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PubMed | University of Cantabria, University of Barcelona, Institute Parasitologia y Biomedicina Lopez Neyra IPBLN and Institute Biomedicina Y Biotecnologia Of Cantabria
Type: | Journal: Journal of proteomics | Year: 2016

Collagen type II-induced arthritis (CIA) is an inflammatory and autoimmune disease. Spleen protein extracts were subjected to 2D-DiGE and MS-MALDI-TOF/TOF analysis to identify protein species that differ in abundance in CD38-KO versus B6 WT mice either with arthritis or with inflammation. Using multivariate analyses, in Col-II-immunized mice, 23 distinct spleen protein species were able to discriminate between WT and CD38-KO mice. Among them, several citrullinated proteins and multiple serotransferrin (Tf) species were identified. In contrast, in CFA/IFA-treated mice, the distinct protein profile, which discriminates between CD38-KO and WT mice, was unrelated with Tf, but not with citrullination. Unexpectedly, non-immunized CD38-KO mice showed a distinct proteome profile as compared with that in non-immunized WT mice, and again multiple protein species were identified as Tf. By using a LC-TOF-MS method to separate and detect Tf glycopeptide glycoforms, increases in fucosylation and glycan branching was observed in sera from mice CIA(+) versus non-immunized, and between WT and CD38-KO with arthritis. Data on 2-DE Tf spots indicated differences in glycosylation related with NeuGc content. Thus, Tf changed significantly in its glycosylation pattern in arthritic mice. The MS data have been deposited to the ProteomeXchange Consortium with the dataset identifiers: PXD002644, PXD002643, PXD003183, and PXD003163.2-DE followed by LC-TOF-MS could be implemented to identify Tf glycoforms linked to specific protein species, and correlate a particular Tf species to a function. To gain insight into the relationship between transferrin glycoforms and its biological function it is particularly interesting to study putative differences in the glycosylation pattern of Tf in specific tissues associated with the disease (i.e.: joints), or in specific compartments such as exosomes/microvesicles, which are highly enriched in Tf receptors.


PubMed | University of Oregon and Institute Parasitologia y Biomedicina Lopez Neyra IPBLN
Type: | Journal: Parasites & vectors | Year: 2016

Mitochondria play essential biological functions including the synthesis and trafficking of porphyrins and iron/sulfur clusters (ISC), processes that in mammals involve the mitochondrial ATP-Binding Cassette (ABC) transporters ABCB6 and ABCB7, respectively. The mitochondrion of pathogenic protozoan parasites such as Leishmania is a promising goal for new therapeutic approaches. Leishmania infects human macrophages producing the neglected tropical disease known as leishmaniasis. Like most trypanosomatid parasites, Leishmania is auxotrophous for heme and must acquire porphyrins from the host.LmABCB3, a new Leishmania major protein with significant sequence similarity to human ABCB6/ABCB7, was identified and characterized using bioinformatic tools. Fluorescent microscopy was used to determine its cellular localization, and its level of expression was modulated by molecular genetic techniques. Intracellular in vitro assays were used to demonstrate its role in amastigotes replication, and an in vivo mouse model was used to analyze its role in virulence. Functional characterization of LmABCB3 was carried out in Leishmania promastigotes and Saccharomyces cerevisiae. Structural analysis of LmABCB3 was performed using molecular modeling software.LmABCB3 is an atypical ABC half-transporter that has a unique N-terminal extension not found in any other known ABC protein. This extension is required to target LmABCB3 to the mitochondrion and includes a potential metal-binding domain. We have shown that LmABCB3 interacts with porphyrins and is required for the mitochondrial synthesis of heme from a host precursor. We also present data supporting a role for LmABCB3 in the biogenesis of cytosolic ISC, essential cofactors for cell viability in all three kingdoms of life. LmABCB3 fully complemented the severe growth defect shown in yeast lacking ATM1, an orthologue of human ABCB7 involved in exporting from the mitochondria a gluthatione-containing compound required for the generation of cytosolic ISC. Indeed, docking analyzes performed with a LmABCB3 structural model using trypanothione, the main thiol in this parasite, as a ligand showed how both, LmABCB3 and yeast ATM1, contain a similar thiol-binding pocket. Additionally, we show solid evidence suggesting that LmABCB3 is an essential gene as dominant negative inhibition of LmABCB3 is lethal for the parasite. Moreover, the abrogation of only one allele of the gene did not impede promastigote growth in axenic culture but prevented the replication of intracellular amastigotes and the virulence of the parasites in a mouse model of cutaneous leishmaniasis.Altogether our results present the previously undescribed LmABCB3 as an unusual mitochondrial ABC transporter essential for Leishmania survival through its role in the generation of heme and cytosolic ISC. Hence, LmABCB3 could represent a novel target to combat leishmaniasis.


