates prepared from atherosclerotic segments of human aorta were investigated for the presence of citrulline-modified proteins and specifically citrullinated fibrinogen (cFb) by immunoprecipitation and/or immunoblotting followed by mass spectrometry. Immunohistochemistry was performed in coronary artery plaques for the presence of citrullinated proteins and the PAD4 enzyme. Serum levels of anti-cyclic citrullinated peptide (CCP), anti-citrullinated vimentin (cVim), and anti-cFb antibodies were measured in 134 women with seropositive RA previously characterized for the presence of subclinical atherosclerosis by electron beam CT scan (EBCT). Western analysis of atherosclerotic plaque lysates demonstrated several citrullinated proteins and the presence of cFb was confirmed by immunoprecipitation, and mass spectrometry. Immunohistochemistry demonstrated co-localization of citrullinated proteins and the PAD4 enzyme within the coronary artery plaque. In age-adjusted regression models, antibodies targeting cFb and cit-vimentin, but not CCP2, were associated with an increased aortic plaque burden. CONCLUSION: Citrullinated proteins are prevalent within the atherosclerotic plaque, and certain ACPAs are associated with atherosclerotic burden. These observations suggest that targeting of citrullinated epitopes, specifically cFb, within the atherosclerotic plaque could provide a mechanism for accelerated atherosclerosis observed in patients with RA. © 2013 American College of Rheumatology.
Arthritis & Rheumatism 04/2013; · 7.87 Impact Factor
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Dong Hyun Sohn,
Jeremy Sokolove, Orr Sharpe,
Jennifer C Erhart,
Piyanka E Chandra,
Lauren J Lahey,
Tamsin M Lindstrom,
Inyong Hwang,
Katherine A Boyer,
Thomas P Andriacchi,
William H Robinson
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ABSTRACT: Osteoarthritis (OA) is a degenerative disease characterized by cartilage breakdown in the synovial joints. The presence of low-grade inflammation in OA joints is receiving increasing attention, with synovitis shown to be present even in the early stages of the disease. How the synovial inflammation arises is unclear, but proteins in the synovial fluid of affected joints could conceivably contribute. We therefore surveyed the proteins present in OA synovial fluid and assessed their immunostimulatory properties.
We used mass spectrometry to survey the proteins present in the synovial fluid of patients with knee OA. We used a multiplex bead-based immunoassay to measure levels of inflammatory cytokines in serum and synovial fluid from patients with knee OA and from patients with rheumatoid arthritis (RA), as well as in sera from healthy individuals. Significant differences in cytokine levels between groups were determined by significance analysis of microarrays, and relations were determined by unsupervised hierarchic clustering. To assess the immunostimulatory properties of a subset of the identified proteins, we tested the proteins' ability to induce the production of inflammatory cytokines by macrophages. For proteins found to be stimulatory, the macrophage stimulation assays were repeated by using Toll-like receptor 4 (TLR4)-deficient macrophages.
We identified 108 proteins in OA synovial fluid, including plasma proteins, serine protease inhibitors, proteins indicative of cartilage turnover, and proteins involved in inflammation and immunity. Multiplex cytokine analysis revealed that levels of several inflammatory cytokines were significantly higher in OA sera than in normal sera, and levels of inflammatory cytokines in synovial fluid and serum were, as expected, higher in RA samples than in OA samples. As much as 36% of the proteins identified in OA synovial fluid were plasma proteins. Testing a subset of these plasma proteins in macrophage stimulation assays, we found that Gc-globulin, α1-microglobulin, and α2-macroglobulin can signal via TLR4 to induce macrophage production of inflammatory cytokines implicated in OA.
Our findings suggest that plasma proteins present in OA synovial fluid, whether through exudation from plasma or production by synovial tissues, could contribute to low-grade inflammation in OA by functioning as so-called damage-associated molecular patterns in the synovial joint.
