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</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%2F38826230%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%2F38826230%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="oKjJi0QyY4ZXkj2mVa4FWoSYdOQx8zUhFx3OVQjUyFMreK8cytHHqwoCLSyJ1asB">
|
||
</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="oKjJi0QyY4ZXkj2mVa4FWoSYdOQx8zUhFx3OVQjUyFMreK8cytHHqwoCLSyJ1asB">
|
||
|
||
|
||
|
||
<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="oKjJi0QyY4ZXkj2mVa4FWoSYdOQx8zUhFx3OVQjUyFMreK8cytHHqwoCLSyJ1asB">
|
||
|
||
<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: 38826230 - PubMed</span>
|
||
<input type="hidden" name="email-subject" value="1 selected item: 38826230"/>
|
||
<input type="hidden" name="email-subject-hash" value="d993fffb7311060b62a8ea100481715c55f991049fefbe0ffba414facb3f0997"/>
|
||
</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="oKjJi0QyY4ZXkj2mVa4FWoSYdOQx8zUhFx3OVQjUyFMreK8cytHHqwoCLSyJ1asB">
|
||
|
||
|
||
|
||
<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="oKjJi0QyY4ZXkj2mVa4FWoSYdOQx8zUhFx3OVQjUyFMreK8cytHHqwoCLSyJ1asB">
|
||
|
||
|
||
|
||
<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="oKjJi0QyY4ZXkj2mVa4FWoSYdOQx8zUhFx3OVQjUyFMreK8cytHHqwoCLSyJ1asB">
|
||
|
||
<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="oKjJi0QyY4ZXkj2mVa4FWoSYdOQx8zUhFx3OVQjUyFMreK8cytHHqwoCLSyJ1asB">
|
||
|
||
|
||
|
||
<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="oKjJi0QyY4ZXkj2mVa4FWoSYdOQx8zUhFx3OVQjUyFMreK8cytHHqwoCLSyJ1asB">
|
||
|
||
<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="38826230">
|
||
<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/10.1101/2024.05.22.595315"
|
||
target="_blank"
|
||
rel="noopener"
|
||
|
||
ref="linksrc=fulltextorjournal_fulltext&is_pmc=False&PrId=7368&itool=Abstract-def&log$=linkouticon&uid=38826230&db=pubmed&nlmid=101680187"
|
||
title="See full text options at Cold Spring Harbor Laboratory"
|
||
|
||
data-ga-category="full_text"
|
||
data-ga-action="Cold Spring Harbor Laboratory"
|
||
data-ga-label="38826230"
|
||
><img src="https://cdn.ncbi.nlm.nih.gov/corehtml/query/egifs/https:--biorxiv.s3.amazonaws.com-bioRxiv_link_icon.gif" alt="Cold Spring Harbor Laboratory full text link"><span class="text">
|
||
|
||
Cold Spring Harbor Laboratory
|
||
|
||
</span></a><a class="link-item
|
||
pmc
|
||
"
|
||
href="https://pmc.ncbi.nlm.nih.gov/articles/pmid/38826230/"
|
||
target="_blank"
|
||
rel="noopener"
|
||
|
||
ref="linksrc=fulltextorjournal_fulltext&is_pmc=True&PrId=3494&itool=Abstract-def&log$=linkouticon&uid=38826230&db=pubmed&nlmid=101680187"
|
||
title="Free full text at PubMed Central"
|
||
|
||
data-ga-category="full_text"
|
||
data-ga-action="PMC"
|
||
data-ga-label="38826230"
|
||
><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="/38826230/citations/"
|
||
data-citation-style="nlm"
|
||
data-pubmed-format-link="/38826230/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="38826230" 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%2F38826230%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="oKjJi0QyY4ZXkj2mVa4FWoSYdOQx8zUhFx3OVQjUyFMreK8cytHHqwoCLSyJ1asB"><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"
|
||
data-ga-category="collections_button"
|
||
data-ga-action="click"
|
||
data-ga-label="cancel">
|
||
Cancel
|
||
</button></div></form></div></div></div></div><button class="more-actions-button more-actions-dialog-trigger"
|
||
title="Open dialog with more actions to take"
|
||
ref="linksrc=more_actions_btn"></button><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="sidebar-actions-display-format"><option value="abstract">Abstract</option><option value="pubmed">PubMed</option><option value="pmid">PMID</option></select></div></div></div></div></div></div>
|
||
|
||
<div class="social-sharing">
|
||
<h3 class="title">
|
||
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</a></li></ul></div></div></div><span class="preprint"> [Preprint]</span><span class="period">. </span><span class="cit">2024 May 26:2024.05.22.595315.</span>
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Granzyme K drives a newly-intentified pathway of complement activation
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Granzyme K drives a newly-intentified pathway of complement activation
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</a><span class="author-sup-separator"> </span><a class="affiliation-link" title="Department of Biomedical Informatics, Harvard Medical School, Boston, MA USA." href="#short-view-affiliation-7" ref="linksrc=author_aff">
