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<span class="elsevierStyleItalic">have broken new ground in the research of how this cation directs cell fate&#44; especially in T cells and B&#46; This review focuses primarily on the roles of Ca</span><span class="elsevierStyleSup"><span class="elsevierStyleItalic">2&#43;</span></span><span class="elsevierStyleItalic">in the last 2 cell groups and their involvement in autoimmunity&#46;</span></p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Calcium as an Intracellular Signaling Element</span><p id="par0010" class="elsevierStylePara elsevierViewall">For normal cell function&#44; especially regarding the immune system&#44; the starting point is a basic principle consisting in the presence of the following elements&#58;<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">-</span><p id="par0015" class="elsevierStylePara elsevierViewall">An external signal&#46;</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">-</span><p id="par0020" class="elsevierStylePara elsevierViewall">A receptor&#46;</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">-</span><p id="par0025" class="elsevierStylePara elsevierViewall">An internal signal&#44; which depends on turn on the modifications undergone by the receptor in contact with the external signal and the cofactors that amplify the received signal&#46;</p></li><li class="elsevierStyleListItem" id="lsti0020"><span class="elsevierStyleLabel">-</span><p id="par0030" class="elsevierStylePara elsevierViewall">A transcription factor which moves to the nucleus&#46;</p></li><li class="elsevierStyleListItem" id="lsti0025"><span class="elsevierStyleLabel">-</span><p id="par0035" class="elsevierStylePara elsevierViewall">Transcription of ribonucleic acid &#40;RNA&#41; and translation to generate the protein&#40;s&#41; induced by the external signal&#46;</p></li></ul></p><p id="par0040" class="elsevierStylePara elsevierViewall">Molecular biology studies and recent descriptions of<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> new proteins have advanced the understanding of how these components of cell signaling work&#46; External signals are formed by different proteins or peptide derivatives &#40;cytokines&#44; chemokines&#44; pathogen associated peptides&#44; etc&#46;&#41; which are picked up by a receptor located on the cell membrane&#46; In the case of T and B lymphocytes&#44; these receptors require the participation of other elements or co-receptors&#44; which allow adequate extracellular signal synapses in order to activate the intracellular signaling cascade&#46; The internal signal &#40;or second messenger&#41; is generated by multiple mechanisms &#40;usually phosphorylation and dephosphorylation&#41; through different routes&#44; including JAK-STAT pathway MAP kinases&#44; G-protein pathways&#44; etc&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">Ca<span class="elsevierStyleSup">2&#43;</span> acts as a second messenger and its importance is becoming more known thanks to recent findings regarding SOCE and its implications on the durability of the cellular responses to Ca<span class="elsevierStyleSup">2&#43;</span> flux&#46; Ca<span class="elsevierStyleSup">2&#43;</span>-induced signals were known for several decades&#44; mainly due to their importance in RNA synthesis and cell division in leukocytes and thymocytes&#46;<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6&#44;7</span></a> Currently&#44; there are various known functions dependent on the amount of Ca<span class="elsevierStyleSup">2&#43;</span> present at the intracellular level&#46; When Ca<span class="elsevierStyleSup">2&#43;</span> levels increase during a short period they reduce lymphocyte mobility&#44; thus enhancing the immunological synapse&#46; In the case of other cell groups&#44; high levels of short lived Ca<span class="elsevierStyleSup">2&#43;</span> lead to other phenomena such as T cell-mediated cytotoxicity&#44; release of lytic granules and&#47;or cellular recognition processes as well as apoptosis&#46; In contrast&#44; when Ca<span class="elsevierStyleSup">2&#43;</span> levels rise for a prolonged period&#44; they can regulate transcriptional responses that will mark the cell fate of T and B lymphocytes &#40;e&#46;g&#46; Cytokine production&#44; cell differentiation&#44; effector functions&#44; non responsive states&#44; etc&#46;&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> These Ca<span class="elsevierStyleSup">2&#43;</span> levels in lymphocytes are regulated dynamically through various channels&#44; among which we find<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a>&#58;<ul class="elsevierStyleList" id="lis0010"><li class="elsevierStyleListItem" id="lsti0030"><span class="elsevierStyleLabel">-</span><p id="par0050" class="elsevierStylePara elsevierViewall">Intracellular channel receptors and the receptor for inositol-1&#44;4&#44;5-triphosphate &#40;IP3&#41; located in the sarcoplasmic reticulum&#46;</p></li><li class="elsevierStyleListItem" id="lsti0035"><span class="elsevierStyleLabel">-</span><p id="par0055" class="elsevierStylePara elsevierViewall">Plasma membrane channels&#44; including Ca<span class="elsevierStyleSup">2&#43;</span> release-activated Ca<span class="elsevierStyleSup">2&#43;</span> chnnels &#40;CRAC&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0040"><span class="elsevierStyleLabel">-</span><p id="par0060" class="elsevierStylePara elsevierViewall">Ca<span class="elsevierStyleSup">2&#43;</span>-dependent potassium channels activated by voltage&#46;</p></li><li class="elsevierStyleListItem" id="lsti0045"><span class="elsevierStyleLabel">-</span><p id="par0065" class="elsevierStylePara elsevierViewall">Energy dependent transporters channels&#46;</p></li><li class="elsevierStyleListItem" id="lsti0050"><span class="elsevierStyleLabel">-</span><p id="par0070" class="elsevierStylePara elsevierViewall">Nonselective cation channels&#46;</p></li><li class="elsevierStyleListItem" id="lsti0055"><span class="elsevierStyleLabel">-</span><p id="par0075" class="elsevierStylePara elsevierViewall">The sarco-endoplasmic reticulum adenosine triphosphatase pump &#40;SERCA&#41; and plasma membrane Ca<span class="elsevierStyleSup">2&#43;</span> ATPase &#40;PMCA&#41;&#46;</p></li></ul></p><p id="par0080" class="elsevierStylePara elsevierViewall">In addition to these channels&#44; the same concentration of intracellular Ca<span class="elsevierStyleSup">2&#43;</span> entry helps regulate CRAC ion channels and the IP3 pathway&#44; as well as the state of cell membrane repolarization&#46; Once you increase the intracellular levels of Ca<span class="elsevierStyleSup">2&#43;</span>&#44; this activates other signaling cascades that define the lymphocyte cell fate as reviewed below&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Calcium and Signaling in Lymphocytes</span><p id="par0085" class="elsevierStylePara elsevierViewall">Once the T or B lymphocyte is activated by its receptor and the process of costimulation occurs&#44; recruitment&#44; and activation of a group of protein tyrosine kinases&#44; bound to other adapter proteins lead to the phosphorylation and activation of phospholipase C-&#947; &#40;PLC &#947; 1 &#947; PLC in T and B lymphocytes 2&#41;&#46; This enzyme&#44; in turn&#44; hydrolyzes phosphatidylinositol-3&#44;4-bisphosphate &#40;PIP2&#41; from the cell membrane to 2 second messengers&#58;<ul class="elsevierStyleList" id="lis0015"><li class="elsevierStyleListItem" id="lsti0060"><span class="elsevierStyleLabel">-</span><p id="par0090" class="elsevierStylePara elsevierViewall">IP3&#46;</p></li><li class="elsevierStyleListItem" id="lsti0065"><span class="elsevierStyleLabel">-</span><p id="par0095" class="elsevierStylePara elsevierViewall">Diacylglycerol &#40;DAG&#41;&#46;</p></li></ul></p><p id="par0100" class="elsevierStylePara elsevierViewall">IP3 then shifts and binds to its receptor on the membrane of the endoplasmic reticulum &#40;ER&#41; causing the release of Ca<span class="elsevierStyleSup">2&#43;</span> stored inside and activation of other intracellular signals &#40;<a class="elsevierStyleCrossRefs" href="#fig0005">Figs&#46; 1 and 2</a>&#41;&#46; However&#44; the rapid depletion of the ER Ca<span class="elsevierStyleSup">2&#43;</span> leads to a short response&#46; To facilitate the extension of cellular responses&#44; another route of entry of Ca<span class="elsevierStyleSup">2&#43;</span>&#44; called SOCE&#44; is activated&#44; which was recently discovered by large-scale searches of RNA interference&#46; SOCE acts through CRAC channels and its mechanism of activation depends on the interaction of two regulatory molecules<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a>&#58;<ul class="elsevierStyleList" id="lis0020"><li class="elsevierStyleListItem" id="lsti0070"><span class="elsevierStyleLabel">-</span><p id="par0105" class="elsevierStylePara elsevierViewall">A Ca<span class="elsevierStyleSup">2&#43;</span> sensor in the ER or stromal interaction molecule &#40;STIM-1&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0075"><span class="elsevierStyleLabel">-</span><p id="par0110" class="elsevierStylePara elsevierViewall">A CRAC channel pore subunit &#40;Orai1&#41;&#46;</p></li></ul></p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0115" class="elsevierStylePara elsevierViewall">The operation of this mechanism has been described thus&#58; once the Ca<span class="elsevierStyleSup">2&#43;</span> sensing STIM detects the decrease in the concentration of Ca<span class="elsevierStyleSup">2&#43;</span> into the ER&#44; it undergoes a conformational change &#40;oligomerization and aggregation&#41; forming a &#8220;point&#8221;&#44; in juxtaposition to CRAC located as a transmembrane channel&#46; This conformation makes contact with the Orai1 pore channel subunit&#44; allowing the