PubMed | University of Cantabria, University of Barcelona, Institute Parasitologia y Biomedicina Lopez Neyra IPBLN and Institute Biomedicina Y Biotecnologia Of Cantabria
Type: | Journal: Data in brief | Year: 2016

This data article presents the results of all the statistical analyses applied to the relative intensities of the detected 2D-DiGE protein spots for each of the 3 performed DiGE experiments. The data reveals specific subsets of protein spots with significant differences between WT and CD38-deficient mice with either Collagen-induced arthritis (CIA), or with chronic inflammation induced by CFA, or under steady-state conditions. This article also shows the MS data analyses that allowed the identification of the protein species which serve to discriminate the different experimental groups used in this study. Moreover, the article presents MS data on the citrullinated peptides linked to specific protein species that were generated in CIA(+) or CFA-treated mice. Lastly, this data article provides MS data on the efficiency of the analyses of the transferrin (Tf) glycopeptide glycosylation pattern in spleen and serum from CIA(+) mice and normal controls. The data supplied in this work is related to the research article entitled identification of multiple transferrin species in spleen and serum from mice with collagen-induced arthritis which may reflect changes in transferrin glycosylation associated with disease activity: the role of CD38 [1]. All mass spectrometry data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with identifiers PRIDE: PXD002644, PRIDE: PXD002643, PRIDE: PXD003183 and PRIDE: PXD003163.


PubMed | Hospital Regional Universitario Of Malaga, Hospital Ramon y Cajal, Hospital Clinico San Carlos, Centro Andaluz Of Estudios Bioinformaticos Caebi and 4 more.
Type: Journal Article | Journal: Multiple sclerosis (Houndmills, Basingstoke, England) | Year: 2015

Recent findings have shown a correlation between the intrathecal IgG index and variants at the immunoglobulin heavy chain (IGHC) locus in patients with multiple sclerosis (MS).The objective of this paper is to analyse the association of the locus with MS susceptibility and its relationship with intrathecal immunoglobulin (Ig) parameters.We genotyped the rs11621145 variant, located at the IGHC locus, in 2726 patients with MS and 2133 healthy controls. Associations of intrathecal IgG and IgM indexes with rs11621145 were analysed by linear regression analysis in 538 MS patients.We found that rs11621145 showed statistically significant evidence for association with susceptibility to MS (odds ratio = 0.69, p = 1.053E-09), though validation of this result in additional cohorts would be desirable. We confirmed the association between the IgG index and the rs11621145 (p = 6.85E-07, Beta = 0.207). Furthermore, rs11621145 was inversely correlated with IgM index (p = 7.24E-04, Beta = -0.277), and therefore marks a decreased likelihood of presenting IgM oligoclonal bands (odds ratio = 0.38, p = 2.35E-06).Our results suggest that the polymorphism of the IGHC locus could be altering the switching of the Ig isotype in B cells and it may be interfering with T-dependent and T-independent antibody responses.