|
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</a><span class="author-sup-separator"> </span><a class="affiliation-link" title="Center for Data Sciences, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA, USA." href="#short-view-affiliation-8" ref="linksrc=author_aff">
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><sup class="key">3</sup> Current affiliation: Division of Rheumatology and the Center for Health Artificial Intelligence, University of Colorado School of Medicine, Aurora, CO, USA.</li>
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Granzymes are a family of serine proteases mainly expressed by CD8<sup>+</sup> T cells, natural killer cells, and innate-like lymphocytes<sup>1,2</sup>. Although their major role is thought to be the induction of cell death in virally infected and tumor cells, accumulating evidence suggests some granzymes can regulate inflammation by acting on extracellular substrates<sup>2</sup>. Recently, we found that the majority of tissue CD8<sup>+</sup> T cells in rheumatoid arthritis (RA) synovium, inflammatory bowel disease and other inflamed organs express granzyme K (GZMK)<sup>3</sup>, a tryptase-like protease with poorly defined function. Here, we show that GZMK can activate the complement cascade by cleaving C2 and C4. The nascent C4b and C2a fragments form a C3 convertase that cleaves C3, allowing further assembly of a C5 convertase that cleaves C5. The resulting convertases trigger every major event in the complement cascade, generating the anaphylatoxins C3a and C5a, the opsonins C4b and C3b, and the membrane attack complex. In RA synovium, GZMK is enriched in areas with abundant complement activation, and fibroblasts are the major producers of complement C2, C3, and C4 that serve as targets for GZMK-mediated complement activation. Our findings describe a previously unidentified pathway of complement activation that is entirely driven by lymphocyte-derived GZMK and proceeds independently of the classical, lectin, or alternative pathways. Given the widespread abundance of <i>GZMK</i>-expressing T cells in tissues in chronic inflammatory diseases and infection, GZMK-mediated complement activation is likely to be an important contributor to tissue inflammation in multiple disease contexts.
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<div class="figure-caption-contents"><b>a,</b> Representative flow cytometry gating of the T cell and NK cell subsets presented in Fig. 1a,b. <b>b,</b> Expression of T cell subset markers CCR7 and CD45RA by GZMK<sup>+</sup> CD4<sup>+</sup> and CD8<sup>+</sup> T cells, respectively. Data are mean ± s.d. <b>c,</b> Representative flow cytometry gating of CD4<sup>+</sup> and CD8<sup>+</sup> T cells in disaggregated RA synovial tissue presented in Figure 1d,e (<i>n</i> = 10). <b>d,</b> Expression of selected markers in UMAP space for the integrative dataset presented in Fig. 1g.</div>
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<p> Extended Data Fig. 2 |. <i> GZMK </i> is expressed by CD8 <sup> + </sup> T cells in many… </p>
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|
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<div class="figure-caption-contents"><b>a,</b> Contribution of each of the six publicly available single-cell RNA-seq datasets to the integrated dataset of CD4<sup>+</sup>, CD8<sup>+</sup>, and NK cell profiles. <b>b,</b> Expression levels of selected genes by cell profiles the integrative dataset in UMAP space. <b>c,</b> Percentage of cells in all CD4<sup>+</sup> T cell clusters (gray columns) or all CD8<sup>+</sup>T cell clusters (blue columns) with detectable <i>GZMB</i> gene expression, stratified by tissue and disease source.</div>
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alt="Extended Data Fig. 3 |" />
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<p> Extended Data Fig. 3 |. TCR stimulation… </p>
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<strong class="figure-label">
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<p> Extended Data Fig. 3 |. TCR stimulation decreases intracellular GZMK protein expression but increases GZMB… </p>
|
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</strong>
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<strong class="figure-label">
|
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Extended Data Fig. 3 |. TCR stimulation decreases intracellular GZMK protein expression but increases GZMB in CD8<sup>+</sup> T cells.