opening of the channel and the entrance of Ca<span class="elsevierStyleSup">2&#43;</span>&#46; This increases the intracellular levels of the ion and perpetuates the responses generated by the activation of lymphocytes and their respective receptors&#46; Other mechanisms have been described for regulating CRAC channel activity&#44; including the activity of other Ca<span class="elsevierStyleSup">2&#43;</span>-permeable channels such as the TRPC family members&#44; but this mechanism is not entirely clear&#46; Also&#44; other mechanisms have been postulated as regulators of STIM-Orai1 binding&#44; where the cytoskeleton and the negatively charged membrane phospholipids can be an influence&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Signaling Pathways Activated After Calcium Influx</span><p id="par0120" class="elsevierStylePara elsevierViewall">Once the increase in intracytoplasmic Ca<span class="elsevierStyleSup">2&#43;</span> levels is achieved&#44; they activate other signaling pathways and transcription factors that bind DNA and finally lead to the production of proteins&#44; cytokines&#44; etc&#46; related to the inflammatory cascade&#46; Within these pathways we find<a class="elsevierStyleCrossRefs" href="#bib0060"><span class="elsevierStyleSup">12&#8211;14</span></a>&#58;<ul class="elsevierStyleList" id="lis0025"><li class="elsevierStyleListItem" id="lsti0080"><span class="elsevierStyleLabel">-</span><p id="par0125" class="elsevierStylePara elsevierViewall">The calmodulin&#8211;calcineurin pathway&#44; with the final activation of the nuclear factor of activated T cells &#40;NFAT&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0085"><span class="elsevierStyleLabel">-</span><p id="par0130" class="elsevierStylePara elsevierViewall">The Ca<span class="elsevierStyleSup">2&#43;</span>-dependent kinase-calmodulin &#40;CaMK&#41; pathway&#44; which has as transcription factors a protein bound to a response element ofcyclic adenosine monophosphate &#40;CREB&#44; cyclic-adesnosime monophosphate-responsive element binding protein&#41; and myocyte enhancer factor 2&#46;</p></li><li class="elsevierStyleListItem" id="lsti0090"><span class="elsevierStyleLabel">-</span><p id="par0135" class="elsevierStylePara elsevierViewall">The nuclear factor &#954;B &#40;NF-&#954;B&#41;&#46;</p></li></ul></p><p id="par0140" class="elsevierStylePara elsevierViewall">Upon hydrolysis of PIP2&#44; DAG is also obtained&#44; which in turn can activate an additional two signaling pathways&#58;<ul class="elsevierStyleList" id="lis0030"><li class="elsevierStyleListItem" id="lsti0095"><span class="elsevierStyleLabel">-</span><p id="par0145" class="elsevierStylePara elsevierViewall">The protein kinase C pathway &#40;PKC&#41;&#44; and the Ras-mitogen-activated protein kinase&#46;</p></li><li class="elsevierStyleListItem" id="lsti0100"><span class="elsevierStyleLabel">-</span><p id="par0150" class="elsevierStylePara elsevierViewall">The protein kinase C &#40;PKC&#41; pathway&#46;</p></li></ul></p><p id="par0155" class="elsevierStylePara elsevierViewall">These pathways ultimately activate transcription factors such as AP-2 &#40;a transcriptional complex formed by c-Fos and c-Jun&#41; and NF-B&#46; &#954; The various components and pathways related to the flow of Ca<span class="elsevierStyleSup">2&#43;</span> are summarized in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Calcium and Autoimmunity</span><p id="par0160" class="elsevierStylePara elsevierViewall">Signaling through intracellular Ca<span class="elsevierStyleSup">2&#43;</span> has been implicated in the pathogenesis of autoimmune and congenital immunodeficiencies&#46; Diseases such as systemic lupus erythematosus &#40;SLE&#41;&#44; rheumatoid arthritis &#40;RA&#41;&#44; multiple sclerosis &#40;MS&#41; and type 1 diabetes mellitus are related in their pathophysiology by the presence of autoreactive T and B cells that contribute in the generation of the inflammatory process&#46; In SLE&#44; autoreactive T cells replace the X&#916;3-&#950; chain with a &#934;&#967;P&#8211;&#947; common chain&#44; leading to an intracellular signaling via the Syk &#40;spleen tyrosine kinase&#41; pathway and not ZAP-70&#44; as is usual&#46; This&#44; associated with a group of lipid rafts in the plasma membrane of the T cell&#44; increases intracellular Ca<span class="elsevierStyleSup">2&#43;</span> in response to activation of the T cell receptor &#40;TCR&#41; by an autoantigen&#46; The PKC pathway <span class="elsevierStyleSmallCaps">iv</span> calmodulin-dependent &#40;CAMK4&#41; is activated&#44; which binds to CREB and increases the production of interleukin 17 &#40;IL-17&#41; at the expense of the production of IL-2&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> This phenomenon has also been described in diseases such as RA and MS&#46; However&#44; in these conditions the proposed hypothesis is that the autoreactivity of the T cells due to mutations in the ZAP-70 kinase&#44; markedly reduces TCR dependent signaling&#44; including Ca<span class="elsevierStyleSup">2&#43;</span> signals&#44; allowing the autoreactive TCR to &#8216;escape&#8217; negative selection in the thymus but become arthritogenic in peripheral tissues&#46; This raises the issue of Ca<span class="elsevierStyleSup">2&#43;</span> signaling participating in the selection process of thymic T cells&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> B cells&#44; in the absence or lack of response to SHP1&#44; CD22 or Fc &#947; RIIB1 generate increased responses to the influx of Ca<span class="elsevierStyleSup">2&#43;</span> and&#44; therefore&#44; B lymphocyte hyperactivity and autoimmunity&#46; In SLE&#44; Fc &#947; RIIB1 defects are associated with increased response to Ca<span class="elsevierStyleSup">2&#43;</span> in B lymphocytes&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> Although diseases such as SLE are characterized by a systemic component&#44; alterations in calcium signaling have been described in T and B lymphocytes&#44; and have not been associated with susceptibility to specific manifestations of the disease &#40;e&#46;g&#46; increased risk of nephritis&#41;&#46; However&#44; derived from the murine <span class="elsevierStyleItalic">Orai</span><span class="elsevierStyleSup"><span class="elsevierStyleItalic">K1&#47;K1</span></span> model &#40;discussed below&#41;&#44; the lack of calcium signaling in immune cells protects against the development of colitis in the transfer model of inflammatory bowel disease&#46;</p><p id="par0165" class="elsevierStylePara elsevierViewall">As mentioned previously&#44; in T cells&#44; the Ca<span class="elsevierStyleSup">2&#43;</span> entry following antigenic stimulation is essential for the activation of NFAT&#46; It has been demonstrated&#44; in a group of patients with mutations in either STIM 1 u Orai1&#44; that the affected protein function or expression results in a defect of stored Ca<span class="elsevierStyleSup">2&#43;</span> influx and CRAC channel function&#44; resulting in decreased lymphocyte activation These mechanisms lead to the presentation of an inherited form of severe combined immunodeficiency&#44; demonstrating the importance of these channels in the normal function of T-lymphocytes in humans&#46; Similarly&#44; calcium signaling defect can lead to autoreactive T cells to a state of activation which can result in the development of autoimmune diseases&#46; Given the role of calcium in the activation of autoimmune phenomena&#44; Lin et al&#46; have recently published the generation of humanized monoclonal antibodies directed against high affinity human Ora1&#46; These antibodies showed decreased Ca<span class="elsevierStyleSup">2&#43;</span> entry&#44; NFAT transcription and release of cytokines and may represent a new therapeutic target in the treatment of autoimmune diseases&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a> This approach affects different tissues involving calcium signaling&#44; and different immune system effects should be better understood&#46;</p><p id="par0170" class="elsevierStylePara elsevierViewall">In an animal model developed by McCarl et al&#46; the role of Orai1 was described in autoimmunity&#46; In this study&#44; T and B lymphocytes derived from a mouse model of <span class="elsevierStyleItalic">Orai</span><span class="elsevierStyleSup"><span class="elsevierStyleItalic">K1&#47;K1</span></span> expressed a mutated nonfunctional Orai1 protein&#46; These cells showed a severe decrease in the influx of Ca<span class="elsevierStyleSup">2&#43;</span> and CRAC channel function&#44; resulting in decreased expression of several cytokines&#44; including IL-1&#44; IL-4&#44; IL-17&#44; interferon gamma and tumor necrosis factor &#40;TNF&#41; alpha in CD4 and CD8 T lymphocytes&#46; This model showed greater tolerance to skin grafts compared with animals without the mutation and failed to develop colitis type autoimmune phenomena&#46; These findings confirm the importance of these channels and the influx of Ca<span class="elsevierStyleSup">2&#43;</span> on the activation of the adaptive immune system cells&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a></p><p id="par0175" class="elsevierStylePara elsevierViewall">Ca<span class="elsevierStyleSup">2&#43;</span> is also involved in the development of congenital immunodeficiencies&#46; In common severe immunodeficiency&#44; for example&#44; there is a mutation in the T cell&#44; more specifically in the transmembrane domain of Orai1 in CRAC&#44; which allows the entry of Ca<span class="elsevierStyleSup">2&#43;</span> via SOCE&#44; giving rise to T lymphocytes with low proliferative capacity and cytokine production&#46; This defect may also affect SOCE B cells and fibroblasts in this disease&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a> In X-linked a gammaglobulinemia presents