Arthritis research & therapy 01/2012; 14(1):R7. · 4.27 Impact Factor
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ABSTRACT: For 15 y, α B-crystallin (heat shock protein [Hsp] B5) has been labeled an autoantigen in multiple sclerosis (MS) based on humoral and cellular responses found in humans and animal models. However, there have been several scientific inconsistencies with this assignment, ranging from studies demonstrating small differences in anticrystallin responses between patients and healthy individuals to the inability of crystallin-specific T cells to induce symptoms of experimental allergic encephalomyelitis in animal models. Experiments in this article demonstrate that the putative anti-HspB5 Abs from 23 MS patients cross-react with 7 other members of the human small Hsp family and were equally present in normal plasma. Biolayer interferometry demonstrates that the binding was temperature dependent, and that the calculated K(a) increased as the concentration of the sHsp decreased. These two patterns are characteristic of multiple binding sites with varying affinities, the composition of which changes with temperature, supporting the hypothesis that HspB5 bound the Ab and not the reverse. HspB5 also precipitated Ig heavy and L chains from sera from patients with MS. These results establish that small Hsps bind Igs with high affinity and refute much of the serological data used to assign α B-crystallin as an autoantigen.
The Journal of Immunology 02/2011; 186(7):4263-8. · 5.79 Impact Factor
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Ricardo T Paniagua,
Anna Chang,
Melissa M Mariano,
Emily A Stein,
Qian Wang,
Tamsin M Lindstrom, Orr Sharpe,
Claire Roscow,
Peggy P Ho,
David M Lee,
William H Robinson
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ABSTRACT: Tyrosine kinases are key mediators of multiple signaling pathways implicated in rheumatoid arthritis (RA). We previously demonstrated that imatinib mesylate--a Food and Drug Administration (FDA)-approved, antineoplastic drug that potently inhibits the tyrosine kinases Abl, c-Kit, platelet-derived growth factor receptor (PDGFR), and c-Fms--ameliorates murine autoimmune arthritis. However, which of the imatinib-targeted kinases is the principal culprit in disease pathogenesis remains unknown. Here we examine the role of c-Fms in autoimmune arthritis.
We tested the therapeutic efficacy of orally administered imatinib or GW2580, a small molecule that specifically inhibits c-Fms, in three mouse models of RA: collagen-induced arthritis (CIA), anti-collagen antibody-induced arthritis (CAIA), and K/BxN serum transfer-induced arthritis (K/BxN). Efficacy was evaluated by visual scoring of arthritis severity, paw thickness measurements, and histological analysis. We assessed the in vivo effects of imatinib and GW2580 on macrophage infiltration of synovial joints in CIA, and their in vitro effects on macrophage and osteoclast differentiation, and on osteoclast-mediated bone resorption. Further, we determined the effects of imatinib and GW2580 on the ability of macrophage colony-stimulating factor (M-CSF; the ligand for c-Fms) to prime bone marrow-derived macrophages to produce tumor necrosis factor (TNF) upon subsequent Fc receptor ligation. Finally, we measured M-CSF levels in synovial fluid from patients with RA, osteoarthritis (OA), or psoriatic arthritis (PsA), and levels of total and phosphorylated c-Fms in synovial tissue from patients with RA.
GW2580 was as efficacious as imatinib in reducing arthritis severity in CIA, CAIA, and K/BxN models of RA. Specific inhibition of c-Fms abrogated (i) infiltration of macrophages into synovial joints of arthritic mice; (ii) differentiation of monocytes into macrophages and osteoclasts; (iii) osteoclast-mediated bone resorption; and (iv) priming of macrophages to produce TNF upon Fc receptor stimulation, an important trigger of synovitis in RA. Expression and activation of c-Fms in RA synovium were high, and levels of M-CSF were higher in RA synovial fluid than in OA or PsA synovial fluid.
These results suggest that c-Fms plays a central role in the pathogenesis of RA by mediating the differentiation and priming of monocyte lineage cells. Therapeutic targeting of c-Fms could provide benefit in RA.
