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<meta name="description" content="The p110δ subunit of phosphatidylinositol-3-OH kinase (PI(3)K) is selectively expressed in leukocytes and is critical for lymphocyte biology. Here we report fourteen patients from seven families who were heterozygous for three different germline, gain-of-function mutations in PIK3CD (which encodes p …"><meta name="keywords" content="pmid:24165795, PMC4209962, doi:10.1038/ni.2771, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't, Carrie L Lucas, Hye Sun Kuehn, Gulbu Uzel, Antibiotics, Antineoplastic / therapeutic use, Cell Differentiation / genetics, Cells, Cultured, Cellular Senescence / genetics*, Class I Phosphatidylinositol 3-Kinases, Cytomegalovirus Infections / blood, Cytomegalovirus Infections / genetics, Cytomegalovirus Infections / virology, Epstein-Barr Virus Infections / blood, Epstein-Barr Virus Infections / genetics, Epstein-Barr Virus Infections / virology, Female, Genes, Dominant, Germ-Line Mutation*, Humans, Immunoblotting, Immunologic Deficiency Syndromes / drug therapy, Immunologic Deficiency Syndromes / genetics*, Male, Pedigree, Phosphatidylinositol 3-Kinases / chemistry, Phosphatidylinositol 3-Kinases / genetics*, Phosphorylation, Proto-Oncogene Proteins c-akt / metabolism, Sirolimus / therapeutic use, T-Lymphocytes / metabolism*, TOR Serine-Threonine Kinases / metabolism, Viremia / drug therapy, Viremia / genetics, Viremia / virology, PubMed Abstract, NIH, NLM, NCBI, National Institutes of Health, National Center for Biotechnology Information, National Library of Medicine, MEDLINE"><meta name="robots" content="index,nofollow,noarchive"><meta property="og:title" content="Dominant-activating germline mutations in the gene encoding the PI(3)K catalytic subunit p110δ result in T cell senescence and human immunodeficiency - PubMed"><meta property="og:url" content="https://pubmed.ncbi.nlm.nih.gov/24165795/"><meta property="og:description" content="The p110δ subunit of phosphatidylinositol-3-OH kinase (PI(3)K) is selectively expressed in leukocytes and is critical for lymphocyte biology. Here we report fourteen patients from seven families who were heterozygous for three different germline, gain-of-function mutations in PIK3CD (which encodes p …"><meta property="og:image" content="https://cdn.ncbi.nlm.nih.gov/pubmed/persistent/pubmed-meta-image-v2.jpg"><meta property="og:image:secure_url" content="https://cdn.ncbi.nlm.nih.gov/pubmed/persistent/pubmed-meta-image-v2.jpg"><meta property="og:type" content="website"><meta property="og:site_name" content="PubMed"><meta name="twitter:domain" content="pubmed.ncbi.nlm.nih.gov"><meta name="twitter:card" content="summary_large_image"><meta name="twitter:title" content="Dominant-activating germline mutations in the gene encoding the PI(3)K catalytic subunit p110δ result in T cell senescence and human immunodeficiency - PubMed"><meta name="twitter:url" content="https://pubmed.ncbi.nlm.nih.gov/24165795/"><meta name="twitter:description" content="The p110δ subunit of phosphatidylinositol-3-OH kinase (PI(3)K) is selectively expressed in leukocytes and is critical for lymphocyte biology. Here we report fourteen patients from seven families who were heterozygous for three different germline, gain-of-function mutations in PIK3CD (which encodes p …"><meta name="twitter:image" content="https://cdn.ncbi.nlm.nih.gov/pubmed/persistent/pubmed-meta-image-v2.jpg">
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<meta name="citation_authors" content="Lucas CL;Kuehn HS;Zhao F;Niemela JE;Deenick EK;Palendira U;Avery DT;Moens L;Cannons JL;Biancalana M;Stoddard J;Ouyang W;Frucht DM;Rao VK;Atkinson TP;Agharahimi A;Hussey AA;Folio LR;Olivier KN;Fleisher TA;Pittaluga S;Holland SM;Cohen JI;Oliveira JB;Tangye SG;Schwartzberg PL;Lenardo MJ;Uzel G;">
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|
||
<!-- Better for them to look like buttons but no space -->
|
||
<div class="search-links-wrapper content-page-layout">
|
||
<div class="search-links">
|
||
<a href="/advanced/"
|
||
class="search-input-link adv-search-link"
|
||
data-ga-category="featured_link"
|
||
data-ga-action="adv_search">Advanced</a>
|
||
|
||
|
||
<a href="/clipboard/"
|
||
class="search-input-link clipboard-link hidden"
|
||
data-ga-category="featured_link"
|
||
data-ga-action="clipboard">
|
||
Clipboard <span class="amount-in-clipboard"></span>
|
||
</a>
|
||
</div>
|
||
|
||
<span class="search-input-link user-guide-link" role="navigation" aria-label="User guide">
|
||
<a href="/help/"
|
||
data-ga-category="featured_link"
|
||
data-ga-action="user_guide">
|
||
User Guide
|
||
</a>
|
||
</span>
|
||
|
||
</div>
|
||
</div>
|
||
|
||
|
||
</form>
|
||
|
||
|
||
<div id="article-page-header">
|
||
<div id="article-top-actions-bar" class="article-top-actions-bar">
|
||
<div class="inner-wrap">
|
||
<div class="actions-container">
|
||
<div class="return-to-search">
|
||
|
||
|
||
</div>
|
||
|
||
<div class="multiple-results-actions " role="region" aria-label="save, email, send to">
|
||
<button id="save-results-panel-trigger"
|
||
type="button"
|
||
class="save-results save-results-panel-trigger"
|
||
aria-expanded="false"
|
||
aria-controls="save-action-panel"
|
||
data-ga-category="save_share"
|
||
data-ga-action="save"
|
||
data-ga-label="open">
|
||
Save
|
||
</button><button id="email-results-panel-trigger"
|
||
type="button"
|
||
class="email-results email-results-panel-trigger"
|
||
aria-expanded="false"
|
||
aria-controls="email-action-panel"
|
||
data-ga-category="save_share"
|
||
data-ga-action="email"
|
||
data-ga-label="open">
|
||
Email
|
||
</button><div class="more-actions dropdown-block"><button id="more-actions-trigger"
|
||
type="button"
|
||
class="trigger more-actions-trigger"
|
||
ref="linksrc=show_moreactions_btn"
|
||
aria-label="Send to"
|
||
aria-controls="more-actions-dropdown">Send to</button><div id="more-actions-dropdown" class="dropdown dropdown-container" hidden><div class="content"><ul class="more-actions-links"><li><a class="clipboard-panel-trigger dropdown-block-link "
|
||
href="#"
|
||
role="button"
|
||
data-ga-category="save_share"
|
||
data-ga-action="clipboard"
|
||
data-ga-label="send">
|
||
Clipboard
|
||
</a></li><li><a role="button" class="dropdown-block-link bibliography-trigger-target" href="https://account.ncbi.nlm.nih.gov/?back_url=https%3A%2F%2Fpubmed.ncbi.nlm.nih.gov%2F24165795%2F%23open-bibliography-panel">My Bibliography</a></li><li><a role="button" class="dropdown-block-link collections-trigger-target" href="https://account.ncbi.nlm.nih.gov/?back_url=https%3A%2F%2Fpubmed.ncbi.nlm.nih.gov%2F24165795%2F%23open-collections-panel">Collections</a></li><li><a role="button" class="citation-manager-panel-trigger dropdown-block-link citation-manager-trigger-target" href="#">Citation manager</a></li></ul></div></div></div>
