Jones

<!
DOCTYPE html>
<html lang="en" class="no-js">
<head>
<meta charset="UTF-8">
<meta name="viewport" content="width=device-width, initial-scale=1.0, user-
scalable=yes">
<title>The potential immunomodulatory effects of topical retinoids</title>
<meta id="meta-title" property="citation_title" content="The potential
immunomodulatory effects of topical retinoids"/>
<meta id="og-title" property="og:title" content="The potential immunomodulatory
effects of topical retinoids"/>
<meta name="twitter:widgets:autoload" content="off"/>
<meta name="twitter:dnt" content="on"/>
<meta name="twitter:widgets:csp" content="on"/>
<meta name="google-site-verification"
content="lQbRRf0vgPqMbnbCsgELjAjIIyJjiIWo917M7hBshvI"/>
<meta id="meta-description" name="description" content="Author(s): Jones, David
A, MD PhD"/>
<meta id="og-description" name="og:description" content="Author(s): Jones, David
A, MD PhD"/>
<meta id="og-image" property="og:image"
content="https://escholarship.org/images/escholarship-facebook2.jpg"/>
<meta id="og-image-width" property="og:image:width" content="1242"/>
<meta id="og-image-height" property="og:image:height" content="1242"/>
<meta id="meta-author0" name="citation_author" content="Jones, David A, MD PhD"/>
<meta id="meta-publication_date" name="citation_publication_date"
content="2005"/>
<meta id="meta-doi" name="citation_doi" content="10.5070/D394q2x8f1"/>
<meta id="meta-journal_title" name="citation_journal_title" content="Dermatology
Online Journal"/>
<meta id="meta-volume" name="citation_volume" content="11"/>
<meta id="meta-issue" name="citation_issue" content="1"/>
<meta id="meta-online_date" name="citation_online_date" content="2005-01-01"/>
<link rel="canonical" href="https://escholarship.org/uc/item/94q2x8f1"/>
<link rel="stylesheet" href="/css/main-8d76d2bfbd0e968b.css">
<link rel="resource" type="application/l10n"
href="/node_modules/pdfjs-embed2/dist/locale/locale.properties">
<noscript><style> .jsonly { display: none } </style></noscript>
</head>
<body>
<div id="main"><div data-reactroot=""><div class="body"><a href="#maincontent"

class="c-skipnav">Skip to main content</a><div><div><header id="#top" class="c-
header"><a class="c-header__logo2" href="/"><picture><source
srcSet="/images/logo_eschol-small_20_v4.svg" media="(min-width: 870px)"/><img
src="/images/logo_eschol-mobile_20_v3.svg" alt="eScholarship"/></picture><div
class="c-header__logo2-tagline">Open Access Publications from the University of
California</div></a><div class="c-header__search"><form class="c-search2"><div
class="c-search2__inputs"><div class="c-search2__form"><label class="c-
search2__label" for="global-search">Search eScholarship</label><input type="search"
name="q" id="global-search" class="c-search2__field" placeholder="Search"
autoComplete="off" autoCapitalize="off"/></div><fieldset><legend>Refine
Search</legend><div class="c-search2__refine"><input type="radio" id="c-
search2__refine-eschol" name="searchType" value="eScholarship" checked=""/><label
for="c-search2__refine-eschol">All of eScholarship</label><input type="radio"
id="c-search2__refine-campus" name="searchType" value="doj"/><label for="c-
search2__refine-campus">This Journal</label><input type="hidden"
name="searchUnitType" value="journals"/></div></fieldset></div><button
type="submit" class="c-search2__submit-button" aria-label="search"></button><button
type="button" class="c-search2__search-close-button" aria-label="close search
field"></button></form></div><button class="c-header__search-open-button" aria-
label="open search field"></button></header></div><div class="
c-subheader
has-banner
is-wide
has-campus-label
is-black
" style="background-color:#ffffff"><a class="c-subheader__title"
href="/uc/doj"><h1>Dermatology Online Journal</h1></a><a class="c-
subheader__banner" href="/uc/doj"><img
src="/cms-assets/203203ac7f2ff182b5488a28730e1962200a90695148614d7fe28c0b0b85c509"
alt="Dermatology Online Journal banner"/></a><a class="c-subheader__campus"
href="/uc/ucd">UC Davis</a><div id="wizardModalBase" class="c-
subheader__buttons"><button id="wizardlyDeposit"
class="o-button__3">Submit</button><div class="c-modal"></div><button
id="wizardlyManage" class="o-button__3">Manage<span class="c-subheader__button-
fragment">Submissions</span></button><div class="c-modal"></div></div></div><div
class="c-navbar"><nav class="c-nav"><details open="" class="c-nav__main"><summary
class="c-nav__main-button">Menu</summary><ul class="c-nav__main-items"><li><a
href="/uc/doj">Journal Home</a></li><li><details class="c-nav__sub"><summary
class="c-nav__sub-button">Issues</summary><div class="c-nav__sub-items"><button
class="c-nav__sub-items-button" aria-label="return to menu">Main
Menu</button><ul><li><a href="/uc/doj/29/1">Volume 29, Issue 1, 2023</a></li><li><a
href="/uc/doj/28/6">Volume 28, Issue 6, 2022</a></li><li><a
href="/uc/doj/9/5">Volume 9, Issue 5, 2003</a></li><li><a href="/uc/doj/9/4">Volume
9, Issue 4, 2003</a></li><li><a href="/uc/doj/9/3">Volume 9, Issue 3,
2003</a></li><li><a href="/uc/doj/9/2">Volume 9, Issue 2, 2003</a></li><li><a
1, Issue 1, 1995</a></li></ul></div></details></li><li><details class="c-
nav__sub"><summary class="c-nav__sub-button">About</summary><div class="c-nav__sub-
items"><button class="c-nav__sub-items-button" aria-label="return to menu">Main
Menu</button><ul><li><a href="/uc/doj/aboutus">About Us</a></li><li><a
href="/uc/doj/editorialboard">Editorial
Board</a></li></ul></div></details></li><li><a href="/uc/doj/contactus">Contact
us</a></li><li><a href="/uc/doj/policies">Policies</a></li><li><a
href="/uc/doj/submissionguidelines">Instructions for
Authors</a></li></ul></details></nav><div class="c-socialicons"><a
href="http://www.twitter.com/derm_journal"><img src="/images/logo_twitter-circle-
black.svg" alt="Twitter"/></a><a href="/rss/unit/doj"><img src="/images/logo_rss-
circle-black.svg" alt="RSS"/></a></div></div><nav class="c-breadcrumb"><ul><li><a
href="/">eScholarship</a></li><li><a href="/uc/ucd">UC Davis</a></li><li><a
href="/uc/doj">Dermatology Online Journal</a></li><li><a class="c-breadcrumb-link--
active" href="/uc/doj/11/1">Volume 11, Issue 1</a></li></ul></nav><div class="c-
columns--sticky-sidebar"><main id="maincontent"><div><div class="c-
itemactions"><div class="o-download"><a href="" class="o-download__button"
download="eScholarship UC item 94q2x8f1.html">Download HTML</a><details
class="o-download__formats"><summary aria-label="formats"></summary><div><ul
class="o-download__nested-menu"><li class="o-download__nested-list1">Main<ul><li><a
href="">ePub</a></li><li><a
href="">HTML</a></li></ul></li></ul></div></details></div><details class="c-
share"><summary><span>Share</span></summary><div><div class="c-share__list"><a
class="c-share__email" href="">Email</a><a class="c-share__facebook"
href="">Facebook</a><a class="c-share__twitter"
href="">Twitter</a></div></div></details></div></div><h2 class="c-tabcontent__main-
heading" tabindex="-1"><div class="c-clientmarkup">The potential immunomodulatory
effects of topical retinoids</div></h2><div class="c-authorlist"><time class="c-
authorlist__year">2005</time><ul class="c-authorlist__list"><li class="c-
authorlist__begin"><a href="/search/?q=author%3AJones%2C%20David%20A%2C%20MD
%20PhD">Jones, David A, MD PhD</a> </li></ul></div><div class="c-pubinfo"><h2
class="c-pubinfo__location-heading">Published Web Location</h2><a
href="https://doi.org/10.5070/D394q2x8f1"
class="c-pubinfo__link">https://doi.org/10.5070/D394q2x8f1</a></div><div class="c-
tabs"><div class="c-tabs__tabs"><button class="c-tabs__button-more" aria-
label="Show all tabs">...</button><button class="c-tabs__button--active">Main
Content</button><button class="c-tabs__button">Metrics</button><button class="c-
tabs__button">Author & Article Info</button></div><div
class="c-tabs__content"><div class="c-tabcontent"><details class="c-togglecontent"
open=""><a name="article_main"></a><summary>Main Content</summary><div class="c-
clientmarkup"><?xml version="1.0" encoding="UTF-8"?>
<html xmlns="http://www.w3.org/1999/xhtml">
<body>
<h4><font size="+1">The potential immunomodulatory effects of topical
retinoids</font><br/>
David A Jones MD PhD<br/>
<small>Dermatology Online Journal 11 (1): 3 </small><br/></h4>
<font size="-1">Department of Dermatology, Brigham and Women's Hospital,
Harvard Medical School, Boston, Massachusetts. dajones@partners.org</font>
<br/>
<hr/>
<font size="-1">
<a name="section-1-0-0"></a>
</font>
<h3>
<font size="-1">Abstract</font>
</h3>
<p>
<font size="-1">New research has refined our understanding of the
immunopathophysiology of acne. Various immune factors, including both innate
and adaptive immune responses, have been implicated in the
pathophysiology of inflammatory acne. Topical retinoids such as
tretinoin, adapalene, and tazarotene, exhibit immunomodulatory effects
that may help to explain their efficacy in the resolution
of inflammatory lesions.</font>
</p>
<hr/>
<br/>
<h3>The immunopathophysiology of acne revised</h3>
<p>An immune basis for the pathophysiology of acne vulgaris has long been
recognized. Inflammation is well established as one
of the four pathophysiologic factors in the development of acne vulgaris.
In the 1970s Kligman suggested that the initial
inflammatory event in acne vulgaris involved the disruption of the
follicular epithelium into the dermis, allowing the comedonal
contents to have contact with the vascular and immune systems [<a
href="#1">1</a>]. Kligman and others believed that neutrophils were the first
immune cells involved in the follicular inflammation, and for
many years neutrophils along with the pathogen <i>Propionibacterium acnes
</i>(<i>P. acnes</i>) were regarded as the fundamental instigators of the
inflammation in acne [<a href="#1">1</a>, <a href="#2">2</a>, <a href="#3">3</a>]
More recent research refines our understanding of the pathophysiology of acne
vulgaris and suggests a more complex pathophysiology
than previously suspected. This review will discuss a portion of this acne
research focusing on direct immunomodulatory properties
of retinoids.