an inherited deficit in B cells&#44; which is characterized by mutations in Bruton tyrosine kinase&#44; the enzyme responsible for the activation of PLC &#947; 2 with the effect of reducing the Ca<span class="elsevierStyleSup">2&#43;</span> entry pathway mediated by SOCE due to<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> low IP3 generation&#46; Finally&#44; common variable immunodeficiency also presented alterations in the functioning of B lymphocytes&#44; especially mutations in CD19&#44; decreasing Ca<span class="elsevierStyleSup">2&#43;</span> influx into the cell&#44; compromising the response to antigens and reducing CD27 positive B cell generation&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusions</span><p id="par0180" class="elsevierStylePara elsevierViewall">Intracellular Ca<span class="elsevierStyleSup">2&#43;</span> signaling is a component of signaling cascades that are generated in different cells after exposure of its receptors to a specific stimulus&#46; In the case of T and B lymphocytes&#44; these signals give rise to multiple changes in intracellular DNA expression&#44; with the consequent production of various inflammatory markers&#46; Research in this area also has established the importance of Ca<span class="elsevierStyleSup">2&#43;</span> pathways in the development of autoimmune diseases&#44; both due to overproduction as well as inactivity&#46; As progress is made in the study of all these concepts&#44; it becomes important to consider intervention on these pathways and receptors for therapeutic purposes&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Ethical Responsibilities</span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Protection of people and animals</span><p id="par0185" class="elsevierStylePara elsevierViewall">The authors declare that experiments have not been performed on humans or animals&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Data confidentiality</span><p id="par0190" class="elsevierStylePara elsevierViewall">The authors state that no patient data appear in this article&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Right to privacy and informed consent</span><p id="par0195" class="elsevierStylePara elsevierViewall">The authors state that no patient data appear in this article&#46;</p></span></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Conflict of Interest</span><p id="par0200" class="elsevierStylePara elsevierViewall">The authors declare no conflict of interest&#46;</p></span></span>"
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          "titulo" => "Overview"
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          "titulo" => "Calcium as an Intracellular Signaling Element"
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          "titulo" => "Calcium and Signaling in Lymphocytes"
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          "titulo" => "Signaling Pathways Activated After Calcium Influx"
        ]
        8 => array:2 [
          "identificador" => "sec0025"
          "titulo" => "Calcium and Autoimmunity"
        ]
        9 => array:2 [
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          "titulo" => "Conclusions"
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          "titulo" => "Ethical Responsibilities"
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              "titulo" => "Protection of people and animals"
            ]
            1 => array:2 [
              "identificador" => "sec0045"
              "titulo" => "Data confidentiality"
            ]
            2 => array:2 [
              "identificador" => "sec0050"
              "titulo" => "Right to privacy and informed consent"
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          "titulo" => "Conflict of Interest"
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    "fechaRecibido" => "2013-03-31"
    "fechaAceptado" => "2013-05-08"
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          "identificador" => "xpalclavsec294608"
          "palabras" => array:8 [
            0 => "Calcium signals"
            1 => "T lymphocyte"
            2 => "B lymphocyte"
            3 => "Store-operated calcium entry"
            4 => "Calcium-release-activated calcium"
            5 => "Stromal interaction molecule"
            6 => "Orai1"
            7 => "Autoimmune diseases"
          ]
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          "titulo" => "Palabras clave"
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          "palabras" => array:8 [
            0 => "Calcio"
            1 => "Linfocito T"
            2 => "Linfocito B"
            3 => "Store-operated calcium entry"
            4 => "Calcium-release-activated calcium"
            5 => "Stromal interaction molecule"
            6 => "Orai1"
            7 => "Enfermedades autoinmunes"
          ]
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        "titulo" => "Abstract"
        "resumen" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Calcium &#40;Ca<span class="elsevierStyleSup">2&#43;</span>&#41; is an important cation able to function as a second messenger in different cells of the immune system&#44; particularly in B and T lymphocytes&#44; macrophages&#44; and mastocytes&#44; among others&#46; Recent discoveries related to the entry of Ca<span class="elsevierStyleSup">2&#43;</span> through the store-operated calcium entry &#40;SOCE&#41; have opened a new investigation area about the cell destiny regulated by Ca<span class="elsevierStyleSup">2&#43;</span> especially in B and T lymphocytes&#46; SOCE acts through calcium-release-activated calcium &#40;CRAC&#41; channels&#46; The function of CRAC depends upon two recently discovered regulators&#58; the Ca<span class="elsevierStyleSup">2&#43;</span> sensor in the endoplasmic reticulum or stromal interaction molecule &#40;STIM-1&#41; and one subunit of CRAC channels called Orai1&#46;</p><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">This review focuses on the role of Ca<span class="elsevierStyleSup">2&#43;</span> signals in B and T lymphocytes functions&#44; the signaling pathways leading to Ca<span class="elsevierStyleSup">2&#43;</span> influx&#44; and the relationship between Ca<span class="elsevierStyleSup">2&#43;</span> signals and autoimmune diseases&#46;</p>"
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        "resumen" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">El calcio &#40;Ca2&#43;&#41; es un cati&#243;n con capacidad multifuncional como segundo mensajero en diferentes grupos celulares del sistema inmunitario que incluyen los linfocitos T y B&#44; los macr&#243;fagos&#44; los mastocitos&#44; entre otras&#46; Los recientes descubrimientos en relaci&#243;n con la entrada de Ca2&#43; dependiente de dep&#243;sito &#40;SOCE por su sigla en ingl&#233;s&#44; <span class="elsevierStyleItalic">store operated calcium entry</span>&#41; han abierto nuevos caminos en la investigaci&#243;n de c&#243;mo este cati&#243;n dirige el destino celular&#44; en especial en los linfocitos T y B&#46; La SOCE act&#250;a a trav&#233;s de canales CRAC &#40;del ingl&#233;s <span class="elsevierStyleItalic">Ca2&#43; release-activated Ca2&#43; channels</span>&#41; y su mecanismo de activaci&#243;n depende de la interacci&#243;n de dos mol&#233;culas reguladoras&#58; un sensor del Ca2&#43; del ret&#237;culo endopl&#225;smico o mol&#233;cula de interacci&#243;n estromal &#40;STIM-1&#44; del ingl&#233;s <span class="elsevierStyleItalic">stromal interaction molecule</span>&#41; y una subunidad poro del canal CRAC &#40;Orai1&#41;&#46;</p><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Esta revisi&#243;n se centra principalmente en las funciones del Ca2&#43; en los linfocitos B y T&#44; as&#237; como las alteraciones de estas v&#237;as implicadas en el desarrollo de enfermedades autoinmunes&#46;</p>"
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      0 => array:2 [
        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Izquierdo JH&#44; Bonilla-Abad&#237;a F&#44; Ca&#241;as CA&#44; Tob&#243;n GJ&#46; Calcio&#44; canales&#44; se&#241;alizaci&#243;n intracelular y autoinmunidad&#46; Reumatol Clin&#46; 2014&#59;10&#58;43&#8211;47&#46;</p>"
      ]
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      0 => array:7 [
        "identificador" => "fig0005"
        "etiqueta" => "Figure 1"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
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        "descripcion" => array:1 [
          "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Calcium signaling in B lymphocyte&#46; Antigen recognition by the B cell receptor activates different protein kinases&#44; such as Lyn and Syk BLNK&#44; leading to the activation of PLC &#947; 2&#44; which hydrolyzes membrane bound PIP2 into small amounts of DAG and IP3&#46; IP3 binds to its receptor IP3R located in the endoplasmic reticulum membrane and allows the release of stored calcium&#46; Subsequently&#44; the decrease in calcium level into the lumen of the endoplasmic reticulum generates the translocation of STIM1&#44; which leads to the opening of the calcium channel to induce Orai1 dependent calcium entry from reservoir &#40;SOCE&#41;&#46; The CD19 receptor facilitates activation of the PI3K p110 subunit&#46; This enzyme phosphorylates PIP2 to produce PIP3&#46; The Fc receptor to low affinity IgG &#40;FcgRIIB1&#41; and CD22 are both negative regulators of calcium signaling during stimulation of B-cell receptor The negative function of these receptors is mediated by SHIP and SHP1&#46; Additionally&#44; CD22 inhibits signaling through calcium efflux mediated by PMCA4&#46; Calcium entry generates activation of transcription factors responsible for the induction of new proteins responsible for the functions of proliferation&#44; differentiation&#44; and immune response&#46;</p>"