|
||
</div>
|
||
|
||
|
||
|
||
<div class="display-options" data-format-key="format"
|
||
data-default-format-value="abstract"
|
||
data-current-format-value="abstract" role="region">
|
||
<button
|
||
class="trigger usa-button"
|
||
title="Change format"
|
||
data-ga-category="display_options"
|
||
data-ga-action="display_options_dialog">
|
||
<span class="button-label">Display options</span>
|
||
</button>
|
||
|
||
<div class="dropdown" hidden>
|
||
<div class="title">
|
||
Display options
|
||
</div>
|
||
|
||
<div class="content">
|
||
|
||
<div class="format-container">
|
||
<span class="option-label">
|
||
Format
|
||
</span>
|
||
<select name="format" data-initial-value="abstract" aria-label="Display format" id="article-display-format">
|
||
<option value="abstract">Abstract</option>
|
||
|
||
<option value="pubmed">PubMed</option>
|
||
|
||
<option value="pmid">PMID</option>
|
||
|
||
</select>
|
||
</div>
|
||
|
||
</div>
|
||
</div>
|
||
</div>
|
||
<input type="hidden" name="csrfmiddlewaretoken" value="CNHfJ7h1E0Ub4EaLqRO3gTCgf3YWNc3DTArkmXKneBHFY5gB3ar5K18UN7G8GNBX">
|
||
</div>
|
||
</div>
|
||
</div>
|
||
|
||
<div id="article-panels-container" class="article-panels-container">
|
||
<div id="save-action-panel" class="save-action-panel action-panel" aria-hidden="true">
|
||
<div class="inner-wrap">
|
||
<h2 class="action-panel-heading">
|
||
Save citation to file
|
||
</h2>
|
||
<form id="save-action-panel-form"
|
||
class="action-panel-content action-form"
|
||
action="/results-export-ids/"
|
||
data-by-search-action="/results-export-search-data/"
|
||
data-by-ids-action="/results-export-ids/"
|
||
method="post"
|
||
data-by-search-method="post"
|
||
data-by-ids-method="post">
|
||
|
||
<input type="hidden" name="csrfmiddlewaretoken" value="CNHfJ7h1E0Ub4EaLqRO3gTCgf3YWNc3DTArkmXKneBHFY5gB3ar5K18UN7G8GNBX">
|
||
|
||
|
||
|
||
<div class="action-panel-control-wrap">
|
||
<label for="save-action-format" class="action-panel-label">
|
||
Format:
|
||
</label>
|
||
<select id="save-action-format" name="results-format" class="action-panel-selector">
|
||
<option value="summary-text">Summary (text)</option>
|
||
<option value="pubmed-text">PubMed</option>
|
||
<option value="pmid">PMID</option>
|
||
<option value="abstract">Abstract (text)</option>
|
||
<option value="csv">CSV</option>
|
||
</select>
|
||
</div>
|
||
|
||
<div class="action-panel-actions">
|
||
<button class="action-panel-submit"
|
||
type="submit"
|
||
data-loading-label="Saving..."
|
||
data-ga-category="save_share"
|
||
data-ga-action="save"
|
||
data-ga-label="save">
|
||
Create file
|
||
</button>
|
||
<button class="action-panel-cancel"
|
||
aria-label="Close 'Save citations to file' panel"
|
||
ref="linksrc=close_save_panel"
|
||
aria-controls="save-action-panel"
|
||
aria-expanded="false"
|
||
data-ga-category="save_share"
|
||
data-ga-action="save"
|
||
data-ga-label="cancel">
|
||
Cancel
|
||
</button>
|
||
</div>
|
||
</form>
|
||
</div>
|
||
</div>
|
||
|
||
|
||
|
||
|
||
<div id="email-action-panel"
|
||
class="email-action-panel action-panel"
|
||
aria-hidden="true"
|
||
data-recaptcha-script-url="https://www.recaptcha.net/recaptcha/enterprise.js?render=explicit&onload=onloadCaptchaCallback"
|
||
data-recaptcha-enabled="true">
|
||
<div class="inner-wrap">
|
||
<h2 class="action-panel-heading">
|
||
Email citation
|
||
</h2>
|
||
<form id="email-action-panel-form"
|
||
class="action-panel-content action-form"
|
||
action="/send-email/"
|
||
data-by-search-action="/results-export-email-by-search-data/"
|
||
data-by-ids-action="/send-email/"
|
||
data-by-search-method="post"
|
||
data-by-ids-method="post"
|
||
method="post"
|
||
>
|
||
<input type="hidden" name="csrfmiddlewaretoken" value="CNHfJ7h1E0Ub4EaLqRO3gTCgf3YWNc3DTArkmXKneBHFY5gB3ar5K18UN7G8GNBX">
|
||
|
||
<div class="action-panel-control-wrap">
|
||
<span class="action-panel-label">
|
||
Subject:
|
||
</span>
|
||
<span class="email-subject" id="email-subject" aria-label="Email subject">1 selected item: 24165795 - PubMed</span>
|
||
<input type="hidden" name="email-subject" value="1 selected item: 24165795"/>
|
||
<input type="hidden" name="email-subject-hash" value="ab553cbff75a4df48b28e0be6a5540b83977e823928a1ee3dc147e3c98ce9af4"/>
|
||
</div>
|
||
|
||
<div class="action-panel-control-wrap">
|
||
<label for="email-to" class="action-panel-label required-field-asterisk">
|
||
To:
|
||
</label>
|
||
<input type="email" aria-label="Recipient Email Address" placeholder="email@example.com" id="email-to" class="email-to" pattern="^[a-zA-Z0-9_.+-]+@[a-zA-Z0-9-]+\.[a-zA-Z0-9-.]+$" maxlength="100" required>
|
||
</div>
|
||
|
||
<div class="action-panel-control-wrap">
|
||
<label for="email-from" class="action-panel-label">
|
||
From:
|
||
</label>
|
||
<input type="email" aria-label="Sender Email Address" placeholder="email@example.com" id="email-from" class="email-from" pattern="^[a-zA-Z0-9_.+-]+@[a-zA-Z0-9-]+\.[a-zA-Z0-9-.]+$" maxlength="256">
|
||
</div>
|
||
|
||
|
||
|
||
<div class="action-panel-control-wrap">
|
||
<label for="email-citation-format" class="action-panel-label">
|
||
Format:
|
||
</label>
|
||
<select id="email-citation-format" name="citation-format" class="action-panel-selector email-citation-format">
|
||
<option selected="selected" value="summary">Summary</option>
|
||
<option value="summary-text">Summary (text)</option>
|
||
<option value="abstract">Abstract</option>
|
||
<option value="abstract-text">Abstract (text)</option>
|
||
|
||
</select>
|
||
</div>
|
||
<div class="include-supplemental-container">
|
||
<input type="checkbox" aria-label="Include MeSH and other data" name="include-supplemental" id="email-include-supplemental" class="email-include-supplemental">
|
||
<label for="email-include-supplemental" class="email-include-supplemental-label">MeSH and other data</label>
|
||
</div>
|
||
|
||
|
||
|
||
<div class="form-field recaptcha ">
|
||
|
||
|
||
|
||
<div class="g-recaptcha" id="id-recaptcha" data-sitekey="6LfsWHMdAAAAAClKbtOpjQ2pMjgsGxvv7NdZW9uI"></div>
|
||
|
||
|
||
|
||
|
||
|
||
</div>
|
||
<div id="captcha-error-message" class="usa-input-error-message captcha-validation-message" role="alert"></div>
|
||
|
||
|
||
|
||
<div class="action-panel-actions">
|
||
<button class="action-panel-submit"
|
||
type="submit"
|
||
data-loading-label="Sending..."