|
||
</strong>
|
||
|
||
|
||
|
||
<div class="figure-caption-contents"><b>a,</b> Flow cytometry plots showing intracellular GZMK and GZMB staining among CD8<sup>+</sup> T cells from the donors used for the immunoblot shown in Fig. 3a. <b>b,c,</b> Representative flow cytometry plots and aggregate data showing frequency of intracellular GZMK and GZMB staining among purified primary human CD8<sup>+</sup> T cells cultured either in media alone (unstimulated) or with anti-CD3/CD28 antibody-coated beads for four days. Data in <b>c</b> show mean ± s.d. of four donors from a representative out of four independent experiments.</div>
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data-figure-id="F9">
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src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/70ef/11142156/5788d1bcd70d/nihpp-2024.05.22.595315v1-f0009.gif"
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<strong class="figure-label">
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<p> Extended Data Fig. 4 |. GZMK is… </p>
|
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<strong class="figure-label">
|
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<p> Extended Data Fig. 4 |. GZMK is highly homologous to complement factor D but does… </p>
|
||
</strong>
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<strong class="figure-label">
|
||
Extended Data Fig. 4 |. GZMK is highly homologous to complement factor D but does not cleave factor B or C3 directly.
|
||
</strong>
|
||
|
||
|
||
|
||
<div class="figure-caption-contents"><b>a,</b> Results of a protein blast comparing the protein sequence of GZMK to all human protein sequences. <b>b,</b> Serum-purified complement factor B (CFB) was incubated with either complement factor D (CFD) or increasing concentrations of GZMK in the presence or absence of C3b and cleavage products were analyzed by immunoblot. Serum-purified Bb was used as a control to identify cleavage of CFB into Bb. <b>c,</b> Serum-purified C3 was incubated with GZMK and cleavage products were assessed by immunoblot. As a positive control for C3 cleavage, C3 was incubated with C3b + CFB + CFD in the presence of increasing concentrations of properdin. Serum-purified C3b was used to confirm the presence of the C3b cleaved fragment. (<b>b,c)</b> Data are representative of three independent experiments.</div>
|
||
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data-image-alt="Extended Data Fig. 5 |"
|
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|
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data-figure-id="F10">
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id="article-image-4"
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src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/70ef/11142156/a6594b9e7deb/nihpp-2024.05.22.595315v1-f0010.gif"
|
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|
||
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||
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|
||
<strong class="figure-label">
|
||
<p> Extended Data Fig. 5 |. GZMK binds… </p>
|
||
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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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||
|
||
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||
|
||
|
||
<strong class="figure-label">
|
||
<p> Extended Data Fig. 5 |. GZMK binds plasma membranes to trigger formation of membrane-bound C3… </p>
|
||
</strong>
|
||
|
||
|
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|
||
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|
||
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||
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|
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|
||
|
||
|
||
<strong class="figure-label">
|
||
Extended Data Fig. 5 |. GZMK binds plasma membranes to trigger formation of membrane-bound C3 and C5 convertases.