        ]
      ]
      1 => array:7 [
        "identificador" => "fig0010"
        "etiqueta" => "Figure 2"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr2.jpeg"
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        "descripcion" => array:1 [
          "en" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Calcium signaling in the T cell&#46; Antigen recognition by the T cell receptor leads to tyrosine kinase activation inside the T cell&#44; such as LCK and ZAP70&#44; which results in phosphorylation and activation of &#947; PLC 1&#46; PIP2 latter hydrolyzed in IP3 and DAG&#46; The IP3 receptor opens the IP3R located in the endoplasmic reticulum and allows the output of calcium from the endoplasmic deposits&#46; Calcium sensors detect STIM2 STIM1 and reducing calcium deposits by the N-terminal region of the lumen of the endoplasmic reticulum&#46; STIM proteins are added in small groups in the endoplasmic reticulum membrane and produce extracellular calcium entry via the CRAC channel&#44; Orai1&#46; Intracellular calcium concentration activates the calcineurin pathway&#44; NFAT&#44; and the Ras-MAP kinase pathway&#46;</p>"
        ]
      ]
      2 => array:7 [
        "identificador" => "tbl0005"
        "etiqueta" => "Table 1"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:1 [
          "tablatextoimagen" => array:1 [
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              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Molecule&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Calcium signal&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Cell biology&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">BTK&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Increases output of Ca<span class="elsevierStyleSup">2&#43;</span> from ER&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Early B lymphocyte development&#44; immune response&#44; immune function loss&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">BLNK &#40;SLP-65&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Increases output of Ca<span class="elsevierStyleSup">2&#43;</span> from ER&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Early B lymphocyte development&#44; immune response&#44; immune function loss&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">PLC &#947; 2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Increases output of Ca<span class="elsevierStyleSup">2&#43;</span> from ER&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Early B lymphocyte development&#44; immune response&#44; autoimmunity by gain of function&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">PLC &#947; 1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Increases output of Ca<span class="elsevierStyleSup">2&#43;</span> from ER&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">T lymphocyte development&#44; immune response&#44; immunodeficiency due to loss of function&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CD19&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Increases output of Ca<span class="elsevierStyleSup">2&#43;</span> from ER&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">B lymphocyte development&#44; immunodeficiency due to loss of function&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">SHP1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Inhibits Ca<span class="elsevierStyleSup">2&#43;</span> increase&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Autoimmunity by loss of function&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">SHIP&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Inhibits Ca<span class="elsevierStyleSup">2&#43;</span> increase&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">B lymphocyte development&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CD22&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Inhibits Ca<span class="elsevierStyleSup">2&#43;</span> increase&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Autoimmunity by loss of function&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#947; Fc RIIB&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Inhibits Ca<span class="elsevierStyleSup">2&#43;</span> increase&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Autoimmunity by loss of function&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">ITPKb&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Inhibits SOCE&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">T lymphocyte development&#44; immune response&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Grb2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Inhibits &#40;IgM B lymphocytes&#41; or increases &#40;IgG B lymphocytes&#41; Ca<span class="elsevierStyleSup">2&#43;</span> output&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">B lymphocyte development&#44; immune response&#44; production of autoantibodies by loss of function&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">STIM-1&#47;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Increases SOCE&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Suppression of autoimmune inflammation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Zap70&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Increases output of Ca<span class="elsevierStyleSup">2&#43;</span> from ER&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">T cell activation&#44; gene expression&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">LCK&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Increases output of Ca<span class="elsevierStyleSup">2&#43;</span> from ER&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">T cell activation&#44; gene expression&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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        "descripcion" => array:1 [
          "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Calcium and Cell Function in B and T Lymphocytes&#46;</p>"
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      ]
    ]
    "bibliografia" => array:2 [
      "titulo" => "References"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "bibs0005"
          "bibliografiaReferencia" => array:22 [
            0 => array:3 [
              "identificador" => "bib0005"
              "etiqueta" => "1"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Calcium signaling in lymphocytes"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "M&#46; Oh-hora"
                            1 => "A&#46; Rao"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
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                      "Revista" => array:6 [
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                        "fecha" => "2008"
                        "volumen" => "20"
                        "paginaInicial" => "250"
                        "paginaFinal" => "258"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18515054"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            1 => array:3 [
              "identificador" => "bib0010"
              "etiqueta" => "2"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
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                      "titulo" => "A model for receptor-regulated calcium entry"
                      "autores" => array:1 [
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                          "etal" => false
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                            0 => "J&#46;W&#46; Putney Jr&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Cell Calcium"
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                        "volumen" => "7"
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                        "paginaFinal" => "12"
                        "link" => array:1 [
                          0 => array:2 [
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                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            2 => array:3 [
              "identificador" => "bib0015"
              "etiqueta" => "3"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Store-operated calcium channels"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "A&#46;B&#46; Parekh"
                            1 => "J&#46;W&#46; Putney Jr&#46;"
                          ]
                        ]
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                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1152/physrev.00057.2003"
                      "Revista" => array:6 [
                        "tituloSerie" => "Physiol Rev"
                        "fecha" => "2005"
                        "volumen" => "85"
                        "paginaInicial" => "757"
                        "paginaFinal" => "810"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15788710"
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                          ]
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            ]
            3 => array:3 [
              "identificador" => "bib0020"
              "etiqueta" => "4"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "An integrated encyclopedia of DNA elements in the human genome"
                      "autores" => array:1 [
                        0 => array:2 [
                          "colaboracion" => "ENCODE&#44; Project consortium"
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                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
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Review Article
Calcium, Channels, Intracellular Signaling and Autoimmunity
Calcio, canales, señalización intracelular y autoinmunidad
Jorge-Hernán Izquierdo, Fabio Bonilla-Abadía, Carlos A. Cañas, Gabriel J. Tobón
Corresponding author
gtobon1@yahoo.com

Corresponding author.