|
||
data-ga-category="save_share"
|
||
data-ga-action="email"
|
||
data-ga-label="send">
|
||
Send email
|
||
</button>
|
||
<button class="action-panel-cancel"
|
||
aria-label="Close 'Email citations' panel"
|
||
ref="linksrc=close_email_panel"
|
||
aria-controls="email-action-panel"
|
||
aria-expanded="false"
|
||
data-ga-category="save_share"
|
||
data-ga-action="email"
|
||
data-ga-label="cancel">
|
||
Cancel
|
||
</button>
|
||
</div>
|
||
<input type="hidden" name="email-search-details" value="" />
|
||
<input type="hidden" name="email-search-details-hash" value="0e42663a6c3bd85498fcb88798998fed7bfdc45d457db35281e41afe13cc0524" />
|
||
</form>
|
||
</div>
|
||
</div>
|
||
|
||
<div id="collections-action-panel"
|
||
class="collections-action-panel action-panel in-progress-dots-panel"
|
||
aria-hidden="true"
|
||
data-collections-open-panel-enabled="false"
|
||
data-collections-open-panel-url-hash="#open-collections-panel">
|
||
<div class="inner-wrap">
|
||
<h3 class="action-panel-heading">
|
||
Add to Collections
|
||
</h3>
|
||
|
||
|
||
<form id="collections-action-panel-form"
|
||
class="collections-action-panel-form action-panel-content action-form action-panel-smaller-selectors"
|
||
data-existing-collections-url="/list-existing-collections/"
|
||
data-add-to-existing-collection-url="/add-to-existing-collection/"
|
||
data-create-and-add-to-new-collection-url="/create-and-add-to-new-collection/"
|
||
data-get-article-ids-by-search-url="/get-article-ids-by-search/"
|
||
data-myncbi-max-collection-name-length="100"
|
||
data-add-to-collection-max-amount="1000"
|
||
data-collections-root-url="https://www.ncbi.nlm.nih.gov/myncbi/collections/">
|
||
|
||
<input type="hidden" name="csrfmiddlewaretoken" value="CNHfJ7h1E0Ub4EaLqRO3gTCgf3YWNc3DTArkmXKneBHFY5gB3ar5K18UN7G8GNBX">
|
||
|
||
|
||
|
||
<div class="choice-group" role="radiogroup">
|
||
<ul class="radio-group-items">
|
||
<li>
|
||
<input type="radio"
|
||
id="collections-action-panel-new"
|
||
class="collections-new"
|
||
name="collections"
|
||
value="new"
|
||
data-ga-category="save_share"
|
||
data-ga-action="collections"
|
||
data-ga-label="collections_radio_new">
|
||
<label for="collections-action-panel-new">Create a new collection</label>
|
||
</li>
|
||
<li>
|
||
<input type="radio"
|
||
id="collections-action-panel-existing"
|
||
class="collections-existing"
|
||
name="collections"
|
||
value="existing"
|
||
checked="true"
|
||
data-ga-category="save_share"
|
||
data-ga-action="collections"
|
||
data-ga-label="collections_radio_existing">
|
||
<label for="collections-action-panel-existing">Add to an existing collection</label>
|
||
</li>
|
||
</ul>
|
||
</div>
|
||
|
||
<div class="controls-wrapper">
|
||
<div class="action-panel-control-wrap new-collections-controls">
|
||
<label for="collections-action-panel-add-to-new" class="action-panel-label required-field-asterisk">
|
||
Name your collection:
|
||
</label>
|
||
<input
|
||
type="text"
|
||
name="add-to-new-collection"
|
||
id="collections-action-panel-add-to-new"
|
||
class="collections-action-add-to-new"
|
||
pattern="[^"&=<>\/]*" title="The following characters are not allowed in the Name field: "&=<>/"
|
||
maxlength="100"
|
||
data-ga-category="save_share"
|
||
data-ga-action="create_collection"
|
||
data-ga-label="non_favorties_collection">
|
||
<div class="collections-new-name-too-long usa-input-error-message selection-validation-message">
|
||
Name must be less than 100 characters
|
||
</div>
|
||
</div>
|
||
<div class="action-panel-control-wrap existing-collections-controls">
|
||
<label for="collections-action-panel-add-to-existing" class="action-panel-label">
|
||
Choose a collection:
|
||
</label>
|
||
<select id="collections-action-panel-add-to-existing"
|
||
class="action-panel-selector collections-action-add-to-existing"
|
||
data-ga-category="save_share"
|
||
data-ga-action="select_collection"
|
||
data-ga-label="($('#collections-action-add-to-existing').val() === 'Favorites') ? 'Favorites' : 'non_favorites_collection'">
|
||
</select>
|
||
<div class="collections-retry-load-on-error usa-input-error-message selection-validation-message">
|
||
Unable to load your collection due to an error<br>
|
||
<a href="#">Please try again</a>
|
||
</div>
|
||
</div>
|
||
</div>
|
||
|
||
<div class="action-panel-actions">
|
||
<button class="action-panel-submit"
|
||
type="submit"
|
||
data-loading-label="Adding..."
|
||
data-pinger-ignore
|
||
data-ga-category="save_share"
|
||
data-ga-action="collections"
|
||
data-ga-label="add">
|
||
Add
|
||
</button>
|
||
<button class="action-panel-cancel"
|
||
aria-label="Close 'Add to Collections' panel"
|
||
ref="linksrc=close_collections_panel"
|
||
aria-controls="collections-action-panel"
|
||
aria-expanded="false"
|
||
data-ga-category="save_share"
|
||
data-ga-action="collections"
|
||
data-ga-label="cancel">
|
||
Cancel
|
||
</button>
|
||
</div>
|
||
</form>
|
||
</div>
|
||
</div>
|
||
|
||
<div id="bibliography-action-panel"
|
||
class="bibliography-action-panel action-panel in-progress-dots-panel"
|
||
aria-hidden="true"
|
||
data-bibliography-open-panel-enabled="false"
|
||
data-bibliography-open-panel-url-hash="#open-bibliography-panel">
|
||
<div class="inner-wrap">
|
||
<h3 class="action-panel-heading">
|
||
Add to My Bibliography
|
||
</h3>
|
||
<form id="bibliography-action-panel-form"
|
||
class="bibliography-action-panel-form action-panel-content action-form action-panel-smaller-selectors"
|
||
data-add-to-bibliography-max-amount="100"
|
||
data-add-to-bibliography-batch-size="10"
|
||
data-bibliography-delegates-url="/list-bibliography-delegates/"
|
||
data-add-to-bibliography-url="/add-to-bibliography/"
|
||
data-get-article-ids-by-search-url="/get-article-ids-by-search/"
|
||
data-mybib-root-url="https://www.ncbi.nlm.nih.gov/myncbi/collections/mybibliography/">
|
||
|
||
<input type="hidden" name="csrfmiddlewaretoken" value="CNHfJ7h1E0Ub4EaLqRO3gTCgf3YWNc3DTArkmXKneBHFY5gB3ar5K18UN7G8GNBX">
|
||
|
||
|
||
|
||
<div class="action-panel-control-wrap bibliographies-controls">
|
||
<div class="choice-group">
|
||
<ul class="bibliographies-action-add radio-group-items">
|
||
<li>
|
||
<input name="bibliography" id="my-bibliography" class="my-bibliography" type="radio" checked/>
|
||
<label for="my-bibliography">My Bibliography</label>
|
||
</li>
|
||
</ul>
|
||
</div>
|
||
</div>
|
||
|
||
<div class="bibliographies-retry-load-on-error usa-input-error-message selection-validation-message">
|
||
Unable to load your delegates due to an error<br>
|
||
<a href="#">Please try again</a>
|
||
</div>
|
||
|
||
<div class="action-panel-actions">
|
||
<button class="action-panel-submit"
|
||
type="submit"
|
||
data-loading-label="Adding..."