|
||
</strong>
|
||
|
||
|
||
|
||
<div class="figure-caption-contents"><b>a</b>, HUVEC cells, synovial fibroblasts, and THP-1 monocytes were left untreated or were treated with an isotype control or a cell-type specific sensitizing antibody (anti-HLA-A/B/ for fibroblasts, anti-CD31 for HUVEC and THP-1 cells). Cells were then incubated with either C1s or the C1 complex and surface C1s was measured by flow cytometry. <b>b</b>, HUVEC cells were incubated for 4 hours with serum-purified C2 + C3 + C4 alone or in combination with GZMK or GZMA, and C3b deposition was measured by flow cytometry. Histograms depict representative data. Aggregate data is shown in Fig. 4c. <b>c</b>, HUVEC cells were incubated for 4 hours with serum-purified C2 + C3 + C4 alone or in combination with GZMK in the presence or absence of heparin and surface-bound GZMK and C3b were measured by flow cytometry. Aggregate data is shown in Fig. 4d. <b>d</b>, C5aR1-expressing Chem-1 reporter cells labeled with Fluo-5F were incubated with C5, C5a, or the supernatants obtained after incubating HUVEC cells with C2 + C3 + C4 + C5 with or without GZMA or GZMK. Calcium flux was immediately assessed by flow cytometry. Aggregate data is shown in Fig. 4g. <b>e</b>, HUVEC cells were incubated with serum-purified C2 + C3 + C4 + C5 + C6 + C7 + C8 + C9 with increasing amounts of GZMK or GZMA in the presence of dynasore to inhibit endocytosis. C5,b-9 was used as the positive control. Terminal complement complex formation (TCC) was then measured by flow cytometry. <b>f,</b> Surface deposition of C3b (left), C4d (middle), and TCC formation (right) on HUVEC cells after incubation with C1q-depleted serum and increasing concentrations of GZMK, as measured by flow cytometry. NHS was used as a positive control. Histograms depict representative data. Aggregate data is shown in Fig. 4i. (<b>a-e</b>) Data are representative of at least three independent experiments. (<b>e</b>) Data are mean ± s.d of three independent experiments. <i>P</i> values were calculated using one-way analysis of variance (ANOVA) with Dunnett’s multiple comparisons tests. *P < 0.05, **P < 0.01, NS = not significant.</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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|
||
data-image-alt="Extended Data Fig. 6 |"
|
||
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|
||
data-figure-id="F11">
|
||
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|
||
id="article-image-5"
|
||
src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/70ef/11142156/48cf79175a88/nihpp-2024.05.22.595315v1-f0011.gif"
|
||
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|
||
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|
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|
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|
||
|
||
|
||
|
||
|
||
|
||
<strong class="figure-label">
|
||
<p> Extended Data Fig. 6 |. The complement… </p>
|
||
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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> Extended Data Fig. 6 |. The complement activation products C3d and C5a are abundant in… </p>
|
||
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|
||
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|
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|
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<strong class="figure-label">
|
||
Extended Data Fig. 6 |. The complement activation products C3d and C5a are abundant in areas rich in GZMK in RA synovial tissue.
|
||
</strong>
|
||
|
||
|
||
|
||
<div class="figure-caption-contents"><b>a</b>, Representative image showing immunofluorescence staining of RA synovial tissue with antibodies against C3d (clone C3D/2891, yellow in top composite), C5a (clone 2952, yellow in bottom composite), and GZMK (red) as well as Hoechst nuclear stain (blue). The area inside the dashed box is shown enlarged in Fig. 5. Scale bar is 50 microns. <b>b</b>, Representative image showing immunofluorescence staining of RA synovial tissue with antibodies against GZMK (red) and C3d (clone 7C10, yellow) as well as Hoechst nuclear stain (blue). Scale bar is 50 microns. <b>c</b>, Enlarged view of area inside box in panel a. Scale bar is 25 microns. <b>d</b>, Representative image showing immunofluorescence staining of RA synovial tissue with antibodies against GZMK (red) and C5a (clone 2942, yellow) as well as Hoechst nuclear stain (blue). Scale bar is 50 microns. <b>e</b>, Enlarged view of area inside box in panel a. Scale bar is 25 microns. All images in this panel are tiled images collected on a confocal microscope. Data are representative of (<b>a-c</b>) three and (<b>d,e</b>) two independent experiments.</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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|
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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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|
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<strong class="figure-label">
|
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<p> Extended Data Fig. 7 |. GZMK activates… </p>
|
||
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|
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|
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<strong class="figure-label">
|
||
<p> Extended Data Fig. 7 |. GZMK activates the entire complement cascade. </p>
|
||
</strong>
|
||
|
||
|
||
|
||
<div class="figure-caption-contents"><b> a. </b> Model for GZMK-mediated…</div>
|
||
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<strong class="figure-label">
|
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Extended Data Fig. 7 |. GZMK activates the entire complement cascade.