Departamento de Medicina Interna, Unidad de Reumatología, Fundación Valle del Lili, Facultad de Medicina Universidad ICESI, Cali, Colombia
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Overview</span><p id="par0005" class="elsevierStylePara elsevierViewall">Calcium &#40;Ca<span class="elsevierStyleSup">2&#43;</span>&#41; is a multifunctional cation capable of acting as a second messenger in various immune cell groups including T and B lymphocytes&#44; macrophages&#44; mast cells&#44; etc&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#8211;3</span></a> Its distribution in intra-and extracellular spaces makes specialized pumps and channels necessary for its functioning and mobilization&#44; as well as the influence of the cell depolarization or repolarization&#46; Furthermore&#44; the amount and duration of the flow of Ca<span class="elsevierStyleSup">2&#43;</span> will determine the type and duration of its effect on intracellular signaling&#46; Recent discoveries in connection with the reservoir dependent Ca<span class="elsevierStyleSup">2&#43;</span> entry &#40;SOCE by its acronym&#41; <span class="elsevierStyleItalic">have broken new ground in the research of how this cation directs cell fate&#44; especially in T cells and B&#46; This review focuses primarily on the roles of Ca</span><span class="elsevierStyleSup"><span class="elsevierStyleItalic">2&#43;</span></span><span class="elsevierStyleItalic">in the last 2 cell groups and their involvement in autoimmunity&#46;</span></p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Calcium as an Intracellular Signaling Element</span><p id="par0010" class="elsevierStylePara elsevierViewall">For normal cell function&#44; especially regarding the immune system&#44; the starting point is a basic principle consisting in the presence of the following elements&#58;<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">-</span><p id="par0015" class="elsevierStylePara elsevierViewall">An external signal&#46;</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">-</span><p id="par0020" class="elsevierStylePara elsevierViewall">A receptor&#46;</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">-</span><p id="par0025" class="elsevierStylePara elsevierViewall">An internal signal&#44; which depends on turn on the modifications undergone by the receptor in contact with the external signal and the cofactors that amplify the received signal&#46;</p></li><li class="elsevierStyleListItem" id="lsti0020"><span class="elsevierStyleLabel">-</span><p id="par0030" class="elsevierStylePara elsevierViewall">A transcription factor which moves to the nucleus&#46;</p></li><li class="elsevierStyleListItem" id="lsti0025"><span class="elsevierStyleLabel">-</span><p id="par0035" class="elsevierStylePara elsevierViewall">Transcription of ribonucleic acid &#40;RNA&#41; and translation to generate the protein&#40;s&#41; induced by the external signal&#46;</p></li></ul></p><p id="par0040" class="elsevierStylePara elsevierViewall">Molecular biology studies and recent descriptions of<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> new proteins have advanced the understanding of how these components of cell signaling work&#46; External signals are formed by different proteins or peptide derivatives &#40;cytokines&#44; chemokines&#44; pathogen associated peptides&#44; etc&#46;&#41; which are picked up by a receptor located on the cell membrane&#46; In the case of T and B lymphocytes&#44; these receptors require the participation of other elements or co-receptors&#44; which allow adequate extracellular signal synapses in order to activate the intracellular signaling cascade&#46; The internal signal &#40;or second messenger&#41; is generated by multiple mechanisms &#40;usually phosphorylation and dephosphorylation&#41; through different routes&#44; including JAK-STAT pathway MAP kinases&#44; G-protein pathways&#44; etc&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">Ca<span class="elsevierStyleSup">2&#43;</span> acts as a second messenger and its importance is becoming more known thanks to recent findings regarding SOCE and its implications on the durability of the cellular responses to Ca<span class="elsevierStyleSup">2&#43;</span> flux&#46; Ca<span class="elsevierStyleSup">2&#43;</span>-induced signals were known for several decades&#44; mainly due to their importance in RNA synthesis and cell division in leukocytes and thymocytes&#46;<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6&#44;7</span></a> Currently&#44; there are various known functions dependent on the amount of Ca<span class="elsevierStyleSup">2&#43;</span> present at the intracellular level&#46; When Ca<span class="elsevierStyleSup">2&#43;</span> levels increase during a short period they reduce lymphocyte mobility&#44; thus enhancing the immunological synapse&#46; In the case of other cell groups&#44; high levels of short lived Ca<span class="elsevierStyleSup">2&#43;</span> lead to other phenomena such as T cell-mediated cytotoxicity&#44; release of lytic granules and&#47;or cellular recognition processes as well as apoptosis&#46; In contrast&#44; when Ca<span class="elsevierStyleSup">2&#43;</span> levels rise for a prolonged period&#44; they can regulate transcriptional responses that will mark the cell fate of T and B lymphocytes &#40;e&#46;g&#46; Cytokine production&#44; cell differentiation&#44; effector functions&#44; non responsive states&#44; etc&#46;&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> These Ca<span class="elsevierStyleSup">2&#43;</span> levels in lymphocytes are regulated dynamically through various channels&#44; among which we find<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a>&#58;<ul class="elsevierStyleList" id="lis0010"><li class="elsevierStyleListItem" id="lsti0030"><span class="elsevierStyleLabel">-</span><p id="par0050" class="elsevierStylePara elsevierViewall">Intracellular channel receptors and the receptor for inositol-1&#44;4&#44;5-triphosphate &#40;IP3&#41; located in the sarcoplasmic reticulum&#46;</p></li><li class="elsevierStyleListItem" id="lsti0035"><span class="elsevierStyleLabel">-</span><p id="par0055" class="elsevierStylePara elsevierViewall">Plasma membrane channels&#44; including Ca<span class="elsevierStyleSup">2&#43;</span> release-activated Ca<span class="elsevierStyleSup">2&#43;</span> chnnels &#40;CRAC&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0040"><span class="elsevierStyleLabel">-</span><p id="par0060" class="elsevierStylePara elsevierViewall">Ca<span class="elsevierStyleSup">2&#43;</span>-dependent potassium channels activated by voltage&#46;</p></li><li class="elsevierStyleListItem" id="lsti0045"><span class="elsevierStyleLabel">-</span><p id="par0065" class="elsevierStylePara elsevierViewall">Energy dependent transporters channels&#46;</p></li><li class="elsevierStyleListItem" id="lsti0050"><span class="elsevierStyleLabel">-</span><p id="par0070" class="elsevierStylePara elsevierViewall">Nonselective cation channels&#46;</p></li><li class="elsevierStyleListItem" id="lsti0055"><span class="elsevierStyleLabel">-</span><p id="par0075" class="elsevierStylePara elsevierViewall">The sarco-endoplasmic reticulum adenosine triphosphatase pump &#40;SERCA&#41; and plasma membrane Ca<span class="elsevierStyleSup">2&#43;</span> ATPase &#40;PMCA&#41;&#46;</p></li></ul></p><p id="par0080" class="elsevierStylePara elsevierViewall">In addition to these channels&#44; the same concentration of intracellular Ca<span class="elsevierStyleSup">2&#43;</span> entry helps regulate CRAC ion channels and the IP3 pathway&#44; as well as the state of cell membrane repolarization&#46; Once you increase the intracellular levels of Ca<span class="elsevierStyleSup">2&#43;</span>&#44; this activates other signaling cascades that define the lymphocyte cell fate as reviewed below&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Calcium and Signaling in Lymphocytes</span><p id="par0085" class="elsevierStylePara elsevierViewall">Once the T or B lymphocyte is activated by its receptor and the process of costimulation occurs&#44; recruitment&#44; and activation of a group of protein tyrosine kinases&#44; bound to other adapter proteins lead to the phosphorylation and activation of phospholipase C-&#947; &#40;PLC &#947; 1 &#947; PLC in T and B lymphocytes 2&#41;&#46; This enzyme&#44; in turn&#44; hydrolyzes phosphatidylinositol-3&#44;4-bisphosphate &#40;PIP2&#41; from the cell membrane to 2 second messengers&#58;<ul class="elsevierStyleList" id="lis0015"><li class="elsevierStyleListItem" id="lsti0060"><span class="elsevierStyleLabel">-</span><p id="par0090" class="elsevierStylePara elsevierViewall">IP3&#46;</p></li><li class="elsevierStyleListItem" id="lsti0065"><span class="elsevierStyleLabel">-</span><p id="par0095" class="elsevierStylePara elsevierViewall">Diacylglycerol &#40;DAG&#41;&#46;</p></li></ul></p><p id="par0100" class="elsevierStylePara elsevierViewall">IP3 then shifts and binds to its receptor on the membrane of the endoplasmic reticulum &#40;ER&#41; causing the release of Ca<span class="elsevierStyleSup">2&#43;</span> stored inside and activation of other intracellular signals &#40;<a class="elsevierStyleCrossRefs" href="#fig0005">Figs&#46; 1 and 2</a>&#41;&#46; However&#44; the rapid depletion of the ER Ca<span class="elsevierStyleSup">2&#43;</span> leads to a short response&#46; To facilitate the extension of cellular responses&#44; another route of entry of Ca<span class="elsevierStyleSup">2&#43;</span>&#44; called SOCE&#44; is activated&#44; which was recently discovered by large-scale searches of RNA interference&#46; SOCE acts through CRAC channels and its mechanism of activation depends on the interaction of two regulatory molecules<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a>&#58;<ul class="elsevierStyleList" id="lis0020"><li class="elsevierStyleListItem" id="lsti0070"><span class="elsevierStyleLabel">-</span><p id="par0105" class="elsevierStylePara elsevierViewall">A Ca<span class="elsevierStyleSup">2&#43;</span> sensor in the ER or stromal interaction molecule &#40;STIM-1&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0075"><span class="elsevierStyleLabel">-</span><p id="par0110" class="elsevierStylePara elsevierViewall">A CRAC channel pore subunit &#40;Orai1&#41;&#46;</p></li></ul></p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0115" class="elsevierStylePara elsevierViewall">The operation of this mechanism has been described thus&#58; once the Ca<span class="elsevierStyleSup">2&#43;</span> sensing STIM detects the decrease in the concentration of Ca<span class="elsevierStyleSup">2&#43;</span> into the ER&#44; it undergoes a conformational change &#40;oligomerization and