</p>
<br/>
<h4>Follicular wall permeability versus overt rupture</h4>
<p>The inflammatory process which results in acne lesions is complex, involving
interactions among multiple cell types and many
soluble mediators. Structural abnormalities of the follicle including
comedone formation are also important in the development
of inflammatory acne, but overt rupture of comedones may not be a required
initiating event. Eady and Cove have suggested
that increased permeability of the follicular wall secondary to the
release of the proinflammatory and cell-differentiating
cytokine interleukin 1 alpha (IL-1α) may be all that is necessary to
initiate the intradermal inflammatory process that characterizes
inflammatory lesions [<a href="#4">4</a>].
</p>
<br/>
<h4>Neutrophils versus T-cell lymphocytes as the primary instigators of the
immunopathophysiology of acne </h4>
<p>As noted, Kligman and subsequent researchers suggest that neutrophils are
the first immune cells in acne lesions [<a href="#1">1</a>, <a href="#2">2</a>].
However, Cunliffe and Norris challenge this view; their biopsies demonstrate T
lymphocytes to be the predominant cells
in early inflammatory lesions [<a href="#5">5</a>]. More research will be
required to reproduce and refine these observations. Subsequent <i>in vitro</i>
studies have demonstrated that antigens from <i>P. acnes</i> can stimulate the
development of subclasses of T cells [<a href="#6">6</a>]. Whether neutrophils or
lymphocytes are first at the lesion site, evidence suggests that both immune cells
are involved
in the immunopathophysiology of acne.
</p>
<br/>
<h4>The role of <i>P. acnes</i> as an instigator of inflammation
</h4>
<p>Zouboulis has questioned the predominant role of <i>P. acnes</i> as an
instigator of inflammation in acne lesions. He suggests that the pilosebaceous
gland itself may be the origin of certain
immune factors, although the presence of a pathogen such as <i>P.
acnes</i> may amplify this initial immune response [<a href="#7">7</a>]. <i>In
vitro</i> studies demonstrate that IL-1α can be synthesized by sebocytes and
follicular keratinocytes without the presence of microorganisms
[<a href="#8">8</a>, <a href="#9">9</a>]. It is also suggested that the
free fatty acids in sebum and certain leukotrienes, which are proinflammatory
mediators derived
from arachidonic acid, are also involved in the immunopathophysiology of
acne [<a href="#7">7</a>].
</p>
<br/>
<h4>The identification of novel immune factors: human β defensins and toll-like
receptors </h4>
<p>Recent progress in the study of innate immunity identifies two key factors
relevant to acne: β defensins and toll-like receptors
(TLRs). This identification brings the elucidation of the
immunopathophysiology full circle by again implicating microflora
such as <i>P. acnes</i> in the etiology of acne vulgaris. Human β
defensins are antimicrobial peptides [<a href="#10">10</a>]. The role of these
peptides in various plant and animal species is to protect against various
pathogens, such as bacteria
[<a href="#10">10</a>]. A recent <i>in vitro</i> study examines biopsies
of normal pilosebaceous follicles from the backs of healthy patients and those with
inflammatory
lesions. Human β defensin-1 and -2 are found to be upregulated in
inflammatory acne lesions. The researchers suggest that
this upregulation of β defensins may be a protective mechanism for
controlling pathogens in patients with acne [<a href="#10">10</a>].
</p>
<p>Toll-like receptors (TLRs) are expressed on human macrophages and identify
general molecular patterns that occur on bacteria
and other pathogens but not on the host [<a href="#11">11</a>]. As such,
they are a key subset of pattern recognition receptors (PRRs) [<a
href="#11">11</a>]. This receptor recognition is critical to the innate immune
response.
</p>
<br/>
<table align="right" border="0" width="192" cellpadding="5">
<tr>
<td align="center">
<a href="/content/qt94q2x8f1/3.png">
<img src="/content/qt94q2x8f1/3s.png" width="192" height="128"
align="center"/>
</a>
</td>
</tr>
<tr>
<th align="center">Figure 1</th>
</tr>
<tr>
<td>
<b>Actions of toll-like receptors on antigen-presenting cell (dendritic
cell) in activating subsets of T cells.</b>
</td>
</tr>
</table>
<p>It now appears that this interaction between the pathogen-associated
molecular pattern (PAMP) and the TLR is also critical
to the adaptive immune response [<a href="#11">11</a>]. Specifically, this
interaction is now thought to be necessary before a macrophage can release IL-1α.
This cytokine in turn
activates the macrophage through an autocrine process and also activates
subsets of helper T cells (Fig. 1) [<a href="#11">11</a>].
</p>
<p>It is known that <i>P. acnes</i> can induce monocytes to secrete
proinflammatory cytokines, including tumor necrosis factor alpha (TNF-α),
interleukin 1 beta
(IL-1β), and interleukin-8 (IL-8) [<a href="#12">12</a>]. TLRs appear to
be involved in mediating the activation of monocytes, ultimately resulting in the
release of these proinflammatory
cytokines. When these receptor subtypes are activated by cell-wall
components of gram-positive bacteria, such as <i>P. acnes</i>, or by
lipopolysaccharides of gram-negative bacteria, they begin intracellular signaling
of transcription factors for various
proinflammatory mediators [<a href="#13">13</a>]. A recent study of
macrophages from mice with TLR-1 and TLR-6 receptors removed, but TLR-2 receptors
intact, demonstrates
that <i>P. acnes</i> induces the release of IL-12 and IL-8. A monoclonal
antibody to the TLR-2 receptor inhibits the release of these proinflammatory
cytokines. The researchers conclude that <i>P. acnes</i> induces the
release of proinflammatory cytokines by activation of the TLR-2 receptor [<a
href="#14">14</a>].
</p>
<br/>
<h3>The potential immunomodulating effects of topical retinoids</h3>
<p>Topical retinoids (e.g., tretinoin, adapalene, and tazarotene) normalize
hyperkeratinization and thereby exert indirect immunomodulatory
effects by changing the comedonal environment [<a href="#15">15</a>]. In
essence, by preventing hypercornification of the pilosebaceous unit, they promote a
more aerobic environment inhospitable
to <i>P. acnes</i> [<a href="#16">16</a>]. However, <i>in vitro</i> and
<i>in vivo</i> studies suggest that topical retinoids also demonstrate direct
effects on a number of additional immune factors implicated
in the pathophysiology of acne vulgaris.
</p>
<br/>
<h4><i>In vitro</i> models
</h4>
<p>A number of <i>in vitro</i> models were used to study the anti-inflammatory
effects of retinoids (tretinoin, adapalene, isotretinoin, and etretinate);
a corticosteroid (betamethasone-17-valerate); and a nonsteroidal anti-
inflammatory drug (NSAID, indomethacin) [<a href="#17">17</a>]. The actions of
these agents on a number of inflammatory mediators and mechanisms were assessed.
These included the activity
of 15-lipoxygenase, the enzyme responsible for the conversion of
arachidonic acid to a leukotriene family of inflammatory
mediators; the production of other eicosanoids (5- and 15-
hydroxyeicosatetraenoic acid or HETE); and chemotaxis. Adapalene
is associated with greater inhibition of the lipoxygenase pathways and
greater inhibition of leukotriene production compared
with all other agents, including the other retinoids tested. Adapalene and
tretinoin also demonstrate significant inhibition
of oxygen free radicals released from PMNs derived from rabbits. Adapalene
also inhibits human chemotaxis of PMNs (<a
href="/content/qt94q2x8f1/tables.htm">Table 1</a>) [<a href="#17">17</a>, <a
href="#18">18</a>].
</p>
<br/>
<table align="right" border="0" width="192" cellpadding="5">
<tr>
<td align="center">
<a href="/content/qt94q2x8f1/5.png">
<img src="/content/qt94q2x8f1/5s.png" width="192" height="128"
align="center"/>
</a>
</td>
</tr>
<tr>
<th align="center">Figure 2</th>
</tr>
<tr>
<td>
<b>Effect of adapalene and tretinoin (retinoic acid) on down-regulating
TLR2 expression on monocytes.</b>
</td>
</tr>
</table>
<p>A recent <i>in vitro</i> study involving the retinoids adapalene and
tretinoin, demonstrates that these agents inhibit the expression of mammalian
TLR-2 on human monocytes derived from healthy volunteers [<a
href="#13">13</a>]. First, monoclonal antibodies were used to determine the
expression of TLR receptors. After 4 days of culture, TLR-2 is
strongly expressed in untreated cells, whereas TLR-4 is only weakly
expressed. The monocytes then were cultured with different
concentrations of the two retinoids. At low concentrations of retinoids,
approximately 100 percent of the monocytes express
TLR-2 (Fig. 2). At higher concentrations, only approximately 20 percent of
monocytes express this receptor [<a href="#13">13</a>]. It is interesting to note
that the retinoid concentration achieved in follicles is actually higher than the
concentrations
used in this <i>in vitro</i> study.
</p>
<br/>
<h4><i>In vivo</i> animal models
</h4>
<p>Ultraviolet (UV) light irradiation is used to induce erythema in animal
models. In a guinea pig model, both adapalene and
tretinoin significantly decreased erythema [<a href="#17">17</a>].
</p>
<p>Cutaneous inflammation can be induced through use of croton oil. This type
of skin inflammation can be inhibited by corticosteroids
but not by NSAIDs. In this animal model, adapalene demonstrates moderate
inhibition of inflammation; tretinoin exhibits very
little effect. Although both retinoids exhibit anti-inflammatory effects,
the findings of this study suggest that adapalene
and tretinoin may address different aspects of inflammation (<a
href="/content/qt94q2x8f1/tables.htm">Table 2</a>) [<a href="#17">17</a>, <a
href="#18">18</a>].
</p>
<p>The prostaglandin and leukotriene family of inflammatory mediators are both
derived from arachidonic acid. In the arachidonic
acid-induced ear edema mouse model, adapalene is associated with
significant anti-inflammatory effects; tretinoin is associated
with less inhibition (<a href="/content/qt94q2x8f1/tables.htm">Table
2</a>) [<a href="#17">17</a>, <a href="#18">18</a>].
</p>
<p>Another animal model of inflammation involves edema induced by carrageenan.
NSAIDs exert significant anti-inflammatory effects
in this model [<a href="#17">17</a>]. In a rat model, adapalene
demonstrates anti-inflammatory effects equivalent to those of indomethacin;
tretinoin does not
demonstrate significant anti-inflammatory effects (Table 2) [<a
href="#17">17</a>].