|
||
data-pinger-ignore>
|
||
Add
|
||
</button>
|
||
<button class="action-panel-cancel"
|
||
aria-label="Close 'Add to bibliography' panel"
|
||
ref="linksrc=close_bibliography_panel"
|
||
aria-controls="bibliography-action-panel"
|
||
aria-expanded="false"
|
||
data-ga-category="save_share"
|
||
data-ga-action="mybib"
|
||
data-ga-label="cancel">
|
||
Cancel
|
||
</button>
|
||
</div>
|
||
</form>
|
||
</div>
|
||
</div>
|
||
|
||
|
||
|
||
|
||
<div id="saved-search-action-panel" class="saved-search-action-panel action-panel " aria-hidden="true"
|
||
data-saved-search-open-panel-enabled="false"
|
||
data-saved-search-open-panel-url-hash="#open-saved-search-panel">
|
||
<div class="inner-wrap">
|
||
<h2 class="action-panel-heading">
|
||
Your saved search
|
||
</h2>
|
||
|
||
<form id="saved-search-action-panel-form"
|
||
class="saved-search-action-panel-form action-panel-content action-form"
|
||
data-create-saved-search-url="/create-saved-search/"
|
||
data-try-search-terms-url="/try-search-term/"
|
||
data-saved-search-root-url="https://www.ncbi.nlm.nih.gov/myncbi/searches/">
|
||
|
||
<input type="hidden" name="csrfmiddlewaretoken" value="CNHfJ7h1E0Ub4EaLqRO3gTCgf3YWNc3DTArkmXKneBHFY5gB3ar5K18UN7G8GNBX">
|
||
|
||
<div class="action-panel-control-wrap">
|
||
<label for="saved-search-name" class="action-panel-label saved-search-name-label required-field-asterisk">
|
||
Name of saved search:
|
||
</label>
|
||
<input maxlength="200"
|
||
type="text"
|
||
name="saved-search-name"
|
||
id="saved-search-name"
|
||
class="saved-search-name"
|
||
value=""
|
||
required
|
||
pattern="[^"&=<>\/]*" title="The following characters are not allowed in the Name field: "&=<>/">
|
||
</div>
|
||
|
||
<div class="action-panel-control-wrap">
|
||
<label for="saved-search-term" class="action-panel-label required-field-asterisk">
|
||
Search terms:
|
||
</label>
|
||
<textarea name="saved-search-term" id="saved-search-term" class="saved-search-term" required></textarea>
|
||
</div>
|
||
<div class="test-search-term-wrap">
|
||
<a href="#" class="try-search-term">Test search terms</a>
|
||
</div>
|
||
<div class="choice-group action-panel-extra-margin-top">
|
||
<span class="action-panel-label" id="fieldset-label">
|
||
Would you like email updates of new search results?
|
||
</span>
|
||
<fieldset id="saved-search-alert" aria-describedby="fieldset-label">
|
||
<legend class="usa-sr-only">Saved Search Alert Radio Buttons</legend>
|
||
<ul class="radio-group-items">
|
||
<li>
|
||
<input type="radio" id="saved-search-alert-yes" class="saved-search-alert-yes" name="saved-search-alert" value="yes" checked>
|
||
<label for="saved-search-alert-yes" class="action-panel-label">Yes</label>
|
||
</li>
|
||
<li>
|
||
<input aria-label="No radio input" type="radio" id="saved-search-alert-no" class="saved-search-alert-no" name="saved-search-alert" value="no">
|
||
<label for="saved-search-alert-no" class="action-panel-label">No</label>
|
||
</li>
|
||
</ul>
|
||
</fieldset>
|
||
</div>
|
||
|
||
<div class="alert-schedule-wrap">
|
||
<div class="action-panel-control-wrap">
|
||
<label class="action-panel-label">
|
||
Email:
|
||
</label>
|
||
<span aria-label="Email address" id="saved-search-email" class="action-panel-label"><span class="action-panel-label-bold"></span> (<a class="myncbi-account-settings" href="https://www.ncbi.nlm.nih.gov/account/settings/">change</a>)</span>
|
||
</div>
|
||
<div class="action-panel-control-wrap action-panel-extra-margin-top">
|
||
<label for="saved-search-frequency" class="action-panel-label">
|
||
Frequency:
|
||
</label>
|
||
<select id="saved-search-frequency" class="no-border-panel-selector saved-search-frequency">
|
||
<option value="monthly">Monthly</option>
|
||
<option value="weekly">Weekly</option>
|
||
<option value="daily">Daily</option>
|
||
</select>
|
||
</div>
|
||
<div class="action-panel-control-wrap saved-search-monthly-additional">
|
||
<label for="saved-search-monthly-on-day" class="action-panel-label">
|
||
Which day?
|
||
</label>
|
||
<select id="saved-search-monthly-on-day" class="no-border-panel-selector">
|
||
<option value="Sunday">The first Sunday</option>
|
||
<option value="Monday">The first Monday</option>
|
||
<option value="Tuesday">The first Tuesday</option>
|
||
<option value="Wednesday">The first Wednesday</option>
|
||
<option value="Thursday">The first Thursday</option>
|
||
<option value="Friday">The first Friday</option>
|
||
<option value="Saturday">The first Saturday</option>
|
||
<option value="day">The first day</option>
|
||
<option value="weekday">The first weekday</option>
|
||
</select>
|
||
</div>
|
||
<div class="action-panel-control-wrap saved-search-weekly-additional">
|
||
<label for="saved-search-weekly-on-day" class="action-panel-label">
|
||
Which day?
|
||
</label>
|
||
<select id="saved-search-weekly-on-day" class="no-border-panel-selector saved-search-weekly-on-day">
|
||
<option value="Sunday">Sunday</option>
|
||
<option value="Monday">Monday</option>
|
||
<option value="Tuesday">Tuesday</option>
|
||
<option value="Wednesday">Wednesday</option>
|
||
<option value="Thursday">Thursday</option>
|
||
<option value="Friday">Friday</option>
|
||
<option value="Saturday">Saturday</option>
|
||
</select>
|
||
</div>
|
||
<div class="action-panel-control-wrap">
|
||
<label for="saved-search-report" class="action-panel-label">
|
||
Report format:
|
||
</label>
|
||
<select id="saved-search-report" class="no-border-panel-selector saved-search-report">
|
||
<option value="DocSum">Summary</option>
|
||
<option value="DocSumText">Summary (text)</option>
|
||
<option value="Abstract">Abstract</option>
|
||
<option value="AbstractText">Abstract (text)</option>
|
||
<option value="MEDLINE">PubMed</option>
|
||
</select>
|
||
</div>
|
||
<div class="action-panel-control-wrap">
|
||
<label for="saved-search-amount" class="action-panel-label">
|
||
Send at most:
|
||
</label>
|
||
<select id="saved-search-amount" class="no-border-panel-selector saved-search-amount">
|
||
<option value="1">1 item</option>
|
||
<option value="5" selected>5 items</option>
|
||
<option value="10">10 items</option>
|
||
<option value="20">20 items</option>
|
||
<option value="50">50 items</option>
|
||
<option value="100">100 items</option>
|
||
<option value="200">200 items</option>
|
||
</select>
|
||
</div>
|
||
<div>
|
||
<input type="checkbox" id="saved-search-send-if-no-result" class="saved-search-send-if-no-result" name="saved-search-send-if-no-result">
|
||
<label for="saved-search-send-if-no-result" class="action-panel-label smaller-checkbox">
|
||
Send even when there aren't any new results
|
||
</label>
|
||
</div>
|
||
<div class="action-panel-control-wrap option-text-in-email-wrap">
|
||
<label for="saved-search-email-text" class="action-panel-label">
|
||
Optional text in email:
|
||
</label>
|
||
<textarea name="saved-search-email-text"
|
||
id="saved-search-email-text"
|
||
class="saved-search-email-text"></textarea>
|
||
</div>
|
||
|
||
</div>
|
||
|
||
<div class="action-panel-actions">
|
||
<button class="action-panel-submit"
|
||
type="submit"
|
||
data-loading-label="Saving..."
|
||
data-ga-category="save_share"
|
||
data-ga-action="alert"
|
||
data-ga-label="save">
|
||
Save
|
||
</button>
|
||
<button class="action-panel-cancel"
|
||
aria-label="Close 'Your saved search' panel"
|
||
ref="linksrc=close_saved_search_panel"
|
||
aria-controls="saved-search-action-panel"
|
||
aria-expanded="false"
|
||
data-ga-category="save_share"
|
||
data-ga-action="alert"
|
||
data-ga-label="cancel">
|
||
Cancel
|
||
</button>
|
||
</div>
|
||
</form>
|
||
</div>
|
||
</div>
|
||
|
||
<div id="citation-manager-action-panel" class="citation-manager-action-panel action-panel" aria-hidden="true">
|
||
<div class="inner-wrap">
|
||
<h2 class="action-panel-heading">
|
||
Create a file for external citation management software
|
||
</h2>
|
||
<form id="citation-manager-action-panel-form"
|
||
class="action-panel-content action-form"
|
||
action="/results-export-ids/"
|
||
data-by-search-action="/results-export-search-data/"
|
||
data-by-ids-action="/results-export-ids/"
|
||
method="post"
|
||
data-by-search-method="post"
|
||
data-by-ids-method="post">
|
||
|
||
<input type="hidden" name="csrfmiddlewaretoken" value="CNHfJ7h1E0Ub4EaLqRO3gTCgf3YWNc3DTArkmXKneBHFY5gB3ar5K18UN7G8GNBX">
|
||
|
||
|
||
|
||
<input name="results-format" type="hidden" value="pubmed"/>
|
||
|
||
<div class="action-panel-actions">
|
||
<button class="action-panel-submit"
|
||
type="submit"
|
||
data-loading-label="Sending..."