|
||
</strong>
|
||
|
||
|
||
|
||
<div class="figure-caption-contents"><b>a.</b> Model for GZMK-mediated complement activation. <i>GZMK</i>-expressing CD8<sup>+</sup> T cells constitutively release GZMK in the absence of TCR stimulation. Secreted GZMK can bind plasma membranes likely by interacting with heparan sulfate glycosaminoglycans, where it cleaves C4 and C2 generating C4b and C2a. Due to its close proximity to the membrane, newly-cleaved C4b molecules can covalently bind membranes through their exposed thioester, associate with C2a, and form membrane-bound C3 convertases. These C3 convertases can cleave C3 into C3a and C3b. Nascent C3b molecules can opsonize target cells or associate with membrane-bound C3 convertases to form C5 convertases that can cleave C5 into C5a and C5b. C5b molecules associate with C6, C7, C8, and C9 to form a membrane attack complex (MAC) or terminal complement complex (TCC). <b>b.</b> Comparison between the alternative, classical, lectin, and GZMK-mediated pathways of complement activation. Complement activation occurs most efficiently on membranes. Soluble pattern recognition receptors like C1q and mannose-binding lectin initiate this process after recognizing danger signals on a surface. This first step results in the activation of initiator proteases like C1s and MASP1, which cleave the complement components C4 and C2. GZMK can direct complement activation to surfaces independently of soluble pattern recognition receptors due to its intrinsic ability to bind negatively charged molecules such as heparan sulfate glycosaminoglycans. Much like C1s, MASP1/2, and CFD, GZMK acts as an initiator protease that cleaves C4 and C2 into C4b and C2a. In the second step, C4b and C2a assemble at the membrane to form active C3 convertases that cleave C3 into C3a and C3b. In the third step, nascent C3b molecules join pre-existing C3 convertases to form C5 convertases that cleave C5 into C5a and C5b, with the latter associating with C6–9 to assemble the TCC/MAC.</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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|
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|
||
<strong class="figure-label">
|
||
<p> Fig. 1 |. GZMK is expressed by… </p>
|
||
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|
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|
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|
||
<strong class="figure-label">
|
||
<p> Fig. 1 |. GZMK is expressed by CD8 <sup> + </sup> T cells, NK cells, and innate-like… </p>
|
||
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|
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Fig. 1 |. GZMK is expressed by CD8<sup>+</sup> T cells, NK cells, and innate-like T cells in blood and tissues.
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<div class="figure-caption-contents"><b>a,</b> Representative flow cytometry plots showing intracellular GZMK and GZMB staining of the indicated T cell or NK cell subset in healthy peripheral blood. <b>b,</b> Frequency of GZMK expression by the indicated T cell or NK cell subset in peripheral blood from healthy controls. <b>c,</b> Among all GZMK<sup>+</sup> lymphocytes in blood, percentage belonging to each T cell or NK cell subset. In panels b and c, <i>n</i> = 10 for CD4<sup>+</sup> T cells; <i>n</i> = 15 for all other populations. <b>d,e,</b> Representative flow plots and aggregate data showing expression of GZMK protein, as measured by intracellular flow cytometry of unstimulated CD4<sup>+</sup> or CD8<sup>+</sup> T cells from synovial tissue collected from patients with RA (<i>n</i> = 10). <b>f</b>, Representative image showing immunofluorescent staining of RA synovial tissue is shown. Arrowheads indicate examples of GZMK<sup>+</sup> T cells. Data are representative of at least three independent experiments. <b>g,</b> UMAP plots displaying single-cell RNA-seq profiles from 94,056 T cells and 8,497 NK cells from synovial tissue from patients with RA (<i>n</i> = 70) or OA (<i>n</i> = 9) shaded by expression of the indicated protein marker or gene transcript. <b>h,</b> UMAP plot of Louvain clustering of 85,522 integrated single-cell RNA-seq profiles from T cells and NK cells from healthy or diseased tissues from RA synovium, Crohn’s disease (CD) ileum, ulcerative colitis colon, lupus nephritis (SLE) kidney, and COVID-19 BALF. Expression patterns of selected genes are shown for the integrative dataset in UMAP space. <b>i</b>, Percentage of cells in CD4<sup>+</sup> T cell clusters (gray columns) or CD8<sup>+</sup> T cell clusters (blue columns) with detectable <i>GZMK</i> gene expression, stratified by tissue and disease source. (<b>b,c,e)</b> Data are mean ± s.d.</div>
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<p> Fig. 2 |. GZMK cleaves the complement… </p>
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<p> Fig. 2 |. GZMK cleaves the complement components C4 and C2 to generate a C3… </p>
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Fig. 2 |. GZMK cleaves the complement components C4 and C2 to generate a C3 convertase that cleaves C3 into C3a and C3b.