Pavon E.J.,Institute Parasitologia y Biomedicina Lopez Neyra IPBLN | Pavon E.J.,CIBER ISCIII | Zumaquero E.,Institute Parasitologia y Biomedicina Lopez Neyra IPBLN | Zumaquero E.,University of Alabama at Birmingham | And 12 more authors.
Cytokine | Year: 2013

CD38 is a multifunctional protein possessing ADP-ribosyl cyclase activity responsible for both the synthesis and the degradation of several Ca2+-mobilizing second messengers. In mammals, CD38 also functions as a receptor. In this study CD38 expression in CD4+, CD8+, or CD25+ T cells was significantly higher in systemic lupus erythematosus (SLE) patients than in Normal controls. Increased CD38 expression in SLE T cells correlated with plasma levels of Th2 (IL-4, IL-10, IL-13) and Th1 (IL-1β, IL-12, IFN-γ, TNF-α) cytokines, and was more prevalent in clinically active SLE patients than in Normal controls. In contrast, elevated anti-CD38 IgG autoantibodies were more frequent in clinically quiescent SLE patients (SLEDAI=0) than in Normal controls, and correlated with moderate increased plasma levels of IL-10 and IFN-γ. However, clinically active SLE patients were mainly discriminated from quiescent SLE patients by increased levels of IL-10 and anti-dsDNA antibodies, with odds ratios (ORs) of 3.7 and 4.8, respectively. Increased frequency of anti-CD38 autoantibodies showed an inverse relationship with clinical activity (OR=0.43), and in particular with the frequency of anti-dsDNA autoantibodies (OR=0.21). Increased cell death occurred in CD38+ Jurkat T cells treated with anti-CD38+ SLE plasmas, and not in these cells treated with anti-CD38- SLE plasmas, or Normal plasmas. This effect did not occur in CD38-negative Jurkat T cells, suggesting that it could be attributed to anti-CD38 autoantibodies. These results support the hypothesis that anti-CD38 IgG autoantibodies or their associated plasma factors may dampen immune activation by affecting the viability of CD38+ effector T cells and may provide protection from certain clinical SLE features. © 2013 Elsevier Ltd.


PubMed | University of the Basque Country, Ludwig Maximilians University of Munich, Max Planck Institute for Molecular Genetics, Heinrich Heine University Düsseldorf and 26 more.
Type: Journal Article | Journal: Journal of medical genetics | Year: 2015

A recent large-scale study in multiple sclerosis (MS) using the ImmunoChip platform reported on 11 loci that showed suggestive genetic association with MS. Additional data in sufficiently sized and independent data sets are needed to assess whether these loci represent genuine MS risk factors.The lead SNPs of all 11 loci were genotyped in 10796 MS cases and 10793 controls from Germany, Spain, France, the Netherlands, Austria and Russia, that were independent from the previously reported cohorts. Association analyses were performed using logistic regression based on an additive model. Summary effect size estimates were calculated using fixed-effect meta-analysis.Seven of the 11 tested SNPs showed significant association with MS susceptibility in the 21589 individuals analysed here. Meta-analysis across our and previously published MS case-control data (total sample size n=101683) revealed novel genome-wide significant association with MS susceptibility (p<510(-8)) for all seven variants. This included SNPs in or near LOC100506457 (rs1534422, p=4.0310(-12)), CD28 (rs6435203, p=1.3510(-9)), LPP (rs4686953, p=3.3510(-8)), ETS1 (rs3809006, p=7.7410(-9)), DLEU1 (rs806349, p=8.1410(-12)), LPIN3 (rs6072343, p=7.1610(-12)) and IFNGR2 (rs9808753, p=4.4010(-10)). Cis expression quantitative locus effects were observed in silico for rs6435203 on CD28 and for rs9808753 on several immunologically relevant genes in the IFNGR2 locus.This study adds seven loci to the list of genuine MS genetic risk factors and further extends the list of established loci shared across autoimmune diseases.