|
||
data-ga-category="save_share"
|
||
data-ga-action="citation_manager"
|
||
data-ga-label="save">
|
||
Create file
|
||
</button>
|
||
<button class="action-panel-cancel"
|
||
aria-label="Close 'Send citations to citation manager' panel"
|
||
ref="linksrc=close_citation_manager_panel"
|
||
aria-controls="citation-manager-action-panel"
|
||
aria-expanded="false"
|
||
data-ga-category="save_share"
|
||
data-ga-action="citation_manager"
|
||
data-ga-label="cancel">
|
||
Cancel
|
||
</button>
|
||
</div>
|
||
</form>
|
||
</div>
|
||
</div>
|
||
|
||
|
||
|
||
|
||
<div id="rss-action-panel" class="rss-action-panel action-panel " aria-hidden="true">
|
||
<div class="inner-wrap">
|
||
<h2 class="action-panel-heading">
|
||
Your RSS Feed
|
||
</h2>
|
||
|
||
<form id="rss-action-panel-form"
|
||
class="rss-action-panel-form action-panel-content action-form"
|
||
data-create-rss-feed-url="/create-rss-feed-url/"
|
||
data-search-form-term-value="">
|
||
|
||
<input type="hidden" name="csrfmiddlewaretoken" value="CNHfJ7h1E0Ub4EaLqRO3gTCgf3YWNc3DTArkmXKneBHFY5gB3ar5K18UN7G8GNBX">
|
||
|
||
<div class="action-panel-control-wrap">
|
||
<label for="rss-name" class="action-panel-label required-field-asterisk">
|
||
Name of RSS Feed:
|
||
</label>
|
||
<input maxlength="200"
|
||
placeholder="Name"
|
||
type="text"
|
||
name="rss-name"
|
||
id="rss-name"
|
||
class="rss-name"
|
||
value=''
|
||
required
|
||
pattern="[^"&=<>\/]*" title="The following characters are not allowed in the Name field: "&=<>/">
|
||
</div>
|
||
|
||
<div class="rss-limit-wrap">
|
||
<div class="action-panel-control-wrap action-panel-extra-margin-top">
|
||
<label for="rss-limit" class="action-panel-label">
|
||
Number of items displayed:
|
||
</label>
|
||
<select id="rss-limit" class="no-border-panel-selector rss-limit">
|
||
<option value="5">5</option>
|
||
<option value="10">10</option>
|
||
<option value="15" selected="selected">15</option>
|
||
<option value="20">20</option>
|
||
<option value="50">50</option>
|
||
<option value="100">100</option>
|
||
</select>
|
||
</div>
|
||
</div>
|
||
|
||
<div class="action-panel-actions">
|
||
<button class="action-panel-submit"
|
||
type="submit"
|
||
data-loading-label="Creating..."
|
||
data-ga-category="save_share"
|
||
data-ga-action="alert"
|
||
data-ga-label="save">
|
||
Create RSS
|
||
</button>
|
||
<button class="action-panel-cancel"
|
||
aria-label="Close 'Your RSS' panel"
|
||
ref="linksrc=close_rss_panel"
|
||
aria-controls="rss-action-panel"
|
||
aria-expanded="false"
|
||
data-ga-category="save_share"
|
||
data-ga-action="alert"
|
||
data-ga-label="cancel">
|
||
Cancel
|
||
</button>
|
||
</div>
|
||
|
||
<div class="action-panel-control-wrap rss-link-copy-wrap">
|
||
<label for="rss-link" class="usa-sr-only">RSS Link</label>
|
||
<input placeholder="Your RSS Feed Link" type="text" name="rss-link" id="rss-link" class="rss-link" title="RSS Link">
|
||
<button
|
||
type="button"
|
||
disabled
|
||
class="rss-link-copy-button disabled"
|
||
data-ga-category="save_share"
|
||
data-ga-action="rss"
|
||
data-ga-label="copy">
|
||
Copy
|
||
</button>
|
||
</div>
|
||
</form>
|
||
</div>
|
||
</div>
|
||
|
||
</div>
|
||
</div>
|
||
|
||
<div class="article-page" id="article-page" data-article-pmid="24165795">
|
||
<aside class="page-sidebar">
|
||
<div class="inner-wrap">
|
||
|
||
<div class="full-text-links">
|
||
<div class="full-view">
|
||
<h3 class="title">
|
||
Full text links
|
||
</h3>
|
||
<div class="full-text-links-list">
|
||
<a class="link-item
|
||
|
||
dialog-focus"
|
||
href="https://doi.org/10.1038/ni.2771"
|
||
target="_blank"
|
||
rel="noopener"
|
||
|
||
ref="linksrc=fulltextorjournal_fulltext&is_pmc=False&PrId=3094&itool=Abstract-def&log$=linkouticon&uid=24165795&db=pubmed&nlmid=100941354"
|
||
title="See full text options at Nature Publishing Group"
|
||
|
||
data-ga-category="full_text"
|
||
data-ga-action="Nature Publishing Group"
|
||
data-ga-label="24165795"
|
||
><img src="https://cdn.ncbi.nlm.nih.gov/corehtml/query/egifs/https:--www.nature.com-static-images-logos-nature-portfolio-120.png" alt="Nature Publishing Group full text link"><span class="text">
|
||
|
||
Nature Publishing Group
|
||
|
||
</span></a><a class="link-item
|
||
pmc
|
||
"
|
||
href="https://pmc.ncbi.nlm.nih.gov/articles/pmid/24165795/"
|
||
target="_blank"
|
||
rel="noopener"
|
||
|
||
ref="linksrc=fulltextorjournal_fulltext&is_pmc=True&PrId=3494&itool=Abstract-def&log$=linkouticon&uid=24165795&db=pubmed&nlmid=100941354"
|
||
title="Free full text at PubMed Central"
|
||
|
||
data-ga-category="full_text"
|
||
data-ga-action="PMC"
|
||
data-ga-label="24165795"
|
||
><span class="text">
|
||
|
||
Free PMC article
|
||
|
||
</span></a>
|
||
</div>
|
||
|
||
</div>
|
||
|
||
<div class="short-view">
|
||
<a href="#" class="full-text-links-button full-text-links-dialog-trigger">
|
||
Full text links
|
||
</a>
|
||
</div>
|
||
</div>
|
||
|
||
|
||
|
||
|
||
<div class="actions-buttons sidebar"><h3 class="title">Actions</h3><div class="inner-wrap"><button class="citation-button citation-dialog-trigger"
|
||
aria-label="Open dialog with citation text in different styles"
|
||
data-ga-category="save_share"
|
||
data-ga-action="cite"
|
||
data-ga-label="open"
|
||
data-all-citations-url="/24165795/citations/"
|
||
data-citation-style="nlm"
|
||
data-pubmed-format-link="/24165795/export/"><span class="button-label">Cite</span></button><link type="text/css" href="ncbi-overlay-block/src/overlay-block.css"><div class="collections-button-container" data-article-id="24165795" data-article-db="pubmed"><button class="collections-button collections-dialog-trigger"
|
||
aria-label="Save article in MyNCBI collections."