aggregation&#41; forming a &#8220;point&#8221;&#44; in juxtaposition to CRAC located as a transmembrane channel&#46; This conformation makes contact with the Orai1 pore channel subunit&#44; allowing the opening of the channel and the entrance of Ca<span class="elsevierStyleSup">2&#43;</span>&#46; This increases the intracellular levels of the ion and perpetuates the responses generated by the activation of lymphocytes and their respective receptors&#46; Other mechanisms have been described for regulating CRAC channel activity&#44; including the activity of other Ca<span class="elsevierStyleSup">2&#43;</span>-permeable channels such as the TRPC family members&#44; but this mechanism is not entirely clear&#46; Also&#44; other mechanisms have been postulated as regulators of STIM-Orai1 binding&#44; where the cytoskeleton and the negatively charged membrane phospholipids can be an influence&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Signaling Pathways Activated After Calcium Influx</span><p id="par0120" class="elsevierStylePara elsevierViewall">Once the increase in intracytoplasmic Ca<span class="elsevierStyleSup">2&#43;</span> levels is achieved&#44; they activate other signaling pathways and transcription factors that bind DNA and finally lead to the production of proteins&#44; cytokines&#44; etc&#46; related to the inflammatory cascade&#46; Within these pathways we find<a class="elsevierStyleCrossRefs" href="#bib0060"><span class="elsevierStyleSup">12&#8211;14</span></a>&#58;<ul class="elsevierStyleList" id="lis0025"><li class="elsevierStyleListItem" id="lsti0080"><span class="elsevierStyleLabel">-</span><p id="par0125" class="elsevierStylePara elsevierViewall">The calmodulin&#8211;calcineurin pathway&#44; with the final activation of the nuclear factor of activated T cells &#40;NFAT&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0085"><span class="elsevierStyleLabel">-</span><p id="par0130" class="elsevierStylePara elsevierViewall">The Ca<span class="elsevierStyleSup">2&#43;</span>-dependent kinase-calmodulin &#40;CaMK&#41; pathway&#44; which has as transcription factors a protein bound to a response element ofcyclic adenosine monophosphate &#40;CREB&#44; cyclic-adesnosime monophosphate-responsive element binding protein&#41; and myocyte enhancer factor 2&#46;</p></li><li class="elsevierStyleListItem" id="lsti0090"><span class="elsevierStyleLabel">-</span><p id="par0135" class="elsevierStylePara elsevierViewall">The nuclear factor &#954;B &#40;NF-&#954;B&#41;&#46;</p></li></ul></p><p id="par0140" class="elsevierStylePara elsevierViewall">Upon hydrolysis of PIP2&#44; DAG is also obtained&#44; which in turn can activate an additional two signaling pathways&#58;<ul class="elsevierStyleList" id="lis0030"><li class="elsevierStyleListItem" id="lsti0095"><span class="elsevierStyleLabel">-</span><p id="par0145" class="elsevierStylePara elsevierViewall">The protein kinase C pathway &#40;PKC&#41;&#44; and the Ras-mitogen-activated protein kinase&#46;</p></li><li class="elsevierStyleListItem" id="lsti0100"><span class="elsevierStyleLabel">-</span><p id="par0150" class="elsevierStylePara elsevierViewall">The protein kinase C &#40;PKC&#41; pathway&#46;</p></li></ul></p><p id="par0155" class="elsevierStylePara elsevierViewall">These pathways ultimately activate transcription factors such as AP-2 &#40;a transcriptional complex formed by c-Fos and c-Jun&#41; and NF-B&#46; &#954; The various components and pathways related to the flow of Ca<span class="elsevierStyleSup">2&#43;</span> are summarized in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Calcium and Autoimmunity</span><p id="par0160" class="elsevierStylePara elsevierViewall">Signaling through intracellular Ca<span class="elsevierStyleSup">2&#43;</span> has been implicated in the pathogenesis of autoimmune and congenital immunodeficiencies&#46; Diseases such as systemic lupus erythematosus &#40;SLE&#41;&#44; rheumatoid arthritis &#40;RA&#41;&#44; multiple sclerosis &#40;MS&#41; and type 1 diabetes mellitus are related in their pathophysiology by the presence of autoreactive T and B cells that contribute in the generation of the inflammatory process&#46; In SLE&#44; autoreactive T cells replace the X&#916;3-&#950; chain with a &#934;&#967;P&#8211;&#947; common chain&#44; leading to an intracellular signaling via the Syk &#40;spleen tyrosine kinase&#41; pathway and not ZAP-70&#44; as is usual&#46; This&#44; associated with a group of lipid rafts in the plasma membrane of the T cell&#44; increases intracellular Ca<span class="elsevierStyleSup">2&#43;</span> in response to activation of the T cell receptor &#40;TCR&#41; by an autoantigen&#46; The PKC pathway <span class="elsevierStyleSmallCaps">iv</span> calmodulin-dependent &#40;CAMK4&#41; is activated&#44; which binds to CREB and increases the production of interleukin 17 &#40;IL-17&#41; at the expense of the production of IL-2&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> This phenomenon has also been described in diseases such as RA and MS&#46; However&#44; in these conditions the proposed hypothesis is that the autoreactivity of the T cells due to mutations in the ZAP-70 kinase&#44; markedly reduces TCR dependent signaling&#44; including Ca<span class="elsevierStyleSup">2&#43;</span> signals&#44; allowing the autoreactive TCR to &#8216;escape&#8217; negative selection in the thymus but become arthritogenic in peripheral tissues&#46; This raises the issue of Ca<span class="elsevierStyleSup">2&#43;</span> signaling participating in the selection process of thymic T cells&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> B cells&#44; in the absence or lack of response to SHP1&#44; CD22 or Fc &#947; RIIB1 generate increased responses to the influx of Ca<span class="elsevierStyleSup">2&#43;</span> and&#44; therefore&#44; B lymphocyte hyperactivity and autoimmunity&#46; In SLE&#44; Fc &#947; RIIB1 defects are associated with increased response to Ca<span class="elsevierStyleSup">2&#43;</span> in B lymphocytes&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> Although diseases such as SLE are characterized by a systemic component&#44; alterations in calcium signaling have been described in T and B lymphocytes&#44; and have not been associated with susceptibility to specific manifestations of the disease &#40;e&#46;g&#46; increased risk of nephritis&#41;&#46; However&#44; derived from the murine <span class="elsevierStyleItalic">Orai</span><span class="elsevierStyleSup"><span class="elsevierStyleItalic">K1&#47;K1</span></span> model &#40;discussed below&#41;&#44; the lack of calcium signaling in immune cells protects against the development of colitis in the transfer model of inflammatory bowel disease&#46;</p><p id="par0165" class="elsevierStylePara elsevierViewall">As mentioned previously&#44; in T cells&#44; the Ca<span class="elsevierStyleSup">2&#43;</span> entry following antigenic stimulation is essential for the activation of NFAT&#46; It has been demonstrated&#44; in a group of patients with mutations in either STIM 1 u Orai1&#44; that the affected protein function or expression results in a defect of stored Ca<span class="elsevierStyleSup">2&#43;</span> influx and CRAC channel function&#44; resulting in decreased lymphocyte activation These mechanisms lead to the presentation of an inherited form of severe combined immunodeficiency&#44; demonstrating the importance of these channels in the normal function of T-lymphocytes in humans&#46; Similarly&#44; calcium signaling defect can lead to autoreactive T cells to a state of activation which can result in the development of autoimmune diseases&#46; Given the role of calcium in the activation of autoimmune phenomena&#44; Lin et al&#46; have recently published the generation of humanized monoclonal antibodies directed against high affinity human Ora1&#46; These antibodies showed decreased Ca<span class="elsevierStyleSup">2&#43;</span> entry&#44; NFAT transcription and release of cytokines and may represent a new therapeutic target in the treatment of autoimmune diseases&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a> This approach affects different tissues involving calcium signaling&#44; and different immune system effects should be better understood&#46;</p><p id="par0170" class="elsevierStylePara elsevierViewall">In an animal model developed by McCarl et al&#46; the role of Orai1 was described in autoimmunity&#46; In this study&#44; T and B lymphocytes derived from a mouse model of <span class="elsevierStyleItalic">Orai</span><span class="elsevierStyleSup"><span class="elsevierStyleItalic">K1&#47;K1</span></span> expressed a mutated nonfunctional Orai1 protein&#46; These cells showed a severe decrease in the influx of Ca<span class="elsevierStyleSup">2&#43;</span> and CRAC channel function&#44; resulting in decreased expression of several cytokines&#44; including IL-1&#44; IL-4&#44; IL-17&#44; interferon gamma and tumor necrosis factor &#40;TNF&#41; alpha in CD4 and CD8 T lymphocytes&#46; This model showed greater tolerance to skin grafts compared with animals without the mutation and failed to develop colitis type autoimmune phenomena&#46; These findings confirm the importance of these channels and the influx of Ca<span class="elsevierStyleSup">2&#43;</span> on the activation of the adaptive immune system cells&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a></p><p id="par0175" class="elsevierStylePara elsevierViewall">Ca<span class="elsevierStyleSup">2&#43;</span> is also involved in the development of congenital immunodeficiencies&#46; In common severe immunodeficiency&#44; for example&#44; there is a mutation in the T cell&#44; more specifically in the transmembrane domain of Orai1 in CRAC&#44; which allows the entry of Ca<span class="elsevierStyleSup">2&#43;</span> via SOCE&#44; giving rise to T lymphocytes with low proliferative capacity and cytokine production&#46; This defect may also affect SOCE B cells and fibroblasts in this disease&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a> In X-linked a gammaglobulinemia presents an inherited deficit in B cells&#44; which is characterized by mutations in Bruton tyrosine kinase&#44; the enzyme responsible for the activation of PLC &#947; 2 with the effect of reducing the Ca<span class="elsevierStyleSup">2&#43;</span> entry pathway mediated by SOCE due to<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> low IP3 generation&#46; Finally&#44; common variable immunodeficiency also presented alterations in the functioning of B lymphocytes&#44; especially mutations in CD19&#44; decreasing Ca<span class="elsevierStyleSup">2&#43;</span> influx into the cell&#44; compromising the response to antigens and reducing CD27 positive