</p>
<br/>
<h3>The therapeutic implications of retinoid immunomodulatory effects</h3>
<p>On the basis of their immunomodulatory actions, topical retinoids are
expected to effectively reduce inflammatory lesions,
in addition to comedones. The degree to which each particular mechanism
functions in human acne remains to be tested to validate
the in vitro and animal studies reviewed above. However, the reduction in
inflammation demonstrated in preclinical studies
have been validated by clinical trials. Various formulations of adapalene
(gel, cream, solution), tretinoin (gel, microsphere
gel, cream), and tazarotene gel are all found to significantly reduce
inflammatory lesions in well-controlled clinical trials
[<a href="#19">19</a>, <a href="#20">20</a>, <a href="#21">21</a>, <a
href="#22">22</a>, <a href="#23">23</a>, <a href="#24">24</a>, <a
href="#25">25</a>, <a href="#26">26</a>]. Indeed, topical retinoids are recommended
as therapy for all stages of acne except the most severe inflammatory stage [<a
href="#27">27</a>].
</p>
<p>Of course, criteria for choice of acne therapy involve not just efficacy in
the treatment of noninflammatory and inflammatory
lesions but tolerability and the potential for medication compliance. All
topical retinoids can be associated with cutaneous
irritation that can interfere with compliance. Adapalene is found to have
the best cutaneous tolerability [<a href="#19">19</a>, <a href="#20">20</a>, <a
href="#22">22</a>, <a href="#23">23</a>, <a href="#26">26</a>]. Other therapeutic
strategies to decrease the potential for cutaneous irritation involves the use of
new delivery systems
such as the tretinoin microsponge system, and alternative dosing regimens
(e.g., QOD or short-contact therapy) that are used
to subdue the cutaneous irritation seen with tazarotene [<a
href="#28">28</a>, <a href="#29">29</a>, <a href="#30">30</a>].
</p>
<br/>
<h3>Conclusion</h3>
<p>An increasing understanding of the complexity of the pathophysiology of acne
vulgaris is guiding practitioners in their choice
of therapeutic agents. The immunomodulatory effects of topical retinoids
provide a rationale for using these agents in the
treatment not only of comedones but also of inflammatory lesions as well.
</p>
<font size="-1">
</font>
<h3>
<font size="-1">References</font>
</h3>
<font size="-1"><a name="1"></a>1. Kligman AM. An overview of acne. J Invest
Dermatol. 1974;62:268-287.<br/><br/><a name="2"></a>2. Webster GF. Inflammation in
acne vulgaris. J Am Acad Dermatol. 1995;33:247-253.<br/><br/><a name="3"></a>3.
Webster GF, Leyden JJ, Tsai CC, Baehni P, McArthur WP. Polymorphonuclear leukocyte
lysosomal release in response to Propionibacterium
acnes in vitro and its enhancement by sera from inflammatory acne
patients. J Invest Dermatol. 1980;74:398-401.<br/><br/><a name="4"></a>4. Eady EA,
Cove JH. Is acne an infection of blocked pilosebaceous follicles? Implications for
antimicrobial treatment. Am
J Clin Dermatol. 2000; 1: 201-209.<br/><br/><a name="5"></a>5. Norris JF,
Cunliffe WJ. A histological and immunocytochemical study of early acne lesions. Br
J Dermatol. 1988;118:651-659.<br/><br/><a name="6"></a>6. Jappe U, Ingham E,
Henwood J, Holland KT. Propionibacterium acnes and inflammation in acne; P. acnes
has T-cell mitogenic
activity. Br J Dermatol. 2002;146:202-209.<br/><br/><a name="7"></a>7.
Zouboulis CC. Is acne vulgaris a genuine inflammatory disease? Dermatology.
2001;203:277-279.<br/><br/><a name="8"></a>8. Seltmann H, Rudawski IM, Holland KT,
Orfanos CE, Zouboulis CC. Propionibacterium acnes does not influence the
interleukin-1a/interleukin-8
cascade in immortalized human sebocytes in vitro. J Invest Dermatol.
2000;114:816.<br/><br/><a name="9"></a>9. Ingham E, Walters CE, Eady EA, Cove JH,
Kearney JN, Cunliffe WJ. Inflammation in acne vulgaris: failure of skin micro-
organisms
to modulate keratinocyte interleukin 1 alpha production in vitro.
Dermatology. 1998;196:86-88.<br/><br/><a name="10"></a>10. Chronnell CM, Ghali LR,
Ali RS, et al. Human beta defensin-1 and -2 expression in human pilosebaceous
units: upregulation
in acne vulgaris lesions. J Invest Dermatol. 2001;117:1120-1125.
<br/><br/><a name="11"></a>11. Medzhitov R. Toll-like receptors and innate
immunity. Nat Rev Immunol. 2001;1:135-142.<br/><br/><a name="12"></a>12. Vowels BR,
Yang S, Leyden JJ. Induction of proinflammatory cytokines by a soluble factor of
Propionibacterium acnes: implications
for chronic inflammatory acne. Infect Immun 1995;63:3158-3165.<br/><br/><a
name="13"></a>13. Vega-Diaz B, Jonard A, Michel S. Regulation of human monocyte
toll-like receptor 2 (TLR2) expression by adapalene [abstract].
J Eur Acad Dermatol Venereol. 2002;16:123-124. <br/><br/><a
name="14"></a>14. Kim J, Ochoa M-T, Krutzik SR, et al. Activation of toll-like
receptor 2 in acne triggers inflammatory cytokine responses.
J Immunol. 2002;169:1535-1541.<br/><br/><a name="15"></a>15. Wolf JE Jr.
Potential anti-inflammatory effects of topical retinoids and retinoid analogues.
Adv Ther. 2002;19:109-118.<br/><br/><a name="16"></a>16. Shalita A. The integral
role of topical and oral retinoids in the early treatment of acne. J Eur Acad
Dermatol Venereol.
2001;15(suppl 3):43-49.<br/><br/><a name="17"></a>17. Hensby C, Cavey D,
Bouclier M, et al. The in vivo and in vitro anti-inflammatory activity of CD271: a
new retinoid-like
modulator of cell differentiation. Agents Actions.
1990;29:56-58.<br/><br/><a name="18"></a>18. Shroot B, Michel S. Pharmacology and
chemistry of adapalene. J Am Acad Dermatol. 1997;36(suppl 1):S96-S103.<br/><br/><a
name="19"></a>19. Cunliffe WJ, Poncet M, Loesche C, Verschoore M. A comparison of
the efficacy and tolerability of adapalene 0.1% gel versus
tretinoin 0.025% gel in patients with acne vulgaris: a meta-analysis of
five randomized trials. Br J Dermatol. 1998;139(suppl
52):48-56.<br/><br/><a name="20"></a>20. Grosshans E, Marks R, Mascaro JM,
et al. Evaluation of clinical efficacy and safety of adapalene 0.1% gel versus
tretinoin
0.025% gel in the treatment of acne vulgaris, with particular reference to
the onset of action and impact on quality of life.
Br J Dermatol. 1998;139(suppl 52):26-33.<br/><br/><a name="21"></a>21.
Lucky A, Jorizzo JL, Rodriguez D, et al. Efficacy and tolerance of adapalene cream
0.1% compared with its cream vehicle
for the treatment of acne vulgaris. Cutis. 2001;68:34-40.<br/><br/><a
name="22"></a>22. Ellis CN, Millikan LE, Smith EB, et al. Comparison of adapalene
0.1% solution and tretinoin 0.025% gel in the topical
treatment of acne vulgaris. Br J Dermatol. 1998;139(suppl 52):
41-47.<br/><br/><a name="23"></a>23. Thiboutot D, Gold MH, Jarratt MT, et al.
Randomized controlled trial of the tolerability, safety, and efficacy of adapalene
gel 0.1% and tretinoin microsphere gel 0.1% for the treatment of acne
vulgaris. Cutis. 2001:68:10-19.<br/><br/><a name="24"></a>24. Lucky AW, Cullen SI,
Funicella T, Jarratt MT, Jones T, Reddick ME. Double-blind, vehicle-controlled,
multicenter comparison
of two 0.025% tretinoin creams in patients with acne vulgaris. J Am Acad
Dermatol. 1998;38: S24-S30.<br/><br/><a name="25"></a>25. Webster GF, Berson D,
Stein LF, Fivenson DP, Tanghetti EA, Ling M. Efficacy and tolerability of once-
daily tazarotene
0.1% gel versus once-daily tretinoin 0.025% gel in the treatment of facial
acne vulgaris: a randomized trial. Cutis. 2001;67(suppl
6): 4-9.<br/><br/><a name="26"></a>26. Webster GF, Guenther L, Poulin YP,
Solomon BA, Loven K, Lee J. A multicenter, double-blind, randomized comparison
study
of the efficacy and tolerability of once-daily tazarotene 0.1% gel and
adapalene 0.1% gel for the treatment of facial acne
vulgaris. Cutis. 2002;69(suppl 2):4-11.<br/><br/><a name="27"></a>27.