|
||
data-ga-category="collections_button"
|
||
data-ga-action="click"
|
||
data-ga-label="collections_button"
|
||
data-collections-open-dialog-enabled="false"
|
||
data-collections-open-dialog-url="https://account.ncbi.nlm.nih.gov/?back_url=https%3A%2F%2Fpubmed.ncbi.nlm.nih.gov%2F24165795%2F%23open-collections-dialog"
|
||
data-in-collections="false"><span class="button-label">Collections</span></button><div class="overlay" role="dialog"><div id="collections-action-dialog"
|
||
class="dialog collections-dialog"
|
||
aria-hidden="true"><div class="title">Add to Collections</div><div class="collections-action-panel action-panel"><form id="collections-action-dialog-form"
|
||
class="collections-action-panel-form action-panel-content action-form action-panel-smaller-selectors"
|
||
data-existing-collections-url="/list-existing-collections/"
|
||
data-add-to-existing-collection-url="/add-to-existing-collection/"
|
||
data-create-and-add-to-new-collection-url="/create-and-add-to-new-collection/"
|
||
data-myncbi-max-collection-name-length="100"
|
||
data-collections-root-url="https://www.ncbi.nlm.nih.gov/myncbi/collections/"><input type="hidden" name="csrfmiddlewaretoken" value="CNHfJ7h1E0Ub4EaLqRO3gTCgf3YWNc3DTArkmXKneBHFY5gB3ar5K18UN7G8GNBX"><div class="choice-group" role="radiogroup"><ul class="radio-group-items"><li><input type="radio"
|
||
id="collections-action-dialog-new"
|
||
class="collections-new"
|
||
name="collections"
|
||
value="new"
|
||
data-ga-category="collections_button"
|
||
data-ga-action="click"
|
||
data-ga-label="collections_radio_new"><label for="collections-action-dialog-new">Create a new collection</label></li><li><input type="radio"
|
||
id="collections-action-dialog-existing"
|
||
class="collections-existing"
|
||
name="collections"
|
||
value="existing"
|
||
checked="true"
|
||
data-ga-category="collections_button"
|
||
data-ga-action="click"
|
||
data-ga-label="collections_radio_existing"><label for="collections-action-dialog-existing">Add to an existing collection</label></li></ul></div><div class="controls-wrapper"><div class="action-panel-control-wrap new-collections-controls"><label for="collections-action-dialog-add-to-new" class="action-panel-label required-field-asterisk">
|
||
Name your collection:
|
||
</label><input
|
||
type="text"
|
||
name="add-to-new-collection"
|
||
id="collections-action-dialog-add-to-new"
|
||
class="collections-action-add-to-new"
|
||
pattern="[^"&=<>\/]*" title="The following characters are not allowed in the Name field: "&=<>/"
|
||
maxlength="100"
|
||
data-ga-category="collections_button"
|
||
data-ga-action="create_collection"
|
||
data-ga-label="non_favorties_collection"><div class="collections-new-name-too-long usa-input-error-message selection-validation-message">
|
||
Name must be less than 100 characters
|
||
</div></div><div class="action-panel-control-wrap existing-collections-controls"><label for="collections-action-dialog-add-to-existing" class="action-panel-label">
|
||
Choose a collection:
|
||
</label><select id="collections-action-dialog-add-to-existing"
|
||
class="action-panel-selector collections-action-add-to-existing"
|
||
data-ga-category="collections_button"
|
||
data-ga-action="select_collection"
|
||
data-ga-label="($('.collections-action-add-to-existing').val() === 'Favorites') ? 'Favorites' : 'non_favorites_collection'"></select><div class="collections-retry-load-on-error usa-input-error-message selection-validation-message">
|
||
Unable to load your collection due to an error<br><a href="#">Please try again</a></div></div></div><div class="action-panel-actions"><button class="action-panel-submit"
|
||
type="submit"
|
||
data-loading-label="Adding..."
|
||
data-pinger-ignore
|
||
data-ga-category="collections_button"
|
||
data-ga-action="click"
|
||
data-ga-label="add">
|
||
Add
|
||
</button><button class="action-panel-cancel"
|
||
aria-label="Close 'Add to Collections' panel"
|
||
ref="linksrc=close_collections_panel"
|
||
aria-controls="collections-action-panel"
|
||
aria-expanded="false"
|
||
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Dominant-activating germline mutations in the gene encoding the PI(3)K catalytic subunit p110δ result in T cell senescence and human immunodeficiency
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Dominant-activating germline mutations in the gene encoding the PI(3)K catalytic subunit p110δ result in T cell senescence and human immunodeficiency
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</a></sup></span>
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><sup class="key">1</sup> 1] Molecular Development of the Immune System Section, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA. [2].</li>
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<li data-affiliation-id="short-view-affiliation-2"
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id="short-view-affiliation-2"
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><sup class="key">2</sup> 1] Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA. [2].</li>
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<li data-affiliation-id="short-view-affiliation-3"
|
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id="short-view-affiliation-3"
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><sup class="key">3</sup> 1] Cell Signaling Section, Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA. [2] Pritzker School of Medicine, The University of Chicago, Chicago, Illinois, USA. [3].</li>
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<li data-affiliation-id="short-view-affiliation-4"
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id="short-view-affiliation-4"
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><sup class="key">4</sup> Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA.</li>
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<li data-affiliation-id="short-view-affiliation-5"
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id="short-view-affiliation-5"
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><sup class="key">5</sup> 1] Immunology and Immunodeficiency Group, Immunology Program, Garvan Institute of Medical Research, Sydney, Australia. [2] St. Vincent's Clinical School Faculty of Medicine, University of New South Wales, Sydney, Australia.</li>
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><sup class="key">6</sup> Immunology and Immunodeficiency Group, Immunology Program, Garvan Institute of Medical Research, Sydney, Australia.</li>
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id="short-view-affiliation-7"
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><sup class="key">7</sup> Cell Signaling Section, Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.</li>
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<li data-affiliation-id="short-view-affiliation-8"
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id="short-view-affiliation-8"
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><sup class="key">8</sup> Molecular Development of the Immune System Section, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.</li>
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<li data-affiliation-id="short-view-affiliation-9"
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id="short-view-affiliation-9"
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><sup class="key">9</sup> Laboratory of Cell Biology, Division of Monoclonal Antibodies, Office of Biotechnology Products, Center for Drug Evaluation and Research, United States Food and Drug Administration, Bethesda, Maryland, USA.</li>
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id="short-view-affiliation-10"
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><sup class="key">10</sup> Division of Allergy and Immunology, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama, USA.</li>
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id="short-view-affiliation-11"
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><sup class="key">11</sup> 1] Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA. [2] Laboratory of Clinical Infectious Diseases, Clinical Research Directorate-Clinical Monitoring Research Program, Science Applications International Corporation-Frederick, Frederick National Laboratory for Clinical Research, Frederick, Maryland, USA.</li>
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><sup class="key">12</sup> Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.</li>
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<li data-affiliation-id="short-view-affiliation-13"
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id="short-view-affiliation-13"
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><sup class="key">13</sup> Radiology and Imaging and Sciences, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA.</li>
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|
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id="short-view-affiliation-14"
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><sup class="key">14</sup> Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.</li>
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|
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id="short-view-affiliation-15"
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><sup class="key">15</sup> Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.</li>
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<li data-affiliation-id="short-view-affiliation-16"
|
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id="short-view-affiliation-16"
|
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><sup class="key">16</sup> Instituto de Medicina Integral Prof. Fernando Figueira, Recife-Pernambuco, Brazil.</li>
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The p110δ subunit of phosphatidylinositol-3-OH kinase (PI(3)K) is selectively expressed in leukocytes and is critical for lymphocyte biology. Here we report fourteen patients from seven families who were heterozygous for three different germline, gain-of-function mutations in PIK3CD (which encodes p110δ). These patients presented with sinopulmonary infections, lymphadenopathy, nodular lymphoid hyperplasia and viremia due to cytomegalovirus (CMV) and/or Epstein-Barr virus (EBV). Strikingly, they had a substantial deficiency in naive T cells but an over-representation of senescent effector T cells. In vitro, T cells from patients exhibited increased phosphorylation of the kinase Akt and hyperactivation of the metabolic checkpoint kinase mTOR, enhanced glucose uptake and terminal effector differentiation. Notably, treatment with rapamycin to inhibit mTOR activity in vivo partially restored the abundance of naive T cells, largely 'rescued' the in vitro T cell defects and improved the clinical course.