B cell generation&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusions</span><p id="par0180" class="elsevierStylePara elsevierViewall">Intracellular Ca<span class="elsevierStyleSup">2&#43;</span> signaling is a component of signaling cascades that are generated in different cells after exposure of its receptors to a specific stimulus&#46; In the case of T and B lymphocytes&#44; these signals give rise to multiple changes in intracellular DNA expression&#44; with the consequent production of various inflammatory markers&#46; Research in this area also has established the importance of Ca<span class="elsevierStyleSup">2&#43;</span> pathways in the development of autoimmune diseases&#44; both due to overproduction as well as inactivity&#46; As progress is made in the study of all these concepts&#44; it becomes important to consider intervention on these pathways and receptors for therapeutic purposes&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Ethical Responsibilities</span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Protection of people and animals</span><p id="par0185" class="elsevierStylePara elsevierViewall">The authors declare that experiments have not been performed on humans or animals&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Data confidentiality</span><p id="par0190" class="elsevierStylePara elsevierViewall">The authors state that no patient data appear in this article&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Right to privacy and informed consent</span><p id="par0195" class="elsevierStylePara elsevierViewall">The authors state that no patient data appear in this article&#46;</p></span></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Conflict of Interest</span><p id="par0200" class="elsevierStylePara elsevierViewall">The authors declare no conflict of interest&#46;</p></span></span>"
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          "titulo" => "Overview"
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          "titulo" => "Calcium as an Intracellular Signaling Element"
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          "titulo" => "Calcium and Signaling in Lymphocytes"
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          "titulo" => "Signaling Pathways Activated After Calcium Influx"
        ]
        8 => array:2 [
          "identificador" => "sec0025"
          "titulo" => "Calcium and Autoimmunity"
        ]
        9 => array:2 [
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          "titulo" => "Conclusions"
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          "titulo" => "Ethical Responsibilities"
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              "titulo" => "Protection of people and animals"
            ]
            1 => array:2 [
              "identificador" => "sec0045"
              "titulo" => "Data confidentiality"
            ]
            2 => array:2 [
              "identificador" => "sec0050"
              "titulo" => "Right to privacy and informed consent"
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          "titulo" => "Conflict of Interest"
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    "fechaRecibido" => "2013-03-31"
    "fechaAceptado" => "2013-05-08"
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          "identificador" => "xpalclavsec294608"
          "palabras" => array:8 [
            0 => "Calcium signals"
            1 => "T lymphocyte"
            2 => "B lymphocyte"
            3 => "Store-operated calcium entry"
            4 => "Calcium-release-activated calcium"
            5 => "Stromal interaction molecule"
            6 => "Orai1"
            7 => "Autoimmune diseases"
          ]
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          "titulo" => "Palabras clave"
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          "palabras" => array:8 [
            0 => "Calcio"
            1 => "Linfocito T"
            2 => "Linfocito B"
            3 => "Store-operated calcium entry"
            4 => "Calcium-release-activated calcium"
            5 => "Stromal interaction molecule"
            6 => "Orai1"
            7 => "Enfermedades autoinmunes"
          ]
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        "titulo" => "Abstract"
        "resumen" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Calcium &#40;Ca<span class="elsevierStyleSup">2&#43;</span>&#41; is an important cation able to function as a second messenger in different cells of the immune system&#44; particularly in B and T lymphocytes&#44; macrophages&#44; and mastocytes&#44; among others&#46; Recent discoveries related to the entry of Ca<span class="elsevierStyleSup">2&#43;</span> through the store-operated calcium entry &#40;SOCE&#41; have opened a new investigation area about the cell destiny regulated by Ca<span class="elsevierStyleSup">2&#43;</span> especially in B and T lymphocytes&#46; SOCE acts through calcium-release-activated calcium &#40;CRAC&#41; channels&#46; The function of CRAC depends upon two recently discovered regulators&#58; the Ca<span class="elsevierStyleSup">2&#43;</span> sensor in the endoplasmic reticulum or stromal interaction molecule &#40;STIM-1&#41; and one subunit of CRAC channels called Orai1&#46;</p><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">This review focuses on the role of Ca<span class="elsevierStyleSup">2&#43;</span> signals in B and T lymphocytes functions&#44; the signaling pathways leading to Ca<span class="elsevierStyleSup">2&#43;</span> influx&#44; and the relationship between Ca<span class="elsevierStyleSup">2&#43;</span> signals and autoimmune diseases&#46;</p>"
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        "resumen" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">El calcio &#40;Ca2&#43;&#41; es un cati&#243;n con capacidad multifuncional como segundo mensajero en diferentes grupos celulares del sistema inmunitario que incluyen los linfocitos T y B&#44; los macr&#243;fagos&#44; los mastocitos&#44; entre otras&#46; Los recientes descubrimientos en relaci&#243;n con la entrada de Ca2&#43; dependiente de dep&#243;sito &#40;SOCE por su sigla en ingl&#233;s&#44; <span class="elsevierStyleItalic">store operated calcium entry</span>&#41; han abierto nuevos caminos en la investigaci&#243;n de c&#243;mo este cati&#243;n dirige el destino celular&#44; en especial en los linfocitos T y B&#46; La SOCE act&#250;a a trav&#233;s de canales CRAC &#40;del ingl&#233;s <span class="elsevierStyleItalic">Ca2&#43; release-activated Ca2&#43; channels</span>&#41; y su mecanismo de activaci&#243;n depende de la interacci&#243;n de dos mol&#233;culas reguladoras&#58; un sensor del Ca2&#43; del ret&#237;culo endopl&#225;smico o mol&#233;cula de interacci&#243;n estromal &#40;STIM-1&#44; del ingl&#233;s <span class="elsevierStyleItalic">stromal interaction molecule</span>&#41; y una subunidad poro del canal CRAC &#40;Orai1&#41;&#46;</p><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Esta revisi&#243;n se centra principalmente en las funciones del Ca2&#43; en los linfocitos B y T&#44; as&#237; como las alteraciones de estas v&#237;as implicadas en el desarrollo de enfermedades autoinmunes&#46;</p>"
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      0 => array:2 [
        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Izquierdo JH&#44; Bonilla-Abad&#237;a F&#44; Ca&#241;as CA&#44; Tob&#243;n GJ&#46; Calcio&#44; canales&#44; se&#241;alizaci&#243;n intracelular y autoinmunidad&#46; Reumatol Clin&#46; 2014&#59;10&#58;43&#8211;47&#46;</p>"
      ]
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      0 => array:7 [
        "identificador" => "fig0005"
        "etiqueta" => "Figure 1"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
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        "descripcion" => array:1 [
          "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Calcium signaling in B lymphocyte&#46; Antigen recognition by the B cell receptor activates different protein kinases&#44; such as Lyn and Syk BLNK&#44; leading to the activation of PLC &#947; 2&#44; which hydrolyzes membrane bound PIP2 into small amounts of DAG and IP3&#46; IP3 binds to its receptor IP3R located in the endoplasmic reticulum membrane and allows the release of stored calcium&#46; Subsequently&#44; the decrease in calcium level into the lumen of the endoplasmic reticulum generates the translocation of STIM1&#44; which leads to the opening of the calcium channel to induce Orai1 dependent calcium entry from reservoir &#40;SOCE&#41;&#46; The CD19 receptor facilitates activation of the PI3K p110 subunit&#46; This enzyme phosphorylates PIP2 to produce PIP3&#46; The Fc receptor to low affinity IgG &#40;FcgRIIB1&#41; and CD22 are both negative regulators of calcium signaling during stimulation of B-cell receptor The negative function of these receptors is mediated by SHIP and SHP1&#46; Additionally&#44; CD22 inhibits signaling through calcium efflux mediated by PMCA4&#46; Calcium entry generates activation of transcription factors responsible for the induction of new proteins responsible for the functions of proliferation&#44; differentiation&#44; and immune response&#46;</p>"
        ]
      ]
      1 => array:7 [
        "identificador" => "fig0010"
        "etiqueta" => "Figure 2"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr2.jpeg"
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        "descripcion" => array:1 [
          "en" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Calcium signaling in the T cell&#46; Antigen recognition by the T cell receptor leads to tyrosine kinase activation inside the T cell&#44; such as LCK and ZAP70&#44; which results in phosphorylation and activation of &#947; PLC 1&#46; PIP2 latter hydrolyzed in IP3 and DAG&#46; The IP3 receptor opens the IP3R located in the endoplasmic reticulum and allows the output of calcium from the endoplasmic deposits&#46; Calcium sensors detect STIM2 STIM1 and reducing calcium deposits by the N-terminal region of the lumen of the endoplasmic reticulum&#46; STIM proteins are added in small groups in the endoplasmic reticulum membrane and produce extracellular calcium entry via the CRAC channel&#44; Orai1&#46; Intracellular calcium concentration activates the calcineurin pathway&#44; NFAT&#44; and the Ras-MAP kinase pathway&#46;</p>"
        ]
      ]
      2 => array:7 [
        "identificador" => "tbl0005"
        "etiqueta" => "Table 1"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:1 [
          "tablatextoimagen" => array:1 [