Arthritis research & therapy 02/2010; 12(1):R32. · 4.27 Impact Factor
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Peggy P Ho,
Lowen Y Lee,
Xiaoyan Zhao,
Beren H Tomooka,
Ricardo T Paniagua, Orr Sharpe,
Maya J BenBarak,
Piyanka E Chandra,
Wolfgang Hueber,
Lawrence Steinman,
William H Robinson
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ABSTRACT: Rheumatoid arthritis (RA) is an autoimmune synovitis characterized by the presence of anticitrullinated protein Abs, although the exact targets and role of anticitrullinated protein autoimmunity in the pathogenesis of RA remain to be defined. Fibrinogen, which can be citrullinated, has recently emerged as a candidate autoantigen. To determine whether autoimmunity against fibrinogen can mediate inflammatory arthritis, we immunized a variety of common mouse strains with fibrinogen and found that DBA/1 and SJL mice developed an inflammatory and erosive arthritis. Mice with fibrinogen-induced arthritis (FIA) possess fibrinogen-reactive T cells that produce the proinflammatory cytokines IL-6, IL-17, TNF-alpha, and IFN-gamma. FIA can be adoptively transferred with either plasma or fibrinogen-specific T cells from diseased mice. Mice with FIA possess rheumatoid factor, circulating immune complexes, and anticyclic citrullinated peptide Abs, all of which are characteristic of human RA. These observations demonstrate that fibrinogen is arthritogenic in mice and that the pathogenesis of FIA is mediated by both autoantibodies and fibrinogen-reactive T cells.
The Journal of Immunology 11/2009; 184(1):379-90. · 5.79 Impact Factor
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Greg P Coffey,
Ranjani Rajapaksa,
Raymond Liu, Orr Sharpe,
Chiung-Chi Kuo,
Sharon Wald Krauss,
Yael Sagi,
R Eric Davis,
Louis M Staudt,
Jeff P Sharman,
William H Robinson,
Shoshana Levy
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ABSTRACT: CD81 is a tetraspanin family member involved in diverse cellular interactions in the immune and nervous systems and in cell fusion events. However, the mechanism of action of CD81 and of other tetraspanins has not been defined. We reasoned that identifying signaling molecules downstream of CD81 would provide mechanistic clues. We engaged CD81 on the surface of B-lymphocytes and identified the induced tyrosine-phosphorylated proteins by mass spectrometry. This analysis showed that the most prominent tyrosine phosphorylated protein was ezrin, an actin-binding protein and a member of the ezrin-radixin-moesin family. We also found that CD81 engagement induces spleen tyrosine kinase (Syk) and that Syk was involved in tyrosine phosphorylation of ezrin. After engagement of CD81, it colocalized with ezrin and F-actin, and this association was disrupted when Syk activation was blocked. Taken together, these studies suggest a model in which CD81 interfaces between the plasma membrane and the cytoskeleton by activating Syk, mobilizing ezrin, and recruiting F-actin to facilitate cytoskeletal reorganization and cell signaling. This mechanism might explain the pleiotropic effects induced in response to stimulation of cells by anti-CD81 antibodies or by the hepatitis C virus, which uses this molecule as its key receptor.
Journal of Cell Science 09/2009; 122(Pt 17):3137-44. · 6.11 Impact Factor
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ABSTRACT: The 3'untranslated region (UTR) of human LDL receptor (LDLR) mRNA contains three AU-rich elements (AREs) responsible for rapid mRNA turnover and mediates the stabilization induced by berberine (BBR). However, the identities of the specific RNA binding proteins involved in the regulation of LDLR mRNA stability at the steady state level or upon BBR treatment are unknown. By conducting small interfering RNA library screenings, biotinylated RNA pull-down, mass spectrometry analysis, and functional assays, we now identify heterogeneous nuclear ribonucleoprotein D (hnRNP D), hnRNP I, and KH-type splicing regulatory protein (KSRP) as key modulators of LDLR mRNA stability in liver cells. We show that hnRNP D, I, and KSRP interact with AREs of the LDLR 3'UTR with sequence specificity. Silencing the expression of these proteins increased LDLR mRNA and protein levels. We further demonstrate that BBR-induced mRNA stabilization involves hnRNP I and KSRP, as their cellular depletions abolished the BBR effect and BBR treatment reduced the binding of hnRNP I and KSRP to the LDLR mRNA 3'UTR. These new findings demonstrate that LDLR mRNA stability is controlled by a group of ARE binding proteins, including hnRNP D, hnRNP I, and KSRP. Our results suggest that interference with the ability of destabilizing ARE binding proteins to interact with LDLR-ARE motifs is likely a mechanism for regulating LDLR expression by compounds such as BBR and perhaps others.