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<strong class="figure-label">
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<p> Figure 1. A novel primary immunodeficiency characterized… </p>
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<p> Figure 1. A novel primary immunodeficiency characterized by T and B cell accumulation with lymphoid… </p>
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Figure 1. A novel primary immunodeficiency characterized by T and B cell accumulation with lymphoid nodules and defective memory cell populations
|
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<div class="figure-caption-contents"><b>(a)</b> Endoscopic imaging reveals nodules in airways (top, patient E.1) and gastrointestinal tract (bottom, patient A.1) with lymphocytic infiltrates. Data are representative of 6 patients examined. <b>(b)</b> H & E staining of histological sections of a lymphoma biopsy from patient F.II.1 reveals a nodular sclerosis form of classical Hodgkin lymphoma (top); LMP-1 stain revealed EBV latent membrane antigen (brown coloration, 3,3’-Diaminobenzidine) (bottom). <b>(c)</b> Hematoxylin and eosin (H & E) staining (i) and immunoperoxidase staining for IgG (ii) and IgM (iii) on histological sections of lymph node from patient G.1. <b>(d)</b> The proportion (numbers in quadrants are percentages) of transitional (CD10<sup>+</sup>CD27<sup>−</sup>), naïve (CD10<sup>−</sup>CD27<sup>−</sup>) and memory (CD10<sup>−</sup>CD27<sup>+</sup>) cells within the B-cell population of a healthy control (Ctrl, top left) or patient B.III.1 (top right). Representative of 4 independent experiments. Each symbol in the bottom graphs shows cumulative data for memory (bottom left, <i>P</i> = 0.004 by two-tailed, unpaired <i>t</i>-test) and transitional (bottom right, <i>P</i> = 0.0005 by two-tailed, unpaired <i>t</i>-test) B cells represents an individual healthy control (Ctrl, <i>n</i> = 6) or patient (Pt, <i>n</i> = 7), and the horizontal bars represent means. Peripheral blood CD4<sup>+</sup> T cell counts <b>(e)</b> and CD8<sup>+</sup> T cell counts <b>(f)</b> in indicated patients as a function of age in years over time in all nine patients. <b>(g)</b> Thymidine incorporation assay for proliferation in response to the tetanus recall antigen, comparing normal controls (<i>n</i> = 9) and patients (<i>n</i> =9) and showing mean and standard deviation as horizontal lines. Data are cumulative from 9 independent experiments. SI = stimulation index of the value with antigen divided by that with no antigen. <i>P</i> = 0.01 by Mann-Whitney test. <b>(h)</b> Composite graph showing T<sub>naive</sub> (CD45RA<sup>+</sup>CD62L<sup>+</sup>), T<sub>CM</sub> (CD45RA<sup>−</sup>CD62L<sup>+</sup>), T<sub>EM</sub> (CD45RA<sup>−</sup>CD62L<sup>−</sup>), and T<sub>EMRA</sub> (CD45RA<sup>+</sup>CD62L<sup>−</sup>) populations among CD8<sup>+</sup> T cells in all living patients (Pt, <i>n</i> = 11) compared to the clinical normal range derived from 50 healthy controls (Ctrl). <b>(i)</b> Representative flow cytometric dot plots of PBMCs from patient G.1 or a health control (Ctrl) stained for CD8<sup>+</sup> versus CD4<sup>+</sup> T cells (gated on lymphocytes, top) or CCR7 versus CD45RA gated on CD4<sup>+</sup> (middle) or CD8<sup>+</sup> (bottom) lymphocytes, showing T<sub>naive</sub> (CD45RA<sup>+</sup>CCR7<sup>+</sup>), T<sub>CM</sub> (CD45RA<sup>−</sup>CCR7<sup>+</sup>), T<sub>EM</sub> (CD45RA<sup>−</sup>CCR7<sup>−</sup>), and T<sub>EMRA</sub> (CD45RA<sup>+</sup>CCR7<sup>−</sup>) populations. Events falling into each quadrant are given as a percentage of the total. Data are representative of 5 independent experiments on multiple patients (see Supplementary Fig. 1D).</div>
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<strong class="figure-label">
|
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<p> Figure 2. Heterozygous, gain-of-function mutation in PIK3CD… </p>
|
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<strong class="figure-label">
|
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<p> Figure 2. Heterozygous, gain-of-function mutation in PIK3CD in all affected individuals causes AKT hyperphosphorylation </p>
|
||
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|
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|
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<div class="figure-caption-contents"><b> (a)… </b></div>
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<strong class="figure-label">
|
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Figure 2. Heterozygous, gain-of-function mutation in PIK3CD in all affected individuals causes AKT hyperphosphorylation
|
||
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|
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|
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<div class="figure-caption-contents"><b>(a)</b> Schematic of p110δ protein domains (as described in the text) with patient mutations labeled with red lines. <b>(b)</b> Location of patient mutations (green spheres) shown on the structure (PDB 3HHM) of human p110α H1047R mutant (blue) in complex with p85α (pink). Positively charged amino acids along the membrane-binding face of p110 are shown as grey sticks. Location of the p110αH1047R mutation indicated by grey sticks. <b>(c)</b> Pedigrees of affected families with mutation-positive (black), unaffected (white), unscreened (grey), and deceased (diagonal) individuals. <b>(d)</b> Immunoblot on serum-starved, activated T cells using antibodies for p110δ, Akt, p-Akt (S473), and β-tubulin as indicated for patients D.II.1, D.II.2, and E.1 compared to three normal controls (Ctrl) with 10 min anti-CD3 stimulation (+) or not (−). Data are quantified in Supplementary Fig. 4A and are representative of p-Akt (S473) results from 4 independent experiments. <b>(e)</b> Immunoblot for Flag, p-Akt (S473), and total Akt on lysates from unactivated healthy control PBMCs overexpressing empty vector (EV), WT p110δ, or mutant p110δ 16 hr post-transfection. Data are representative of 3 independent experiments that were quantified in Supplementary Fig. 4F.</div>
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<p> Figure 3. Patient PBMCs contain virus-specific CD8… </p>
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<p> Figure 3. Patient PBMCs contain virus-specific CD8 T cells but fail to proliferate upon TCR… </p>
|
||
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<strong class="figure-label">
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Figure 3. Patient PBMCs contain virus-specific CD8 T cells but fail to proliferate upon TCR stimulation in vitro due to terminal differentiation and senescence
|
||
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|
||
|
||
|
||
|
||
<div class="figure-caption-contents"><b>(a)</b> Flow cytometry analysis of EBV-specific tetramer staining of patient G.1 and control PBMCs for detection of EBV lytic and latent antigen-specific CD8<sup>+</sup> T cells. Numbers in quadrants represent the percentage of total. Data are representative of 4 independent experiments. <b>(b)</b> CFSE dilution on gated CD8<sup>+</sup> T cells for patients A.1 or B.III.1 compared to control 72 hrs after stimulation of PBMCs with the indicated mitogen. PHA = phytohemagglutinin. The percentage of cells that have divided is indicated. Data are representative of 8 patients examined in 6 independent experiments. <b>(c)</b> IL-2 secretion 48–72 hrs after activation of PBMCs from normals (<i>n</i> = 13 from combined experiments) and patients (<i>n</i> = 13 from combined experiments) with anti-CD3/CD28 Dynabeads. Horizontal line indicates mean value, and <i>P</i> = 0.0006 by Mann Whitney test. Data are representative of 4 independent experiments. <b>(d)</b> Intracellular flow cytometry for IFN-γ production and T-bet expression in activated CD8<sup>+</sup> T cells stimulated with low-dose, immobilized anti-CD3. Numbers in quadrants represent the percentage of total. Data are quantified in Supplementary Fig. 5D and are representative of 3 independent experiments. <b>(e)</b> Granzyme B expression in activated CD8<sup>+</sup> T cells from patients A.1 and G.1 compared to control. Combined data from independent experiments are quantified in Supplementary Fig. 5E. <b>(f)</b> Flow cytometric measurement of LAMP-1 cycling in unstimulated (US) or stimulated (as indicated) CD8<sup>+</sup> T cells from patients (Pt, <i>n</i> = 4) compared to healthy controls (Ctrl, <i>n</i> = 3). Patients include A.1, E.1, F.II.1, and G.1. Horizontal line indicates mean value, and <i>P</i> = 0.01 obtained using the unpaired, two-tailed <i>t</i>-test. Data are representative of 3 independent experiments. <b>(g)</b> CD57 expression on CD4<sup>+</sup> (left) or CD8<sup>+</sup> (right) T cells from patient B.III.1 compared to healthy control (Ctrl). Data are representative of 4 patients examined in 3 independent experiments, which are quantified in Supplementary Fig. 5H.</div>