Gollnick H, Cunliffe W. Management of acne. A report from a Global Alliance to
Improve Outcomes in Acne. J Am Acad Dermatol
2003;49(Suppl):S1-38.<br/><br/><a name="28"></a>28. Embil K, Nacht S. The
Microsponge Delivery System (MDS): a topical delivery system with reduced irritancy
incorporating
multiple triggering mechanisms for the release of actives. J
Microencapsul. 1996;13:575-588.<br/><br/><a name="29"></a>29. Leyden J, Lowe N,
Kakita L, Draelos Z. Comparison of treatment of acne vulgaris with alternate-day
applications of tazarotene
0.1% gel and once-daily applications of adapalene 0.1% gel: a randomized
trial. Cutis. 2001;67(suppl 6):10-16.<br/><br/><a name="30"></a>30. Bershad S,
Kranjac Singer G, Parente JE, et al. Successful treatment of acne vulgaris using a
new method: results of a
randomized vehicle-controlled trial of short-contact therapy with 0.1%
tazarotene gel. Arch Dermatol. 2002;138:481-489.<br/><br/></font>
<p align="center">© 2005 Dermatology Online Journal</p>
</body>
</html>
</div><br/><br/></details></div><p><br/></p></div></div></main><aside><section
class="o-columnbox1"><header><h2>Jump To</h2></header><div class="c-jump"><a
href="/uc/item/94q2x8f1">Article</a><ul class="c-jump__tree" aria-labelledby="c-
jump__label"><li><a href="/uc/item/94q2x8f1">Abstract</a></li><li><a
href="/uc/item/94q2x8f1">The immunopathophysiology of acne revised</a></li><li><a
href="/uc/item/94q2x8f1">The potential immunomodulating effects of topical
retinoids</a></li><li><a href="/uc/item/94q2x8f1">The therapeutic implications of
retinoid immunomodulatory effects</a></li><li><a
href="/uc/item/94q2x8f1">Conclusion</a></li><li><a
href="/uc/item/94q2x8f1">References</a></li></ul><ul class="c-
jump__siblings"><li><a href="/uc/item/94q2x8f1">Metrics</a></li><li><a
href="/uc/item/94q2x8f1">Author & Article
Info</a></li></ul></div></section><div><section class="o-
columnbox1"><header><h2>Related Items</h2></header><ul class="c-
relateditems"><li><h3><a class="o-textlink__secondary"
href="/uc/item/0tz012ps"><div class="c-clientmarkup">Epstein-Barr virus-positive
CD30+ B-cell lymphoproliferative disease with histologic features resembling grade
III lymphomatoid granulomatosis induced by methotrexate</div></a></h3><div
class="c-authorlist"><ul class="c-authorlist__list"><li class="c-
authorlist__begin"><a href="/search/?q=author%3AQuaye%2C%20Elizabeth%20H">Quaye,
Elizabeth H</a>; </li><li><a href="/search/?q=author%3AD'Angelis%2C
%20Christopher">D'Angelis, Christopher</a>; </li><li class="c-
authorlist__end"><a href="/search/?q=author%3APowell%2C%20Jennifer">Powell,
Jennifer</a> </li></ul></div></li><li><h3><a class="o-textlink__secondary"
href="/uc/item/1016c4g5"><div class="c-clientmarkup">Social support is associated
with reduced impact of hidradenitis suppurativa on quality of life: an
observational study</div></a></h3><div class="c-authorlist"><ul class="c-
authorlist__list"><li class="c-authorlist__begin"><a href="/search/?q=author
%3ASingh%2C%20Rohan">Singh, Rohan</a>; </li><li><a href="/search/?q=author%3AKelly
%2C%20Katherine%20A">Kelly, Katherine A</a>; </li><li><a href="/search/?q=author
%3AParis%2C%20Paul%20H">Paris, Paul H</a>; </li><li><a href="/search/?q=author
%3ASenthilnathan%2C%20Aditi">Senthilnathan, Aditi</a>; </li><li><a href="/search/?
q=author%3AFeldman%2C%20Steven%20R">Feldman, Steven R</a>; </li><li class="c-
authorlist__end"><a href="/search/?q=author%3APichardo%2C%20Rita%20O">Pichardo,
Rita O</a> </li></ul></div></li><li><h3><a class="o-textlink__secondary"
href="/uc/item/1820m79x"><div class="c-clientmarkup">Delayed diagnosis of DRESS
syndrome in a patient with skin of color</div></a></h3><div class="c-
authorlist"><ul class="c-authorlist__list"><li class="c-authorlist__begin"><a
href="/search/?q=author%3ABean%2C%20Eric%20L">Bean, Eric L</a>; </li><li><a
href="/search/?q=author%3ALewis%2C%20Daniel%20J">Lewis, Daniel J</a>; </li><li><a
href="/search/?q=author%3AWeir%2C%20Michelle%20A">Weir, Michelle A</a>; </li><li
class="c-authorlist__end"><a href="/search/?q=author%3AMicheletti%2C%20Robert
%20G">Micheletti, Robert G</a> </li></ul></div></li><li><h3><a class="o-
textlink__secondary" href="/uc/item/1jm0674r"><div class="c-clientmarkup">A case of
self-improving collodion ichthyosis associated with a rare variant of the ALOX12B
gene</div></a></h3><div class="c-authorlist"><ul class="c-authorlist__list"><li
class="c-authorlist__begin"><a href="/search/?q=author%3AAmoedo%2C%20P">Amoedo,
P</a>; </li><li><a href="/search/?q=author%3ACerejeira%2C%20A">Cerejeira, A</a>;
</li><li><a href="/search/?q=author%3APacheco%2C%20J">Pacheco, J</a>; </li><li><a
href="/search/?q=author%3ACruz%2C%20MJ">Cruz, MJ</a>; </li><li class="c-
authorlist__end"><a href="/search/?q=author%3AMota%2C%20A">Mota, A</a>
</li></ul></div></li><li><h3><a class="o-textlink__secondary"
href="/uc/item/3217m2vn"><div class="c-clientmarkup">Nirmatrelvir-ritonivir, COVID-
19, and possible adverse cutaneous reactions</div></a></h3><div class="c-
authorlist"><ul class="c-authorlist__list"><li class="c-authorlist__begin"><a
href="/search/?q=author%3AAlbrecht%2C%20J%20Mark">Albrecht, J Mark</a>; </li><li><a
href="/search/?q=author%3ACooper%2C%20Benjamin%20R">Cooper, Benjamin R</a>;
</li><li><a href="/search/?q=author%3AWaller%2C%20Jacquelyn%20D">Waller, Jacquelyn
D</a>; </li><li><a href="/search/?q=author%3APresley%2C%20Colby%20L">Presley, Colby
L</a>; </li><li><a href="/search/?q=author%3APulsipher%2C%20Kayd%20J">Pulsipher,
Kayd J</a>; </li><li><a href="/search/?q=author%3ARundle%2C%20Chandler%20W">Rundle,
Chandler W</a>; </li><li class="c-authorlist__end"><a href="/search/?q=author
%3ADellavalle%2C%20Robert%20P">Dellavalle, Robert P</a>
</li></ul></div></li></ul></section></div></aside></div></div><div><div class="c-
toplink"><a href="javascript:window.scrollTo(0, 0)">Top</a></div><footer class="c-
footer"><nav class="c-footer__nav"><ul><li><a href="/">Home</a></li><li><a
href="/aboutEschol">About eScholarship</a></li><li><a href="/campuses">Campus
Sites</a></li><li><a href="/ucoapolicies">UC Open Access Policy</a></li><li><a
href="/publishing">eScholarship Publishing</a></li><li><a
href="https://www.cdlib.org/about/accessibility.html">Accessibility</a></li><li><a
href="/privacypolicy">Privacy Statement</a></li><li><a href="/policies">Site
Policies</a></li><li><a href="/terms">Terms of Use</a></li><li><a
href="/login"><strong>Admin Login</strong></a></li><li><a
href="https://help.escholarship.org"><strong>Help</strong></a></li></ul></nav><div
class="c-footer__logo"><a href="/"><img class="c-lazyimage"
data-src="/images/logo_footer-eschol.svg" alt="eScholarship, University of
California"/></a></div><div class="c-footer__icons"><a
href="https://www.facebook.com/eScholarship/"><img class="c-lazyimage"
data-src="/images/logo_facebook-circle-white.svg" alt="Facebook"/></a><a
href="https://twitter.com/escholarship"><img class="c-lazyimage"
data-src="/images/logo_twitter-circle-white.svg" alt="Twitter"/></a></div><div
class="c-footer__copyright">Powered by the<br/><a
href="http://www.cdlib.org">California Digital Library</a><br/>Copyright ©
2017<br/>The Regents of the University of
California</div></footer></div></div></div></div>
<script>window.jscholApp_initialPageData = {"added":"2005-01-
01","advisors":null,"altmetrics_ok":null,"appearsIn":
[{"id":"doj","name":"Dermatology Online
Journal"}],"attrs":{"doi":"10.5070/D394q2x8f1","toc":{"divs":
[{"title":"Abstract","anchor":"section-1-0-0"},{"title":"The immunopathophysiology
of acne revised","anchor":"section-2-0-0"},{"title":"The potential immunomodulating
effects of topical retinoids","anchor":"section-3-0-0"},{"title":"The therapeutic
implications of retinoid immunomodulatory effects","anchor":"section-4-0-0"},
{"title":"Conclusion","anchor":"section-5-0-0"},
{"title":"References","anchor":"section-6-0-
0"}],"source":"html"},"submitter":"help@escholarship.org","pub_status":"internalPub
","is_peer_reviewed":true},"authors":[{"name":"Jones, David A, MD
PhD","fname":"David","lname":"Jones","mname":"A","suffix":"MD PhD"}],"citation":
{"id":"qt94q2x8f1","type":"article","title":"The potential immunomodulatory effects
of topical retinoids","URL":"http://escholarship.org/uc/item/94q2x8f1","issued":
{"raw":["2005-1-1"]},"doi":"10.5070/D394q2x8f1","issn":null,"author":
[{"literal":"Jones, David A, MD
PhD","given":"David","family":"Jones","mname":"A","suffix":"MD
PhD"}],"volume":"11","issue":"1"},"content_html":"<?xml version=\"1.0\"
encoding=\"UTF-8\"?>\n<html xmlns=\"http://www.w3.org/1999/xhtml\">\n <body>\n
<h4><font size=\"+1\">The potential immunomodulatory effects of topical
retinoids</font><br/>\n David A Jones MD PhD<br/>\n
<small>Dermatology Online Journal 11 (1): 3 </small><br/></h4>\n <font size=\"-
1\">Department of Dermatology, Brigham and Women's Hospital, Harvard Medical
School, Boston, Massachusetts. dajones@partners.org</font>\n <br/>\n <hr/>\n
<font size=\"-1\">\n <a name=\"section-1-0-0\"></a>\n </font>\n <h3>\n
<font size=\"-1\">Abstract</font>\n </h3>\n <p>\n <font size=\"-1\">New
research has refined our understanding of the immunopathophysiology of acne.
Various immune factors, including both innate\n and adaptive immune
responses, have been implicated in the pathophysiology of inflammatory acne.