|
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<div class="figure-caption-contents"><b>a,</b> Bulk CD8<sup>+</sup> T cells were MACS sorted from peripheral blood of two donors and either left unstimulated or stimulated with anti-CD3/CD28 dynabeads for 6, 24, or 48 hours. Precipitated supernatants and lysates were analyzed by immunoblot using antibodies against GZMK and GZMB. <b>b,</b> Increasing concentrations of active GZMK or GZMA were incubated with serum-purified C4 for 4 hours and cleavage products were analyzed by immunoblot. Active C1s was used as a positive control for C4 cleavage into C4b. Purified C4b was used to confirm the size of the C4b fragment generated by C1s and GZMK. <b>c,</b> Active GZMK was incubated with C2 for 4 hours in the presence or absence of increasing concentrations of C4 and cleavage products were analyzed by immunoblot. Active C1s was used as a positive control for C2 cleavage into C2a. <b>d,e,</b> Increasing concentrations of active GZMK or GZMA were incubated with C2 + C3 + C4 and cleavage products were analyzed by immunoblot. Active C1s was used as a positive control for generation of a C3 convertase that cleaves C3 into (<b>d</b>) C3a and (<b>e</b>) C3b. Serum-purified C3a and C3b were used to confirm the identity of the fragments generated by C1s and GZMK, while purified iC3b was used to determine whether GZMK generates inactive C3b. Schematic representation of the assays are shown for <b>b-e</b>. Data are representative of at least four independent experiments.</div>
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<p> Fig. 3 |. Synovial fibroblasts are major… </p>
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<p> Fig. 3 |. Synovial fibroblasts are major producers of tissue-derived complement proteins that are substrates… </p>
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Fig. 3 |. Synovial fibroblasts are major producers of tissue-derived complement proteins that are substrates for GZMK.
|
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<div class="figure-caption-contents"><b>a,</b> Expression of complement <i>C2</i>, <i>C3</i>, <i>C4A</i>, and <i>C4B</i> in T cells, B cells, monocytes, and fibroblasts sorted from disaggregated synovial tissue from patients with RA (N = 33) or osteoarthritis (N = 12), measured by low-input RNA-seq using data from the AMP RA/SLE network. Data are mean ± s.d. <b>b,</b> Representative image showing immunoflourescent staining of RA synovial tissue stained with antibodies against complement C3/C3d (yellow) and PDPN (magenta) and Hoechst nuclear stain (blue). Scale bar is 40 microns. <b>c</b>, Synovial fibroblasts were left untreated or stimulated with IFNG or TNF for 24 hours and the supernatants were precipitated and immunoblotted against C2, C3, or C4. Serum-purified C2, C3, C3b, C4 and C4b were run as controls to identify the proper bands. <b>d,</b> Synovial fibroblasts were left untreated or stimulated with IFNG, TNF, or IFNG + TNF for 24 hours and supernatants were assayed for the presence of C2, C3, or C4 by ELISA. Data are mean ± s.d of three technical replicates. <b>e,</b> Synovial fibroblasts were stimulated for 24 hours with IFNG + TNF after which the cell-free supernatants were left untreated or were incubated with C1s, GZMK or GZMA and cleavage products were analyzed by immunoblot for generation of C3a and C3b. Serum-purified C3a and C3b were used to confirm the identity of the fragments generated by C1s and GZMK. (<b>b-e</b>) Data are representative of at least three independent experiments. Schematic representation of the assay is shown for <b>e</b>.</div>
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<p> Figure 4.. GZMK triggers activation of the entire complement cascade. </p>
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<div class="figure-caption-contents"><b> a, </b> LAD2 mast cells were…</div>
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Figure 4.. GZMK triggers activation of the entire complement cascade.