|
||
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<p> Figure 4. Patient T cells exhibit normal… </p>
|
||
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|
||
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<p> Figure 4. Patient T cells exhibit normal TCR signaling responses but elevated mTOR activity and… </p>
|
||
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|
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<strong class="figure-label">
|
||
Figure 4. Patient T cells exhibit normal TCR signaling responses but elevated mTOR activity and glucose uptake in vitro
|
||
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|
||
|
||
|
||
|
||
<div class="figure-caption-contents"><b>(a)</b> Calcium flux (as measured by the ratio of Fluo-4 to FuraRed) induced by anti-CD3 stimulation in T cell blasts from patients A.1, E.1, and F.II.1 compared to controls. The calcimycin ionophore shows is used as a positive control. Data are representative of 2 independent experiments examining cells from 5 different patients. <b>(b)</b> Confocal microscopy showing NF-κB p65 (green, left panels) translocation into the nucleus stained by 4’,6-Diamidino-2-Phenylindole, Dihydrochloride (DAPI, blue, colors merged right panels) in serum-starved T cell blasts following TCR stimulation (+) or not (−). Data are representative of 3 patients examined. <b>(c)</b> Phosflow analysis for phosphorylation of S6 (at residues S235 and S236) in unstimulated T cell blasts (fixed in complete medium) from patients G.1, D.II.1, and D.II.2 compared to controls. Data are representative of 3 independent experiments and are quantified in Supplementary Fig. 8A. <b>(d)</b> Phosflow analysis of S6 phosphorylation at S235, S236 at baseline (0 min) and 10 min or 20 min after stimulation with anti-CD3 plus protein A for patient G.1 (blue) and a healthy control (red). Data are representative of 2 independent experiments. <b>(e)</b> Phosflow analysis of S6 phosphorylation at residues S240 and S244 in unstimulated T cell blasts from patient F.II.1 treated for 20 min with DMSO, 10 µM IC87114 (p110δ inhibitor), or 50 nM rapamycin (mTOR inhibitor) compared to healthy control (Ctrl). Data are representative of 3 independent experiments. <b>(f)</b> Glucose uptake measured by flow cytometry analysis of the fluorescent deoxyglucose analog 2-NBDG in glucose-starved T cell blasts from patient G.1 compared to control (Ctrl). Data are representative of 4 experiments with a quantified analysis shown in Supplementary Fig. 8C. <b>(g)</b> Positron Emission Tomography (PET) scan of patient G.1 following administration of 18F-fludeoxyglucose analog shows glucose uptake most pronounced in the iliac chains and inguinal regions bilaterally. Data are representative of 3 patients examined.</div>
|
||
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|
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|
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|
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|
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|
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|
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||
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|
||
<strong class="figure-label">
|
||
<p> Figure 5. <i> In vivo </i> rapamycin treatment improves… </p>
|
||
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|
||
|
||
|
||
|
||
|
||
|
||
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|
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||
<strong class="figure-label">
|
||
<p> Figure 5. <i> In vivo </i> rapamycin treatment improves <i> in vitro </i> and <i> in vivo </i> disease phenotypes </p>
|
||
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|
||
|
||
|
||
|
||
<div class="figure-caption-contents"><b> (a)… </b></div>
|
||
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||
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||
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||
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||
<strong class="figure-label">
|
||
Figure 5. <i>In vivo</i> rapamycin treatment improves <i>in vitro</i> and <i>in vivo</i> disease phenotypes
|
||
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|
||
|
||
|
||
|
||
<div class="figure-caption-contents"><b>(a)</b> CD4<sup>+</sup> and CD8<sup>+</sup> T cell counts from patient A.1 before and after rapamycin treatment. Dotted lines represent the range of T cell counts for normal controls. <b>(b)</b> PBMCs from patient A.1 before (UT, untreated) and after <i>in vivo</i> rapamycin treatment (Rapa) displaying CD8<sup>+</sup> versus CD4<sup>+</sup> (CD3<sup>+</sup> gate, top) and CD62L versus CD45RA (CD4<sup>+</sup> gate, middle, or CD8<sup>+</sup> gate, bottom). Numbers in quadrants represent the percentage of total. <b>(c)</b>
|
||
<i>In vitro</i> IL-2 production measured by Luminex after 24-hr activation (anti-CD3/CD28 Dynabeads) of PMBCs from an untreated normal control (<i>n</i> = 5) or patient A.1 before (UT, <i>n</i> = 3 independent measurements) rapamycin treatment (Rapa, left) and after (<i>n</i> = 2 independent measurements, right). Horizontal line indicates mean value, and <i>P</i> = 0.04 by the Mann-Whitney test. <b>(d)</b> Cell proliferation measured by CFSE dilution 72 hrs after activation (red) or not (black) of patient or control PBMCs with the indicated stimulus, shown before (UT, top) and after (bottom) <i>in vivo</i> treatment of patient A.1 with rapamycin (Rapa). The percentage of cells that have divided is shown.</div>
|
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<p> Figure 6. Proposed model of effects of… </p>
|
||
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|
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<p> Figure 6. Proposed model of effects of activating mutations (red asterisk) in p110δ </p>
|
||
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|
||
|
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|
||
|
||
<div class="figure-caption-contents"><p> Augmented PI(3)K… </p></div>
|
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Figure 6. Proposed model of effects of activating mutations (red asterisk) in p110δ
|
||
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|
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||
|
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|
||
<div class="figure-caption-contents">Augmented PI(3)K signaling results in increased glycolysis, causing CD8<sup>+</sup> T cells to differentiate into effector cells that proliferate vigorously and then senesce. This results in impaired generation of long-lived memory CD8<sup>+</sup> T cells and, consequently, poor control of EBV and CMV infection.</div>
|
||
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<span class="docsum-authors full-authors">Dulau Florea AE, Braylan RC, Schafernak KT, Williams KW, Daub J, Goyal RK, Puck JM, Rao VK, Pittaluga S, Holland SM, Uzel G, Calvo KR.</span>
|
||
|
||
|
||
|
||
<span class="docsum-authors short-authors">Dulau Florea AE, et al.</span>
|
||
<span class="docsum-journal-citation full-journal-citation">J Allergy Clin Immunol. 2017 Mar;139(3):1032-1035.e6. doi: 10.1016/j.jaci.2016.08.028. Epub 2016 Sep 30.</span>
|
||
<span class="docsum-journal-citation short-journal-citation">J Allergy Clin Immunol. 2017.</span>
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<span class="citation-part">PMID: <span class="docsum-pmid">27697496</span></span>
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<span class="free-resources spaced-citation-item citation-part">Free PMC article.</span>
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Okkenhaug K, Vanhaesebroeck B. PI3K in lymphocyte development, differentiation and activation. Nat. Rev. Immunol. 2003;3:317–330.
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Hemmings BA, Restuccia DF. PI3K-PKB/Akt pathway. Cold Spring Harb Perspect Biol. 2012;4:a011189.
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Chantry D, et al. p110delta, a novel phosphatidylinositol 3-kinase catalytic subunit that associates with p85 and is expressed predominantly in leukocytes. J. Biol. Chem. 1997;272:19236–19241.
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