Topical retinoids such as\n tretinoin, adapalene, and tazarotene,
exhibit immunomodulatory effects that may help to explain their efficacy in the
resolution\n of inflammatory lesions.</font>\n </p>\n <hr/>\n
<br/>\n <a name=\"section-2-0-0\"></a>\n <h3>The immunopathophysiology of
acne revised</h3>\n <p>An immune basis for the pathophysiology of acne vulgaris
has long been recognized. Inflammation is well established as one\n of the
four pathophysiologic factors in the development of acne vulgaris. In the 1970s
Kligman suggested that the initial\n inflammatory event in acne vulgaris
involved the disruption of the follicular epithelium into the dermis, allowing the
comedonal\n contents to have contact with the vascular and immune systems
[<a href=\"#1\">1</a>]. Kligman and others believed that neutrophils were the first
immune cells involved in the follicular inflammation, and for\n many years
neutrophils along with the pathogen <i>Propionibacterium acnes </i>(<i>P.
acnes</i>) were regarded as the fundamental instigators of the inflammation in acne
[<a href=\"#1\">1</a>, <a href=\"#2\">2</a>, <a href=\"#3\">3</a>] More recent
research refines our understanding of the pathophysiology of acne vulgaris and
suggests a more complex pathophysiology\n than previously suspected. This
review will discuss a portion of this acne research focusing on direct
immunomodulatory properties\n of retinoids.\n </p>\n <br/>\n <a
name=\"section-2-1-0\"></a>\n <h4>Follicular wall permeability versus overt
rupture</h4>\n <p>The inflammatory process which results in acne lesions is
complex, involving interactions among multiple cell types and many\n
soluble mediators. Structural abnormalities of the follicle including comedone
formation are also important in the development\n of inflammatory acne, but
overt rupture of comedones may not be a required initiating event. Eady and Cove
have suggested\n that increased permeability of the follicular wall
secondary to the release of the proinflammatory and cell-differentiating\n
cytokine interleukin 1 alpha (IL-1\u03B1) may be all that is necessary to initiate
the intradermal inflammatory process that characterizes\n inflammatory
lesions [<a href=\"#4\">4</a>]. \n </p>\n <br/>\n <a name=\"section-2-2-
0\"></a>\n <h4>Neutrophils versus T-cell lymphocytes as the primary instigators
of the immunopathophysiology of acne </h4>\n <p>As noted, Kligman and
subsequent researchers suggest that neutrophils are the first immune cells in acne
lesions [<a href=\"#1\">1</a>, <a href=\"#2\">2</a>]. However, Cunliffe and Norris
challenge this view; their biopsies demonstrate T lymphocytes to be the predominant
cells\n in early inflammatory lesions [<a href=\"#5\">5</a>]. More research
will be required to reproduce and refine these observations. Subsequent <i>in
vitro</i> studies have demonstrated that antigens from <i>P. acnes</i> can
stimulate the development of subclasses of T cells [<a href=\"#6\">6</a>]. Whether
neutrophils or lymphocytes are first at the lesion site, evidence suggests that
both immune cells are involved\n in the immunopathophysiology of acne. \n
</p>\n <br/>\n <a name=\"section-2-3-0\"></a>\n <h4>The role of <i>P.
acnes</i> as an instigator of inflammation\n </h4>\n <p>Zouboulis has
questioned the predominant role of <i>P. acnes</i> as an instigator of inflammation
in acne lesions. He suggests that the pilosebaceous gland itself may be the origin
of certain\n immune factors, although the presence of a pathogen such as
<i>P. acnes</i> may amplify this initial immune response [<a href=\"#7\">7</a>].
<i>In vitro</i> studies demonstrate that IL-1\u03B1 can be synthesized by sebocytes
and follicular keratinocytes without the presence of microorganisms\n [<a
href=\"#8\">8</a>, <a href=\"#9\">9</a>]. It is also suggested that the free fatty
acids in sebum and certain leukotrienes, which are proinflammatory mediators
derived\n from arachidonic acid, are also involved in the
immunopathophysiology of acne [<a href=\"#7\">7</a>].\n </p>\n <br/>\n
<a name=\"section-2-4-0\"></a>\n <h4>The identification of novel immune factors:
human \u03B2 defensins and toll-like receptors </h4>\n <p>Recent progress in the
study of innate immunity identifies two key factors relevant to acne: \u03B2
defensins and toll-like receptors\n (TLRs). This identification brings the
elucidation of the immunopathophysiology full circle by again implicating
microflora\n such as <i>P. acnes</i> in the etiology of acne vulgaris.
Human \u03B2 defensins are antimicrobial peptides [<a href=\"#10\">10</a>]. The
role of these peptides in various plant and animal species is to protect against
various pathogens, such as bacteria\n [<a href=\"#10\">10</a>]. A recent
<i>in vitro</i> study examines biopsies of normal pilosebaceous follicles from the
backs of healthy patients and those with inflammatory\n lesions. Human \
u03B2 defensin-1 and -2 are found to be upregulated in inflammatory acne lesions.
The researchers suggest that\n this upregulation of \u03B2 defensins may be
a protective mechanism for controlling pathogens in patients with acne [<a
href=\"#10\">10</a>].\n </p>\n <p>Toll-like receptors (TLRs) are expressed
on human macrophages and identify general molecular patterns that occur on
bacteria\n and other pathogens but not on the host [<a
href=\"#11\">11</a>]. As such, they are a key subset of pattern recognition
receptors (PRRs) [<a href=\"#11\">11</a>]. This receptor recognition is critical to
the innate immune response. \n </p>\n <br/>\n <table align=\"right\"
border=\"0\" width=\"192\" cellpadding=\"5\">\n <tr>\n <td
align=\"center\">\n <a href=\"/content/qt94q2x8f1/3.png\">\n
<img src=\"/content/qt94q2x8f1/3s.png\" width=\"192\" height=\"128\"
align=\"center\"/>\n </a>\n </td>\n </tr>\n <tr>\n
<th align=\"center\">Figure 1</th>\n </tr>\n <tr>\n <td>\n
<b>Actions of toll-like receptors on antigen-presenting cell (dendritic cell) in
activating subsets of T cells.</b>\n </td>\n </tr>\n </table>\n
<p>It now appears that this interaction between the pathogen-associated molecular
pattern (PAMP) and the TLR is also critical\n to the adaptive immune
response [<a href=\"#11\">11</a>]. Specifically, this interaction is now thought to
be necessary before a macrophage can release IL-1\u03B1. This cytokine in turn\n
activates the macrophage through an autocrine process and also activates subsets of
helper T cells (Fig. 1) [<a href=\"#11\">11</a>]. \n </p>\n <p>It is known
that <i>P. acnes</i> can induce monocytes to secrete proinflammatory cytokines,
including tumor necrosis factor alpha (TNF-\u03B1), interleukin 1 beta\n
(IL-1\u03B2), and interleukin-8 (IL-8) [<a href=\"#12\">12</a>]. TLRs appear to be
involved in mediating the activation of monocytes, ultimately resulting in the
release of these proinflammatory\n cytokines. When these receptor subtypes
are activated by cell-wall components of gram-positive bacteria, such as <i>P.
acnes</i>, or by lipopolysaccharides of gram-negative bacteria, they begin
intracellular signaling of transcription factors for various\n
proinflammatory mediators [<a href=\"#13\">13</a>]. A recent study of macrophages
from mice with TLR-1 and TLR-6 receptors removed, but TLR-2 receptors intact,
demonstrates\n that <i>P. acnes</i> induces the release of
IL-12 and IL-8. A monoclonal antibody to the TLR-2 receptor inhibits the release
of these proinflammatory\n cytokines. The researchers conclude that <i>P.
acnes</i> induces the release of proinflammatory cytokines by activation of the
TLR-2 receptor [<a href=\"#14\">14</a>].\n </p>\n <br/>\n <a
name=\"section-3-0-0\"></a>\n <h3>The potential immunomodulating effects of
topical retinoids</h3>\n <p>Topical retinoids (e.g., tretinoin, adapalene, and
tazarotene) normalize hyperkeratinization and thereby exert indirect
immunomodulatory\n effects by changing the comedonal environment [<a
href=\"#15\">15</a>]. In essence, by preventing hypercornification of the
pilosebaceous unit, they promote a more aerobic environment inhospitable\n
to <i>P. acnes</i> [<a href=\"#16\">16</a>]. However, <i>in vitro</i> and <i>in
vivo</i> studies suggest that topical retinoids also demonstrate direct effects on
a number of additional immune factors implicated\n in the pathophysiology
of acne vulgaris. \n </p>\n <br/>\n <a name=\"section-3-1-0\"></a>\n
<h4><i>In vitro</i> models\n </h4>\n <p>A number of <i>in vitro</i> models
were used to study the anti-inflammatory effects of retinoids (tretinoin,
adapalene, isotretinoin, and etretinate);\n a corticosteroid
(betamethasone-17-valerate); and a nonsteroidal anti-inflammatory drug (NSAID,
indomethacin) [<a href=\"#17\">17</a>]. The actions of these agents on a number of
inflammatory mediators and mechanisms were assessed. These included the activity\n
of 15-lipoxygenase, the enzyme responsible for the conversion of arachidonic acid
to a leukotriene family of inflammatory\n mediators; the production of
other eicosanoids (5- and 15-hydroxyeicosatetraenoic acid or HETE); and chemotaxis.
Adapalene\n is associated with greater inhibition of the lipoxygenase
pathways and greater inhibition of leukotriene production compared\n with
all other agents, including the other retinoids tested. Adapalene and tretinoin
also demonstrate significant inhibition\n of oxygen free radicals released
from PMNs derived from rabbits. Adapalene also inhibits human chemotaxis of PMNs
(<a href=\"/content/qt94q2x8f1/tables.htm\">Table 1</a>) [<a href=\"#17\">17</a>,
<a href=\"#18\">18</a>]. \n </p>\n <br/>\n <table align=\"right\"
border=\"0\" width=\"192\" cellpadding=\"5\">\n <tr>\n <td
align=\"center\">\n <a href=\"/content/qt94q2x8f1/5.png\">\n
<img src=\"/content/qt94q2x8f1/5s.png\" width=\"192\" height=\"128\"
align=\"center\"/>\n </a>\n </td>\n </tr>\n <tr>\n
<th align=\"center\">Figure 2</th>\n </tr>\n <tr>\n <td>\n
<b>Effect of adapalene and tretinoin (retinoic acid) on down-regulating TLR2
expression on monocytes.</b>\n </td>\n </tr>\n </table>\n <p>A
recent <i>in vitro</i> study involving the retinoids adapalene and tretinoin,
demonstrates that these agents inhibit the expression of mammalian\n TLR-2
on human monocytes derived from healthy volunteers [<a href=\"#13\">13</a>]. First,
monoclonal antibodies were used to determine the expression of TLR receptors. After
4 days of culture, TLR-2 is\n strongly expressed in untreated cells,
whereas TLR-4 is only weakly expressed. The monocytes then were cultured with
different\n concentrations of the two retinoids. At low concentrations of
retinoids, approximately 100 percent of the monocytes express\n TLR-2 (Fig.
2). At higher concentrations, only approximately 20 percent of monocytes express
this receptor [<a href=\"#13\">13</a>]. It is interesting to note that the retinoid
concentration achieved in follicles is actually higher than the concentrations\n
used in this <i>in vitro</i> study. \n </p>\n <br/>\n <a
name=\"section-3-2-0\"></a>\n <h4><i>In vivo</i> animal models\n </h4>\n
<p>Ultraviolet (UV) light irradiation is used to induce erythema in animal models.