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              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Molecule&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Calcium signal&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Cell biology&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">BTK&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Increases output of Ca<span class="elsevierStyleSup">2&#43;</span> from ER&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Early B lymphocyte development&#44; immune response&#44; immune function loss&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">BLNK &#40;SLP-65&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Increases output of Ca<span class="elsevierStyleSup">2&#43;</span> from ER&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Early B lymphocyte development&#44; immune response&#44; immune function loss&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">PLC &#947; 2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Increases output of Ca<span class="elsevierStyleSup">2&#43;</span> from ER&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Early B lymphocyte development&#44; immune response&#44; autoimmunity by gain of function&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">PLC &#947; 1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Increases output of Ca<span class="elsevierStyleSup">2&#43;</span> from ER&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">T lymphocyte development&#44; immune response&#44; immunodeficiency due to loss of function&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CD19&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Increases output of Ca<span class="elsevierStyleSup">2&#43;</span> from ER&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">B lymphocyte development&#44; immunodeficiency due to loss of function&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">SHP1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Inhibits Ca<span class="elsevierStyleSup">2&#43;</span> increase&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Autoimmunity by loss of function&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">SHIP&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Inhibits Ca<span class="elsevierStyleSup">2&#43;</span> increase&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">B lymphocyte development&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CD22&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Inhibits Ca<span class="elsevierStyleSup">2&#43;</span> increase&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Autoimmunity by loss of function&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#947; Fc RIIB&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Inhibits Ca<span class="elsevierStyleSup">2&#43;</span> increase&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Autoimmunity by loss of function&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">ITPKb&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Inhibits SOCE&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">T lymphocyte development&#44; immune response&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Grb2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Inhibits &#40;IgM B lymphocytes&#41; or increases &#40;IgG B lymphocytes&#41; Ca<span class="elsevierStyleSup">2&#43;</span> output&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">B lymphocyte development&#44; immune response&#44; production of autoantibodies by loss of function&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">STIM-1&#47;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Increases SOCE&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Suppression of autoimmune inflammation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Zap70&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Increases output of Ca<span class="elsevierStyleSup">2&#43;</span> from ER&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">T cell activation&#44; gene expression&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">LCK&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Increases output of Ca<span class="elsevierStyleSup">2&#43;</span> from ER&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">T cell activation&#44; gene expression&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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        "descripcion" => array:1 [
          "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Calcium and Cell Function in B and T Lymphocytes&#46;</p>"
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      ]
    ]
    "bibliografia" => array:2 [
      "titulo" => "References"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "bibs0005"
          "bibliografiaReferencia" => array:22 [
            0 => array:3 [
              "identificador" => "bib0005"
              "etiqueta" => "1"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Calcium signaling in lymphocytes"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "M&#46; Oh-hora"
                            1 => "A&#46; Rao"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
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                      "Revista" => array:6 [
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                        "fecha" => "2008"
                        "volumen" => "20"
                        "paginaInicial" => "250"
                        "paginaFinal" => "258"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18515054"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            1 => array:3 [
              "identificador" => "bib0010"
              "etiqueta" => "2"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
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                      "titulo" => "A model for receptor-regulated calcium entry"
                      "autores" => array:1 [
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                          "etal" => false
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                            0 => "J&#46;W&#46; Putney Jr&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Cell Calcium"
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                        "volumen" => "7"
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                        "paginaFinal" => "12"
                        "link" => array:1 [
                          0 => array:2 [
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                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            2 => array:3 [
              "identificador" => "bib0015"
              "etiqueta" => "3"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Store-operated calcium channels"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "A&#46;B&#46; Parekh"
                            1 => "J&#46;W&#46; Putney Jr&#46;"
                          ]
                        ]
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                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1152/physrev.00057.2003"
                      "Revista" => array:6 [
                        "tituloSerie" => "Physiol Rev"
                        "fecha" => "2005"
                        "volumen" => "85"
                        "paginaInicial" => "757"
                        "paginaFinal" => "810"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15788710"
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                          ]
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            ]
            3 => array:3 [
              "identificador" => "bib0020"
              "etiqueta" => "4"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "An integrated encyclopedia of DNA elements in the human genome"
                      "autores" => array:1 [
                        0 => array:2 [
                          "colaboracion" => "ENCODE&#44; Project consortium"
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                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
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Article information
ISSN: 21735743
Original language: English
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2024 October 197 28 225
2024 September 149 33 182
2024 August 151 46 197
2024 July 146 35 181
2024 June 178 37 215
2024 May 155 53 208
2024 April 142 39 181
2024 March 131 31 162
2024 February 113 46 159
2024 January 140 39 179
2023 December 139 24 163
2023 November 162 42 204
2023 October 147 36 183
2023 September 185 40 225
2023 August 117 25 142
2023 July 100 23 123
2023 June 99 26 125
2023 May 117 30 147
2023 April 82 12 94
2023 March 131 34 165
2023 February 110 33 143
2023 January 90 19 109
2022 December 121 45 166
2022 November 179 42 221
2022 October 112 63 175
2022 September 181 49 230
2022 August 130 42 172
2022 July 157 61 218
2022 June 127 49 176
2022 May 138 64 202
2022 April 123 70 193
2022 March 125 65 190
2022 February 100 53 153
2022 January 100 49 149
2021 December 78 50 128
2021 November 75 65 140
2021 October 102 46 148
2021 September 75 61 136
2021 August 91 42 133
2021 July 48 22 70
2021 June 95 38 133
2021 May 107 53 160
2021 April 287 121 408
2021 March 155 31 186
2021 February 111 34 145
2021 January 88 42 130
2020 December 97 28 125
2020 November 88 39 127
2020 October 63 23 86
2020 September 81 23 104
2020 August 45 29 74
2020 July 36 33 69
2020 June 63 18 81
2020 May 39 19 58
2020 April 39 27 66
2020 March 11 16 27
2019 October 0 1 1
2019 August 0 1 1
2019 June 0 1 1
2019 May 0 1 1
2019 April 0 1 1
2019 March 0 1 1
2019 February 0 1 1
2019 January 1 1 2
2018 June 0 1 1
2018 May 28 6 34
2018 April 185 15 200
2018 March 271 11 282
2018 February 114 15 129
2018 January 132 16 148
2017 December 161 13 174
2017 November 149 21 170
2017 October 140 10 150
2017 September 98 20 118
2017 August 119 28 147
2017 July 133 33 166
2017 June 164 21 185
2017 May 172 41 213
2017 April 173 28 201
2017 March 163 36 199
2017 February 127 33 160
2017 January 138 22 160
2016 December 226 26 252
2016 November 287 25 312
2016 October 320 33 353
2016 September 394 23 417
2016 August 341 12 353
2016 July 149 13 162
2016 June 1 0 1
2016 May 0 26 26
2016 April 2 0 2
2016 February 1 0 1
2015 December 2 0 2
2015 September 1 0 1
2015 August 3 0 3
2015 July 90 14 104
2015 June 141 19 160
2015 May 178 29 207
2015 April 150 20 170
2015 March 206 13 219
2015 February 192 11 203
2015 January 164 22 186
2014 December 143 16 159
2014 November 199 9 208
2014 October 167 15 182
2014 September 104 16 120
2014 August 95 17 112
2014 July 82 18 100
2014 June 129 16 145
2014 May 111 25 136
2014 April 97 30 127
2014 March 123 46 169
2014 February 63 30 93
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