The Journal of Lipid Research 02/2009; 50(5):820-31. · 5.56 Impact Factor
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ABSTRACT: Anti-citrullinated protein antibodies have a diagnostic role in rheumatoid arthritis (RA); however, little is known about their origins and contribution to pathogenesis. Citrullination is the post-translational conversion of arginine to citrulline by peptidyl arginine deiminase, and increased citrullination of proteins is observed in the joint tissue in RA and in brain tissue in multiple sclerosis (MS).
We applied synovial and myelin protein arrays to examine epitope spreading of B cell responses to citrullinated epitopes in both the collagen-induced arthritis (CIA) model for RA and the experimental autoimmune encephalomyelitis (EAE) model for MS. Synovial and myelin protein arrays contain a spectrum of proteins and peptides, including native and citrullinated forms, representing candidate autoantigens in RA and MS, respectively. We applied these arrays to characterise the specificity of autoantibodies in serial serum samples derived from mice with acute and chronic stages of CIA and EAE.
In samples from pre-disease CIA and acute-disease EAE, we observed autoantibody targeting of the immunising antigen and responses to a limited set of citrullinated epitopes. Over the course of diseases, the autoantibody responses expanded to target multiple citrullinated epitopes in both CIA and EAE. Using immunoblotting and mass spectrometry analysis, we identified citrullination of multiple polypeptides in CIA joint and EAE brain tissue that have not previously been described as citrullinated.
Our results suggest that anti-citrulline antibody responses develop in the early stages of CIA and EAE, and that autoimmune inflammation results in citrullination of joint proteins in CIA and brain proteins in EAE, thereby creating neoantigens that become additional targets in epitope spreading of autoimmune responses.
Arthritis research & therapy 10/2008; 10(5):R119. · 4.27 Impact Factor
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ABSTRACT: There is increasing evidence that autoantibodies and immune complexes (ICs) contribute to synovitis in rheumatoid arthritis (RA), yet the autoantigens incorporated in ICs in RA remain incompletely characterised.
We used the C1q protein to capture ICs from plasma derived from human RA and control patients. Antibodies specific for immunoglobulin were used to detect ICs, and fibrinogen antibodies were used to detect fibrinogen-containing ICs. RA and control plasma were separated by liquid chromatography, and fractions then characterised by ELISA, immunoblotting and mass spectrometry. Immunohistochemical staining was performed on rheumatoid synovial tissue.
C1q-immunoassays demonstrated increased levels of IgG (p = 0.01) and IgM (p = 0.0002) ICs in plasma derived from RA patients possessing anti-cyclic citrullinated peptide (CCP+) autoantibodies as compared with healthy controls. About one-half of the anti-CCP+ RA possessed circulating ICs containing fibrinogen (p = 0.0004). Fractionation of whole RA plasma revealed citrullinated fibrinogen in the high molecular weight fractions that contained ICs. Positive correlations were observed between fibrinogen-containing ICs and anti-citrullinated fibrinogen autoantibodies, anti-CCP antibody, rheumatoid factor and certain clinical characteristics. Immunohistochemical staining demonstrated co-localisation of fibrinogen, immunoglobulin and complement component C3 in RA pannus tissue. Mass spectrometry analysis of immune complexes immunoprecipitated from RA pannus tissue lysates demonstrated the presence of citrullinated fibrinogen.
Circulating ICs containing citrullinated fibrinogen are present in one-half of anti-CCP+ RA patients, and these ICs co-localise with C3 in the rheumatoid synovium suggesting that they contribute to synovitis in a subset of RA patients.