In a guinea pig model, both adapalene and\n tretinoin significantly
decreased erythema [<a href=\"#17\">17</a>].\n </p>\n <p>Cutaneous
inflammation can be induced through use of croton oil. This type of skin
inflammation can be inhibited by corticosteroids\n but not by NSAIDs. In
this animal model, adapalene demonstrates moderate inhibition of inflammation;
tretinoin exhibits very\n little effect. Although both retinoids exhibit
anti-inflammatory effects, the findings of this study suggest that adapalene\n
and tretinoin may address different aspects of inflammation (<a
href=\"/content/qt94q2x8f1/tables.htm\">Table 2</a>) [<a href=\"#17\">17</a>, <a
href=\"#18\">18</a>].\n </p>\n <p>The prostaglandin and leukotriene family
of inflammatory mediators are both derived from arachidonic acid. In the
arachidonic\n acid-induced ear edema mouse model, adapalene is associated
with significant anti-inflammatory effects; tretinoin is associated\n with
less inhibition (<a href=\"/content/qt94q2x8f1/tables.htm\">Table 2</a>) [<a
href=\"#17\">17</a>, <a href=\"#18\">18</a>]. \n </p>\n <p>Another animal
model of inflammation involves edema induced by carrageenan. NSAIDs exert
significant anti-inflammatory effects\n in this model [<a
href=\"#17\">17</a>]. In a rat model, adapalene demonstrates anti-inflammatory
effects equivalent to those of indomethacin; tretinoin does not\n
demonstrate significant anti-inflammatory effects (Table 2) [<a
href=\"#17\">17</a>]. \n </p>\n <br/>\n <a name=\"section-4-0-0\"></a>\n
<h3>The therapeutic implications of retinoid immunomodulatory effects</h3>\n
<p>On the basis of their immunomodulatory actions, topical retinoids are expected
to effectively reduce inflammatory lesions,\n in addition to comedones. The
degree to which each particular mechanism functions in human acne remains to be
tested to validate\n the in vitro and animal studies reviewed above.
However, the reduction in inflammation demonstrated in preclinical studies\n
have been validated by clinical trials. Various formulations of adapalene (gel,
cream, solution), tretinoin (gel, microsphere\n gel, cream), and tazarotene
gel are all found to significantly reduce inflammatory lesions in well-controlled
clinical trials\n [<a href=\"#19\">19</a>, <a href=\"#20\">20</a>, <a
href=\"#21\">21</a>, <a href=\"#22\">22</a>, <a href=\"#23\">23</a>, <a
href=\"#24\">24</a>, <a href=\"#25\">25</a>, <a href=\"#26\">26</a>]. Indeed,
topical retinoids are recommended as therapy for all stages of acne except the most
severe inflammatory stage [<a href=\"#27\">27</a>]. \n </p>\n <p>Of course,
criteria for choice of acne therapy involve not just efficacy in the treatment of
noninflammatory and inflammatory\n lesions but tolerability and the
potential for medication compliance. All topical retinoids can be associated with
cutaneous\n irritation that can interfere with compliance. Adapalene is
found to have the best cutaneous tolerability [<a href=\"#19\">19</a>, <a
href=\"#20\">20</a>, <a href=\"#22\">22</a>, <a href=\"#23\">23</a>, <a
href=\"#26\">26</a>]. Other therapeutic strategies to decrease the potential for
cutaneous irritation involves the use of new delivery systems\n such as the
tretinoin microsponge system, and alternative dosing regimens (e.g., QOD or short-
contact therapy) that are used\n to subdue the cutaneous irritation seen
with tazarotene [<a href=\"#28\">28</a>, <a href=\"#29\">29</a>, <a
href=\"#30\">30</a>]. \n </p>\n <br/>\n <a name=\"section-5-0-0\"></a>\n
<h3>Conclusion</h3>\n <p>An increasing understanding of the complexity of the
pathophysiology of acne vulgaris is guiding practitioners in their choice\n
of therapeutic agents. The immunomodulatory effects of topical retinoids provide a
rationale for using these agents in the\n treatment not only of comedones
but also of inflammatory lesions as well. \n </p>\n <font size=\"-1\">\n
<a name=\"section-6-0-0\"></a>\n </font>\n <h3>\n <font size=\"-
1\">References</font>\n </h3>\n <font size=\"-1\"><a name=\"1\"></a>1.
Kligman AM. An overview of acne. J Invest Dermatol. 1974;62:268-287.<br/><br/><a
name=\"2\"></a>2. Webster GF. Inflammation in acne vulgaris. J Am Acad Dermatol.
1995;33:247-253.<br/><br/><a name=\"3\"></a>3. Webster GF, Leyden JJ, Tsai CC,
Baehni P, McArthur WP. Polymorphonuclear leukocyte lysosomal release in response to
Propionibacterium\n acnes in vitro and its enhancement by sera from
inflammatory acne patients. J Invest Dermatol. 1980;74:398-401.<br/><br/><a
name=\"4\"></a>4. Eady EA, Cove JH. Is acne an infection of blocked pilosebaceous
follicles? Implications for antimicrobial treatment. Am\n J Clin Dermatol.
2000; 1: 201-209.<br/><br/><a name=\"5\"></a>5. Norris JF, Cunliffe WJ. A
histological and immunocytochemical study of early acne lesions. Br J Dermatol.
1988;118:651-659.<br/><br/><a name=\"6\"></a>6. Jappe U, Ingham E, Henwood J,
Holland KT. Propionibacterium acnes and inflammation in acne; P. acnes has T-cell
mitogenic\n activity. Br J Dermatol. 2002;146:202-209.<br/><br/><a
name=\"7\"></a>7. Zouboulis CC. Is acne vulgaris a genuine inflammatory disease?
Dermatology. 2001;203:277-279.<br/><br/><a name=\"8\"></a>8. Seltmann H, Rudawski
IM, Holland KT, Orfanos CE, Zouboulis CC. Propionibacterium acnes does not
influence the interleukin-1a/interleukin-8\n cascade in immortalized human
sebocytes in vitro. J Invest Dermatol. 2000;114:816.<br/><br/><a name=\"9\"></a>9.
Ingham E, Walters CE, Eady EA, Cove JH, Kearney JN, Cunliffe WJ. Inflammation in
acne vulgaris: failure of skin micro-organisms\n
to modulate keratinocyte interleukin 1 alpha production in vitro.
Dermatology. 1998;196:86-88.<br/><br/><a name=\"10\"></a>10. Chronnell CM, Ghali
LR, Ali RS, et al. Human beta defensin-1 and -2 expression in human pilosebaceous
units: upregulation\n in acne vulgaris lesions. J Invest Dermatol.
2001;117:1120-1125. <br/><br/><a name=\"11\"></a>11. Medzhitov R. Toll-like
receptors and innate immunity. Nat Rev Immunol. 2001;1:135-142.<br/><br/><a
name=\"12\"></a>12. Vowels BR, Yang S, Leyden JJ. Induction of proinflammatory
cytokines by a soluble factor of Propionibacterium acnes: implications\n
for chronic inflammatory acne. Infect Immun 1995;63:3158-3165.<br/><br/><a
name=\"13\"></a>13. Vega-Diaz B, Jonard A, Michel S. Regulation of human monocyte
toll-like receptor 2 (TLR2) expression by adapalene [abstract].\n J Eur
Acad Dermatol Venereol. 2002;16:123-124. <br/><br/><a name=\"14\"></a>14. Kim J,
Ochoa M-T, Krutzik SR, et al. Activation of toll-like receptor 2 in acne triggers
inflammatory cytokine responses.\n J Immunol.
2002;169:1535-1541.<br/><br/><a name=\"15\"></a>15. Wolf JE Jr. Potential anti-
inflammatory effects of topical retinoids and retinoid analogues. Adv Ther.
2002;19:109-118.<br/><br/><a name=\"16\"></a>16. Shalita A. The integral role of
topical and oral retinoids in the early treatment of acne. J Eur Acad Dermatol
Venereol.\n 2001;15(suppl 3):43-49.<br/><br/><a name=\"17\"></a>17. Hensby
C, Cavey D, Bouclier M, et al. The in vivo and in vitro anti-inflammatory activity
of CD271: a new retinoid-like\n modulator of cell differentiation. Agents
Actions. 1990;29:56-58.<br/><br/><a name=\"18\"></a>18. Shroot B, Michel S.
Pharmacology and chemistry of adapalene. J Am Acad Dermatol. 1997;36(suppl 1):S96-
S103.<br/><br/><a name=\"19\"></a>19. Cunliffe WJ, Poncet M, Loesche C, Verschoore
M. A comparison of the efficacy and tolerability of adapalene 0.1% gel versus\n
tretinoin 0.025% gel in patients with acne vulgaris: a meta-analysis of five
randomized trials. Br J Dermatol. 1998;139(suppl\n 52):48-56.<br/><br/><a
name=\"20\"></a>20. Grosshans E, Marks R, Mascaro JM, et al. Evaluation of clinical
efficacy and safety of adapalene 0.1% gel versus tretinoin\n 0.025% gel in
the treatment of acne vulgaris, with particular reference to the onset of action
and impact on quality of life.\n Br J Dermatol. 1998;139(suppl 52):26-
33.<br/><br/><a name=\"21\"></a>21. Lucky A, Jorizzo JL, Rodriguez D, et al.
Efficacy and tolerance of adapalene cream 0.1% compared with its cream vehicle\n
for the treatment of acne vulgaris. Cutis. 2001;68:34-40.<br/><br/><a
name=\"22\"></a>22. Ellis CN, Millikan LE, Smith EB, et al. Comparison of adapalene
0.1% solution and tretinoin 0.025% gel in the topical\n treatment of acne
vulgaris. Br J Dermatol. 1998;139(suppl 52): 41-47.<br/><br/><a name=\"23\"></a>23.
Thiboutot D, Gold MH, Jarratt MT, et al. Randomized controlled trial of the
tolerability, safety, and efficacy of adapalene\n gel 0.1% and tretinoin
microsphere gel 0.1% for the treatment of acne vulgaris. Cutis.
2001:68:10-19.<br/><br/><a name=\"24\"></a>24. Lucky AW, Cullen SI, Funicella T,
Jarratt MT, Jones T, Reddick ME. Double-blind, vehicle-controlled, multicenter
comparison\n of two 0.025% tretinoin creams in patients with acne vulgaris.
J Am Acad Dermatol. 1998;38: S24-S30.<br/><br/><a name=\"25\"></a>25. Webster GF,
Berson D, Stein LF, Fivenson DP, Tanghetti EA, Ling M. Efficacy and tolerability of
once-daily tazarotene\n 0.1% gel versus once-daily tretinoin 0.025% gel in
the treatment of facial acne vulgaris: a randomized trial. Cutis. 2001;67(suppl\n
6): 4-9.<br/><br/><a name=\"26\"></a>26. Webster GF, Guenther L, Poulin YP, Solomon
BA, Loven K, Lee J. A multicenter, double-blind, randomized comparison study\n
of the efficacy and tolerability of once-daily tazarotene 0.1% gel and adapalene
0.1% gel for the treatment of facial acne\n vulgaris. Cutis. 2002;69(suppl
2):4-11.<br/><br/><a name=\"27\"></a>27. Gollnick H, Cunliffe W. Management of
acne. A report from a Global Alliance to Improve Outcomes in Acne. J Am Acad
Dermatol\n 2003;49(Suppl):S1-38.<br/><br/><a name=\"28\"></a>28. Embil K,
Nacht S. The Microsponge Delivery System (MDS): a topical delivery system with
reduced irritancy incorporating\n multiple triggering mechanisms for the
release of actives. J Microencapsul. 1996;13:575-588.<br/><br/><a
name=\"29\"></a>29. Leyden J, Lowe N, Kakita L, Draelos Z. Comparison of treatment
of acne vulgaris with alternate-day applications of tazarotene\n 0.1% gel
and once-daily applications of adapalene 0.1% gel: a randomized trial. Cutis.