PubMed | Autonomous University of Madrid and Institute Parasitologia y Biomedicina Lopez Neyra IPBLN
Type: Journal Article | Journal: European journal of human genetics : EJHG | Year: 2016

Genome-wide association studies (GWAS) in migraine are providing the molecular basis of this heterogeneous disease, but the understanding of its aetiology is still incomplete. Although some biomarkers have currently been accepted for migraine, large amount of studies for identifying new ones is needed. The migraine-associated variant rs12355831:A>G (P=2 10


Rodriguez M.I.,Institute Parasitologia y Biomedicina Lopez Neyra IPBLN | Majuelos-Melguizo J.,Institute Parasitologia y Biomedicina Lopez Neyra IPBLN | Marti Martin-Consuegra J.M.,Institute Parasitologia y Biomedicina Lopez Neyra IPBLN | Ruiz de Almodovar M.,University of Granada | And 2 more authors.
Medicinal Research Reviews | Year: 2015

Poly (ADP-ribose) polymerase (PARP) inhibitors are particularly efficient against tumors with defects in the homologous recombination repair pathway. Nonetheless poly(ADP-ribosylation) (PARylation) modulates prometastasic activities and adaptation of tumor to a hostile microenvironment. Modulation of metastasis-promoting traits is possible through the alteration of key transcription factors involved in the regulation of the hypoxic response, the recruitment of new vessels (or angiogenesis), and the stimulation of epithelial to mesenchymal transition (EMT). In this review, we summarized some of the findings that focalize on PARP-1's action on tumor aggressiveness, suggesting new therapeutic opportunities against an assembly of tumors not necessarily bearing DNA repair defects. Metastasis accounts for the vast majority of mortality derived from solid cancer. PARP-1 is an active player in tumor adaptation to metastasis and PARP inhibitors, recognized as promising therapeutic agents against homologous recombination deficient tumors, has novel properties responsible for the antimetastatic actions in different tumor settings. © 2015 Wiley Periodicals, Inc.


Rosal-Vela A.,Institute Parasitologia y Biomedicina Lopez Neyra IPBLN | Garcia-Rodriguez S.,Institute Parasitologia y Biomedicina Lopez Neyra IPBLN | Postigo J.,University of Cantabria | Iglesias M.,University of Cantabria | And 6 more authors.
Proteomics | Year: 2015

Collagen-type-II-induced arthritis (CIA) is an autoimmune disease, which involves a complex host systemic response including inflammatory and autoimmune reactions. CIA is milder in CD38-/- than in wild-type (WT) mice. ProteoMiner-equalized serum samples were subjected to 2D-DiGE and MS-MALDI-TOF/TOF analyses to identify proteins that changed in their relative abundances in CD38-/- versus WT mice either with arthritis (CIA+), with no arthritis (CIA-), or with inflammation (complete Freund's adjuvant (CFA)-treated mice). Multivariate analyses revealed that a multiprotein signature (n = 28) was able to discriminate CIA+ from CIA- mice, and WT from CD38-/- mice within each condition. Likewise, a distinct multiprotein signature (n = 16) was identified which differentiated CIA+ CD38-/- mice from CIA+ WT mice, and lastly, a third multiprotein signature (n = 18) indicated that CD38-/- and WT mice could be segregated in response to CFA treatment. Further analyses showed that the discriminative power to distinguish these groups was reached at protein species level and not at the protein level. Hence, the need to identify and quantify proteins at protein species level to better correlate proteome changes with disease processes. It is crucial for plasma proteomics at the low-abundance protein species level to apply the ProteoMiner enrichment. All MS data have been deposited in the ProteomeXchange with identifiers PXD001788, PXD001799 and PXD002071 (http://proteomecentral.proteomexchange.org/dataset/PXD001788, http://proteomecentral.proteomexchange.org/dataset/PXD001799 and http://proteomecentral.proteomexchange.org/dataset/PXD002071). © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

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