Arthritis research & therapy 09/2008; 10(4):R94. · 4.27 Impact Factor
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Catherine M Shachaf,
Andrew J Gentles,
Sailaja Elchuri,
Debashis Sahoo,
Yoav Soen, Orr Sharpe,
Omar D Perez,
Maria Chang,
Dennis Mitchel,
William H Robinson,
David Dill,
Garry P Nolan,
Sylvia K Plevritis,
Dean W Felsher
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ABSTRACT: MYC overexpression has been implicated in the pathogenesis of most types of human cancers. MYC is likely to contribute to tumorigenesis by its effects on global gene expression. Previously, we have shown that the loss of MYC overexpression is sufficient to reverse tumorigenesis. Here, we show that there is a precise threshold level of MYC expression required for maintaining the tumor phenotype, whereupon there is a switch from a gene expression program of proliferation to a state of proliferative arrest and apoptosis. Oligonucleotide microarray analysis and quantitative PCR were used to identify changes in expression in 3,921 genes, of which 2,348 were down-regulated and 1,573 were up-regulated. Critical changes in gene expression occurred at or near the MYC threshold, including genes implicated in the regulation of the G(1)-S and G(2)-M cell cycle checkpoints and death receptor/apoptosis signaling. Using two-dimensional protein analysis followed by mass spectrometry, phospho-flow fluorescence-activated cell sorting, and antibody arrays, we also identified changes at the protein level that contributed to MYC-dependent tumor regression. Proteins involved in mRNA translation decreased below threshold levels of MYC. Thus, at the MYC threshold, there is a loss of its ability to maintain tumorigenesis, with associated shifts in gene and protein expression that reestablish cell cycle checkpoints, halt protein translation, and promote apoptosis.
Cancer Research 08/2008; 68(13):5132-42. · 7.86 Impact Factor
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Catherine M Shachaf,
Omar D Perez,
Sawsan Youssef,
Alice C Fan,
Sailaja Elchuri,
Matthew J Goldstein,
Amy E Shirer, Orr Sharpe,
Joy Chen,
Dennis J Mitchell,
Maria Chang,
Garry P Nolan,
Lawrence Steinman,
Dean W Felsher
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ABSTRACT: Statins are a class of drugs that inhibit 3-hydroxy-3-methylglutaryl-coenzyme A (HMGcoA) reductase, a critical enzyme in the mevalonate pathway. Several reports document that statins may prevent different human cancers. However, whether or not statins can prevent cancer is controversial due to discordant results. One possible explanation for these conflicting conclusions is that only some tumors or specific statins may be effective. Here, we demonstrate in an in vivo transgenic model in which atorvastatin reverses and prevents the onset of MYC-induced lymphomagenesis, but fails to reverse or prevent tumorigenesis in the presence of constitutively activated K-Ras (G12D). Using phosphoprotein fluorescence-activated cell sorter (FACS) analysis, atorvastatin treatment was found to result in the inactivation of the Ras and ERK1/2 signaling pathways associated with the dephosphorylation and inactivation of MYC. Correspondingly, tumors with a constitutively activated K-Ras (G12D) did not exhibit dephosphorylation of ERK1/2 and MYC. Atorvastatin's effects on MYC were specific to the inhibition of HMGcoA reductase, as treatment with mevalonate, the product of HMG-CoA reductase activity, abrogated these effects and inhibited the ability of atorvastatin to reverse or suppress tumorigenesis. Also, RNAi directed at HMGcoA reductase was sufficient to abrogate the neoplastic properties of MYC-induced tumors. Thus, atorvastatin, by inhibiting HMGcoA reductase, induces changes in phosphoprotein signaling that in turn prevent MYC-induced lymphomagenesis.
Blood 11/2007; 110(7):2674-84. · 9.90 Impact Factor
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ABSTRACT: To identify biomarkers associated with the development of hepatocellular carcinoma (HCC) in CuZn superoxide dismutase (CuZnSOD, Sod1) deficient mice, 2-DE followed by MS analysis was carried out with liver samples obtained from 18-month-old Sod1-/- and +/+ mice. The intracellular Ca binding protein, regucalcin (RGN), showed a divergent alteration in Sod1-/- samples. Whereas elevated RGN levels were observed in -/- samples with no obvious neoplastic changes, marked reduction in RGN was observed in -/- samples with fully developed HCC. GST mu1 (GSTM1), on the other hand, showed a significant increase only in the neoplastic regions obtained from Sod1-/- livers. No change in GSTM1 was observed in the surrounding normal tissues. Marked reduction was observed in two intracellular lipid transporters, fatty acid binding protein 1 (FABP1) and major urinary protein 11 and 8 (MUP 11&8), in Sod1-/- samples. Analysis of additional samples at 18-22 months of age showed a three-fold increase in enolase activities in Sod1-/- livers. Consistent with previous findings, carbonic anhydrase 3 (CAIII) levels were significantly reduced in Sod1-/- samples, and immunohistochemical analysis revealed that the reduction was not homogenous throughout the lobular structure in the liver.