2001;67(suppl 6):10-16.<br/><br/><a name=\"30\"></a>30. Bershad S, Kranjac Singer
G, Parente JE, et al. Successful treatment of acne vulgaris using a new method:
results of a\n randomized vehicle-controlled trial of short-contact therapy
with 0.1% tazarotene gel. Arch Dermatol. 2002;138:481-489.<br/><br/></font>\n <p
align=\"center\">\u00A9 2005 Dermatology Online Journal</p>\n </body>\n</html>\
n","content_key":"f9b2456a9df1b2b749ae2aa21b0d51a1","content_type":"text/
html","data_digest":"68hET6N6xj0llP6t6+OVMA==","editors":null,"genre":"article","id
":"94q2x8f1","index_digest":"DBvKrHsbrPiIanLGPSITJA==","last_indexed":"2019-02-02
20:30:05
+0000","oa_policy":null,"ordering_in_sect":3,"pdf_url":null,"preview_key":null,"pub
lished":"2005","rights":null,"sidebar":[{"id":1,"kind":"RecentArticles","attrs":
{"items":[{"id":"qt0tz012ps","title":"Epstein-Barr virus-positive CD30+ B-cell
lymphoproliferative disease with histologic features resembling grade III
lymphomatoid granulomatosis induced by methotrexate","authors":[{"name":"Quaye,
Elizabeth H","fname":"Elizabeth","lname":"Quaye","mname":"H","institution":"Jacobs
School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, New
York, USA"},{"name":"D'Angelis,
Christopher","fname":"Christopher","lname":"D'Angelis","institution":"Jacobs School
of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, New York, USA\
nVA Western New York Healthcare System, Buffalo, New York, USA"},{"name":"Powell,
Jennifer","email":"Jennifer.powell5@va.gov","fname":"Jennifer","lname":"Powell","in
stitution":"Jacobs School of Medicine and Biomedical Sciences, University at
Buffalo, Buffalo, New York, USA\nVA Western New York Healthcare System, Buffalo,
New York, USA"}],"genre":"article","author_hide":null,"editors":[],"advisors":[]},
{"id":"qt1016c4g5","title":"Social support is associated with reduced impact of
hidradenitis suppurativa on quality of life: an observational study","authors":
[{"name":"Singh, Rohan","fname":"Rohan","lname":"Singh","institution":"Center for
Dermatology Research, Department of Dermatology, Wake Forest School of Medicine,
Winston-Salem, North Carolina, USA"},{"name":"Kelly, Katherine
A","fname":"Katherine","lname":"Kelly","mname":"A","institution":"Center for
Winston-Salem, North Carolina, USA"},{"name":"Paris, Paul
H","fname":"Paul","lname":"Paris","mname":"H","institution":"Center for Dermatology
Research, Department of Dermatology, Wake Forest School of Medicine, Winston-Salem,
North Carolina, USA"},{"name":"Senthilnathan,
Aditi","fname":"Aditi","lname":"Senthilnathan","institution":"Center for
Winston-Salem, North Carolina, USA"},{"name":"Feldman, Steven
R","fname":"Steven","lname":"Feldman","mname":"R","institution":"Center for
Winston-Salem, North Carolina, USA\nDepartment of Social Sciences & Health Policy,
Wake Forest School of Medicine, Winston-Salem, North Carolina, USA"},
{"name":"Pichardo, Rita
O","fname":"Rita","lname":"Pichardo","mname":"O","institution":"Center for
Winston-Salem, North Carolina,
USA"}],"genre":"article","author_hide":null,"editors":[],"advisors":[]},
{"id":"qt1820m79x","title":"Delayed diagnosis of DRESS syndrome in a patient with
skin of color","authors":[{"name":"Bean, Eric
L","fname":"Eric","lname":"Bean","mname":"L","institution":"Perelman School of
Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA"},
{"name":"Lewis, Daniel
J","email":"dlew2191@gmail.com","fname":"Daniel","lname":"Lewis","mname":"J","insti
tution":"Department of Dermatology, Perelman School of Medicine, University of
Pennsylvania, Philadelphia, Pennsylvania, USA"},{"name":"Weir, Michelle
A","fname":"Michelle","lname":"Weir","mname":"A","institution":"Department of
Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia,
Pennsylvania, USA"},{"name":"Micheletti, Robert
G","fname":"Robert","lname":"Micheletti","mname":"G","institution":"Department of
Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia,
Pennsylvania, USA"}],"genre":"article","author_hide":null,"editors":[],"advisors":
[]},{"id":"qt1jm0674r","title":"A case of self-improving collodion ichthyosis
associated with a rare variant of the ALOX12B gene","authors":[{"name":"Amoedo,
P","email":"amoedo.p.patricia@gmail.com","fname":"P","lname":"Amoedo","institution"
:"Servico de Dermatologia e Venereologia do Centro Hospitalar Universitario de Sao
Joao, Porto, Portugal"},{"name":"Cerejeira,
A","fname":"A","lname":"Cerejeira","institution":"Servico de Dermatologia e
Venereologia do Centro Hospitalar Universitario de Sao Joao, Porto, Portugal"},
{"name":"Pacheco, J","fname":"J","lname":"Pacheco","institution":"Servico de
Dermatologia e Venereologia do Centro Hospitalar Universitario de Sao Joao,
Porto, Portugal"},{"name":"Cruz,
MJ","fname":"MJ","lname":"Cruz","institution":"Servico de Dermatologia e
Venereologia do Centro Hospitalar Universitario de Sao Joao, Porto, Portugall\
nFacudade de Medicina da Universidade do Porto e CINTESIS, Porto, Portugal"},
{"name":"Mota, A","fname":"A","lname":"Mota","institution":"Servico de Dermatologia
e Venereologia do Centro Hospitalar Universitario de Sao Joao, Porto, Portugal\
nFacudade de Medicina da Universidade do Porto e CINTESIS, Porto,
Portugal"}],"genre":"article","author_hide":null,"editors":[],"advisors":[]},
{"id":"qt3217m2vn","title":"Nirmatrelvir-ritonivir, COVID-19, and possible adverse
cutaneous reactions","authors":[{"name":"Albrecht, J
Mark","fname":"J","lname":"Albrecht","mname":"Mark","institution":"School of
Medicine, University of Utah, Salt Lake City, Utah, USA"},{"name":"Cooper, Benjamin
R","fname":"Benjamin","lname":"Cooper","mname":"R","institution":"College of
Osteopathic Medicine, Rocky Vista University, Parker, Colorado, USA"},
{"name":"Waller, Jacquelyn
D","fname":"Jacquelyn","lname":"Waller","mname":"D","institution":"Department of
Biomedical Sciences, Rocky Vista University, Parker, Colorado, USA"},
{"name":"Presley, Colby
L","fname":"Colby","lname":"Presley","mname":"L","institution":"Division of
Dermatology, Lehigh Valley Health Network, Allentown, Pennsylvania, USA"},
{"name":"Pulsipher, Kayd
J","fname":"Kayd","lname":"Pulsipher","mname":"J","institution":"Department of
Dermatology, Campbell University at Sampson Regional Medical Center, Clinton, North
Carolina, USA"},{"name":"Rundle, Chandler
W","fname":"Chandler","lname":"Rundle","mname":"W","institution":"Department of
Dermatology, Duke University Hospital, Durham, North Carolina, USA"},
{"name":"Dellavalle, Robert
P","email":"Robert.dellavalle@ucdenver.edu","fname":"Robert","lname":"Dellavalle","
mname":"P","institution":"Department of Epidemiology, Colorado School of Public
Health, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA\
nDermatology Service, U.S. Department of Veterans Affairs Rocky Mountain Regional
Medical Center, Aurora, Colorado,
USA"}],"genre":"article","author_hide":null,"editors":[],"advisors":
[]}],"title":"Related
Items"}}],"source":"doj","status":"published","submitted":"2005-01-01","title":"The
potential immunomodulatory effects of topical retinoids","unit":
{"id":"doj","name":"Dermatology Online
Journal","type":"journal","status":"active"},"usage":[{"month":"2005-
01","hits":0,"downloads":0},{"month":"2013-06","hits":12,"downloads":0},
{"month":"2013-07","hits":25,"downloads":0},{"month":"2013-
02","hits":35,"downloads":0},{"month":"2023-
03","hits":21,"downloads":0}],"unit_attrs":{"apc":"varies by manuscript
type","logo":
{"width":258,"height":129,"asset_id":"203203ac7f2ff182b5488a28730e1962200a906951486
14d7fe28c0b0b85c509","is_banner":true,"image_type":"jpeg"},"about":"<p><em>Dermatol
ogy Online Journal</em> is an open-access, refereed publication intended to meet
reference and education needs of the international dermatology community\n
since 1995. <em>Dermatology Online Journal</em> is supported by the <a
href=\"http://www.ucdmc.ucdavis.edu/dermatology/\">Department of Dermatology UC\n
Davis</a>, and by the <a href=\"http://www.northerncalifornia.va.gov/\">Northern
California Veterans Administration</a>.</p>","eissn":"1087-
2108","oaspa":"notSubmitted","bgColor":"#ffffff","elColor":"black","indexed":"doaj"
,"nav_bar":[{"id":1,"name":"About","type":"folder","sub_nav":[{"id":2,"name":"About
Us","slug":"aboutus","type":"page"},{"id":3,"name":"Editorial
Board","slug":"editorialboard","type":"page"}]},{"id":4,"name":"Contact
us","slug":"contactus","type":"page"},
{"id":5,"name":"Policies","slug":"policies","type":"page"},
{"id":6,"name":"Instructions for
Authors","slug":"submissionguidelines","type":"page"},{"id":7,"name":"other
pages","type":"folder","hidden":true,"sub_nav":[{"id":8,"name":"Issue
19:6","slug":"editorialboard_19_6","type":"page"},{"id":9,"name":"Issue
1:1","slug":"editorialboard_1_1","type":"page"}]}],"twitter":"derm_journal","pub_fr