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<div class="figure-caption-contents"><b>a,</b> LAD2 mast cells were incubated with C3, C3a, or the reaction products obtained after incubating C1s or GZMK with C2 + C3 + C4. Degranulation was then assessed by flow cytometric staining of surface LAMP-1. <b>b</b>, HUVEC cells, synovial fibroblasts, or THP-1 monocytes were incubated with recombinant GZMK for 1 hour on ice, and surface-bound GZMK was then measured by flow cytometry after staining of unfixed, unpermeabilized cells. <b>c</b>, Surface deposition of C3b on HUVEC cells after incubation with C2 + C3 + C4 with or without C1s, GZMK, or GZMA, as measured by flow cytometry. Normal human serum (NHS) was used as a positive control. <b>d</b>, GZMK surface binding (left) and C3b deposition (right) on HUVEC cells after incubation with C2 + C3 + C4 with or without GZMK in the presence or absence of heparin. NHS was used as a control. <b>e</b>, GZMK either pre-bound to the surface of HUVECs or in solution without HUVECs was incubated with C2 + C3 + C4 for 0.5, 1, 2 or 4 h and the supernatants were analyzed by immunoblot for generation of C4a, C2b, and C3a. Purified C4a, C2b, and C3a were used to confirm the size of the fragments generated by GZMK. <b>f,</b> HUVEC cells were incubated with C2 + C3 + C4 + C5 with or without GZMA or GZMK and the generation of C5a was then measured by ELISA. <b>g</b>, C5aR1-expressing Chem-1 reporter cells labeled with Fluo-5F were incubated with C5, C5a, or the supernatants obtained after incubating HUVEC cells with C2 + C3 + C4 + C5 with or without GZMA or GZMK. Calcium flux was immediately assessed by flow cytometry and is presented as MFI (MFI minus unstimulated MFI). <b>h</b>, HUVEC cells were incubated with C2 + C3 + C4 + C5 + C6 + C7 + C8 + C9 with increasing concentrations of GZMK or GZMA. C5b,6–9 was used as a positive control. Terminal complement complex formation was then measured by flow cytometry. Histograms depict representative data. <b>i</b>, Surface deposition of C3b (left) and C4d (middle), and TCC formation (right) on HUVEC cells after incubation with C1q-depleted serum and increasing concentrations of GZMK, as measured by flow cytometry. NHS was used as a positive control. Data in <b>a-i</b> are representative of at least 3 independent experiments. <i>P</i> values were calculated using (<b>c, f-i</b>) one-way analysis of variance (ANOVA) with Dunnett’s multiple comparisons tests or (<b>d</b>) a two-way ANOVA with Sidak’s multiple comparisons tests. *<i>P</i> < 0.05, **<i>P</i> < 0.01, ***<i>P</i> < 0.001 and ****<i>P</i> < 0.0001, NS = not significant. Data are mean ± s.d. of (<b>c,d,f,h</b>) three or (i) five independent experiments or (<b>g</b>) three technical replicates from a representative of three independent experiments. <b>(b)</b> Data are representative of three independent experiments.</div>
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Figure 5.. GZMK is enriched in regions with abundant complement activation within RA synovial tissue.
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<div class="figure-caption-contents">Representative image showing immunofluorescence staining of RA synovial tissue with antibodies against C3d (clone C3D/2891, yellow in top composite), C5a (clone 2952, yellow in bottom composite), and GZMK (red) as well as Hoechst nuclear stain (blue). Scale bar represents 50 microns. Data are representative of 3 independent experiments.</div>
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Chowdhury D. & Lieberman J. Death by a thousand cuts: granzyme pathways of programmed cell death. Annu. Rev. Immunol. 26, 389–420 (2008).
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