PROTEOMICS 06/2007; 7(12):2121-9. · 4.51 Impact Factor
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Ricardo T Paniagua, Orr Sharpe,
Peggy P Ho,
Steven M Chan,
Anna Chang,
John P Higgins,
Beren H Tomooka,
Fiona M Thomas,
Jason J Song,
Stuart B Goodman,
David M Lee,
Mark C Genovese,
Paul J Utz,
Lawrence Steinman,
William H Robinson
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ABSTRACT: Tyrosine kinases play a central role in the activation of signal transduction pathways and cellular responses that mediate the pathogenesis of rheumatoid arthritis. Imatinib mesylate (imatinib) is a tyrosine kinase inhibitor developed to treat Bcr/Abl-expressing leukemias and subsequently found to treat c-Kit-expressing gastrointestinal stromal tumors. We demonstrate that imatinib potently prevents and treats murine collagen-induced arthritis (CIA). We further show that micromolar concentrations of imatinib abrogate multiple signal transduction pathways implicated in RA pathogenesis, including mast cell c-Kit signaling and TNF-alpha release, macrophage c-Fms activation and cytokine production, and fibroblast PDGFR signaling and proliferation. In our studies, imatinib attenuated PDGFR signaling in fibroblast-like synoviocytes (FLSs) and TNF-alpha production in synovial fluid mononuclear cells (SFMCs) derived from human RA patients. Imatinib-mediated inhibition of a spectrum of signal transduction pathways and the downstream pathogenic cellular responses may provide a powerful approach to treat RA and other inflammatory diseases.
Journal of Clinical Investigation 11/2006; 116(10):2633-42. · 15.39 Impact Factor
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ABSTRACT: This paper describes an analytical method for the determination of ceruloplasmin (Cp) in human serum. The method uses immunoaffinity chromatography and size-exclusion chromatography (SEC) to "purify" the serum sample prior to analysis of 63Cu and 65Cu by inductively-coupled plasma mass spectrometry (ICPMS). By removing the six most abundant proteins from serum with immunoaffinity chromatography and by using SEC to separate Cu bound by Cp from any free Cu that might be present in the serum sample, we demonstrated that SEC-ICPMS can accurately and reproducibly measure Cp in the ERM DA470 reference serum. Cp identification is based on retention time match of the unknown in the serum sample with the Cp external standard and the presence of 63Cu and 65Cu at a ratio of 2.2+/-0.1. This method was used to analyze a reference serum certified for Cp, 47 serum samples from four different diseases and a set of normal controls. The reference serum and a serum sample from a patient with myocardial infarction, as well as a Cp standard, were also analyzed by electrospray mass spectrometry to confirm the presence of Cp in the SEC fraction known to contain 63Cu.
Analytical and Bioanalytical Chemistry 10/2006; 386(1):180-7. · 3.78 Impact Factor
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ABSTRACT: In this study, we further characterize the humoral autoimmune response in the recently described anti-CD1 autoreactive T cell receptor-transgenic mouse lupus model (CD1 lupus model). We discovered and characterized novel autoantigens, comprising a protein of 105 kDa (p105) and a novel RNA molecule of 140 base pairs (bp) that is likely associated with p105, and several additional factors with distinct biochemical properties. In the CD1 lupus model, lethally irradiated BALB/c/nu/nu mice were injected intravenously with sorted bone marrow cells and sorted splenic T cells from donor BALB/c mice expressing TCR alpha and beta transgenes that encode autoreactivity for CD1d. Adoptive hosts injected with the single-positive (CD4(+) and CD8(+)) subset of transgenic cells developed anti-double-stranded DNA antibodies and a lupus-like illness. Sera were analyzed by Western blotting and immunoprecipitation. Antigens were characterized by biochemical and serological methods. Serum autoantibodies from 5 of 12 (42%) CD1 lupus mice immunoprecipitated a 105-kDa protein, termed p105. p105 was associated with a small RNA of approximately 140 bp. Anti-p105 autoantibodies appeared early in the course of disease. Serological and biochemical characterization suggested that p105 was distinct from known lupus autoantigens of similar molecular masses, indicating that p105 represents a novel autoantigen in lupus.
European Journal of Immunology 07/2004; 34(6):1654-62. · 5.10 Impact Factor