eq":"monthly","disciplines":"medicine"},"header":{"campusID":"ucd","campusName":"UC
Davis","ancestorID":"ucd","ancestorName":"UC Davis","campuses":
[{"id":"","name":"eScholarship at..."},{"id":"ucb","name":"UC Berkeley"},
{"id":"ucd","name":"UC Davis"},{"id":"uci","name":"UC Irvine"},
{"id":"ucla","name":"UCLA"},{"id":"ucm","name":"UC Merced"},{"id":"ucr","name":"UC
Riverside"},{"id":"ucsd","name":"UC San Diego"},{"id":"ucsf","name":"UCSF"},
{"id":"ucsb","name":"UC Santa Barbara"},{"id":"ucsc","name":"UC Santa Cruz"},
{"id":"ucop","name":"UC Office of the President"},{"id":"lbnl","name":"Lawrence
Berkeley National Laboratory"},{"id":"anrcs","name":"UC Agriculture & Natural
Resources"}],"logo":{"url":"/cms-assets/203203ac7f2ff182b5488a28730e1962200a9069514
8614d7fe28c0b0b85c509","width":258,"height":129,"is_banner":true},"bgColor":"#fffff
f","elColor":"black","directSubmit":null,"directSubmitURL":null,"directManageURLaut
hor":null,"directManageURLeditor":null,"nav_bar":[{"id":-
9999,"type":"fixed_page","name":"Journal Home","url":"/uc/doj"},
{"id":0,"type":"fixed_folder","name":"Issues","url":null,"sub_nav":
[{"issue_id":2920,"unit_id":"doj","volume":"29","issue":"1","published":"2023-01-
01","attrs":{"rights":"https://creativecommons.org/licenses/by-nc-nd/
4.0/","description":""},"id":-1,"url":"/uc/doj/29/1","name":"Volume 29, Issue 1,
2023","type":"page"},
{"issue_id":2876,"unit_id":"doj","volume":"28","issue":"6","published":"2022-01-
4.0/","description":"November-December
2022"},"id":-2,"url":"/uc/doj/28/6","name":"Volume 28, Issue 6,
2022","type":"page"},
2022","type":"page"},
2022","type":"page"},
2022","type":"page"},
2022","type":"page"},
2022","type":"page"},
2021","type":"page"},
2021","type":"page"},
01","att
rs":{"rights":"https://creativecommons.org/licenses/by-nc-nd/
2021","type":"page"},
2021","type":"page"},
2021","type":"page"},
2021","type":"page"},
01","attrs":{"rights":"https://creativecommons.org/licenses/by-nc-nd/4.0/"},"id":-
14,"url":"/uc/doj/27/6","name":"Volume 27, Issue 6, 2021","type":"page"},
2021","type":"page"},
2021","type":"page"},
2021","type":"page"},
2021","type":"page"},
2021","type":"page"},
2020","type":"page"},
2020","type":"page"},
2020","type":"page"},
2020","type":"page"},
2020","type":"page"},
2020","type":"page"},
2020","type":"page"},
2020","type":"page"},
2020","type":"page"},
2020","type":"page"},
2020","type":"page"},
2020","type":"page"},
2019","type":"page"},
2019","type":"page"},
2019","type":"page"},
2019","type":"page"},
2019","type":"page"},
2019","type":"page"},
2019","type":"page"},
2019","type":"page"},
2019","type":"page"},
2019","type":"page"},
2019","type":"page"},
2019","type":"page"},
2018","type":"page"},
2018","type":"page"},
2018","type":"page"},
2018","type":"page"},
2018","type":"page"},
4.0/","description":""},"id":-49,"url":"/uc/doj/24/7","name":"Volume
24, Issue 7, 2018","type":"page"},
2018","type":"page"},
2018","type":"page"},
2018","type":"page"},
2018","type":"page"},
2018","type":"page"},
2018","type":"page"},
2017","type":"page"},
2017","type":"page"},
2017","type":"page"},
2017","type":"page"},
2017","type":"page"},
2017","type":"page"},
2017","type":"page"},
2017","type":"page"},
2017","type":"page"},
2017","type":"page"},
2017","type":"page"},
2017","type":"page"},
2016","type":"page"},
2016","type":"page"},
2016","type":"page"},
2016","type":"page"},
2016","type":"page"},
2016","type":"page"},
2016","type":"page"},
2016","type":"page"},
2016","type":"page"},
2016","type":"page"},
2016","type":"page"},
2016","type":"page"},
2015","type":"page"},
2015","type":"page"},
2015","type":"page"},
2015","type":"page"},
2015","type":"page"},
2015","type":"page"},
2015","type":"page"},
2015","type":"page"},
2015","type":"page"},
01","attrs":{"rights":"https://creativecommons.org/lice
nses/by-nc-nd/4.0/","description":""},"id":-89,"url":"/uc/doj/21/3","name":"Volume
21, Issue 3, 2015","type":"page"},
2015","type":"page"},
2015","type":"page"},
01","attrs":{"title":"Nicholas A. Soter, MD, Guest
Editor","rights":"https://creativecommons.org/licenses/by-nc-nd/4.0/","description"
:""},"id":-92,"url":"/uc/doj/20/12","name":"Volume 20, Issue 12,
2015","type":"page"},
2014","type":"page"},
2014","type":"page"},
2014","type":"page"},
2014","type":"page"},
2014","type":"page"},
2014","type":"page"},
2014","type":"page"},
2014","type":"page"},
2014","type":"page"},
2014","type":"page"},
01","attrs":{"title":"Nicholas A. Soter, MD, Guest
Editor","rights":"https://creativecommons.org/licenses/by-nc-nd/4.0/","description"
:""},"id":-104,"url":"/uc/doj/19/12","name":"Volume 19, Issue 12,
2013","type":"page"},
01","attrs":null,"id":-112,"url":"/uc/doj/19/4","name":"Volume 19, Issue 4,
2013","type":"page"},
2013","type":"page"},
2013","type":"page"},
2013","type":"page"},
2012","type":"page"},
2012","type":"page"},
2012","type":"page"},
2012","type":"page"},
2012","type":"page"},
2012","type":"page"},
2012","type":"page"},
2012","type":"page"},
2012","type":"page"},
2012","type":"page"},
2012","type":"page"},
2012","type":"page"},
2011","type":"page"},
2011","type":"page"},
2011","type":"page"},
2011","type":"page"},
2011","type":"page"},
2011","type":"page"},
2011","type":"page"},
2011","type":"page"},
01","attrs":null,"id":-136,"url":"/uc/doj/17/4"
,"name":"Volume 17, Issue 4, 2011","type":"page"},
2011","type":"page"},
2011","type":"page"},
2011","type":"page"},
2010","type":"page"},
2010","type":"page"},
2010","type":"page"},
2010","type":"page"},
2010","type":"page"},
2010","type":"page"},
2010","type":"page"},
2010","type":"page"},
2010","type":"page"},
2010","type":"page"},
2010","type":"page"},
2010","type":"page"},
2009","type":"page"},
2009","type":"page"},
2009","type":"page"},
2009","type":"page"},
2009","type":"page"},
2009","type":"page"},
2009","type":"page"},
2009","type":"page"},
2009","type":"page"},
2009","type":"page"},
2009","type":"page"},
2009","type":"page"},
2008","type":"page"},
2008","type":"page"},
2008","type":"page"},
2008","type":"page"},
2008","type":"page"},
2008","type":"page"},
2008","type":"page"},
2008","type":"page"},
2008","type":"page"},
2008","type":"page"},
2008","type":"page"},
2008","type":"page"},
2007","type":"page"},
2007","type":"page"},
2007","type":"page"},
2007","type":"page"},
2006","type":"page"},
2006","type":"page"},
2006","type":"page"},
2006","type":"page"},
2006","type":"page"},
2006","type":"page"},
2006","type":"page"},
2005","type":"page"},
2005","type":"page"},
2005","type":"page"},
2005","type":"page"},
2004","type":"page"},
01","attrs":null,"id":-192,"url":"/uc/doj/10/2","name":"Volume
10, Issue 2, 2004","type":"page"},
2004","type":"page"},
2003","type":"page"},
2003","type":"page"},
2003","type":"page"},
2003","type":"page"},
2003","type":"page"},
2002","type":"page"},
2002","type":"page"},
2001","type":"page"},
2001","type":"page"},
2000","type":"page"},
1999","type":"page"},
1999","type":"page"},
1998","type":"page"},
1997","type":"page"},
1997","type":"page"},
1996","type":"page"},
1995","type":"page"},
1995","type":"page"}]},{"id":1,"name":"About","type":"folder","sub_nav":
[{"id":2,"name":"About Us","slug":"aboutus","type":"page","url":"/uc/doj/aboutus"},
{"id":3,"name":"Editorial
Board","slug":"editorialboard","type":"page","url":"/uc/doj/editorialboard"}]},
{"id":4,"name":"Contact
us","slug":"contactus","type":"page","url":"/uc/doj/contactus"},
{"id":5,"name":"Policies","slug":"policies","type":"page","url":"/uc/doj/
policies"},{"id":6,"name":"Instructions for
Authors","slug":"submissionguidelines","type":"page","url":"/uc/doj/
submissionguidelines"},{"id":7,"name":"other
pages","type":"folder","hidden":true,"sub_nav":[{"id":8,"name":"Issue
19:6","slug":"editorialboard_19_6","type":"page","url":"/uc/doj/editorialboard_19_6
"},{"id":9,"name":"Issue
18:12","slug":"editorialboard_18_12","type":"page","url":"/uc/doj/
editorialboard_18_12"},{"id":15,"name":"Issue
9:5","slug":"editorialboard_9_5","type":"page","url":"/uc/doj/editorialboard_9_5"},
{"id":93,"name":"Issue
1:1","slug":"editorialboard_1_1","type":"page","url":"/uc/doj/editorialboard_1_1"}]
}],"social":{"facebook":null,"twitter":"derm_journal","rss":"/rss/unit/
doj"},"breadcrumb":[{"name":"eScholarship","id":"root","url":"/"},{"name":"UC
Davis","id":"ucd","url":"/uc/ucd"},{"name":"Dermatology Online
Journal","id":"doj","url":"/uc/doj"},{"name":"Volume 11, Issue
1","id":"doj:11:1","url":"/uc/doj/11/1"}]},"numbering":null,"commenting_ok":null};<
/script>
<script src="/js/vendors~app-bundle-00d43f548dc81cb601d0.js"></script>
<script src="/js/app-bundle-e7dcfe8c21afd5982d33.js"></script>
</body>
</html>

Jones

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Jones

Uploaded by

Copyright:

Available Formats

<!

<div id="main"><div data-reactroot=""><div class="body"><a href="#maincontent"

You might also like