Dermal dendritic cells indermatitis, and norm

Loren E. Clarke, MD,a,b Klaus F. Helm, MD,a,b Jeannieand Jennie T. Clarke, MDa

Hershey, Pennsylvania

tensor skin is unknown. We hypothesized that PSO mayerences in the number or type of dermal dendritic cells

distribution in normal-appearing flexural and extensor

he number, distribution, and type of Langerhans cells,

Gflam

cellnod0190-9622/$36.00

systemic circulation, and eventually migrate intoperipheral tissues. Although they are related to 2010 by the American Academy of Dermatology, Inc.major histocompatibility complex molecules to Tlymphocytes and B lymphocytes.2-4 They also pro-duce cytokines and inflammatory mediators thatstimulate and regulate T lymphocytes and otherDCs. DCs originate in the bone marrow, enter the

From the Departments of Dermatologya and Pathology,b Penn

State Hershey Medical Center.

Supported by Penn State Hershey, Pathology Department Re-

search Initiation Grant Program.

Conflicts of interest: None declared.

Reprint requests: Loren E. Clarke, MD, Department of Pathology,

Penn State Hershey Medical Center, H179, 500 University Dr, PO

Box 850, Hershey PA 17033. E-mail: lclarke@hmc.psu.edu.

Published online June 13, 2011.

PSO: psoriasisdoi:1

98ues also contain dendritic cells (DCs). DCs ares that take up antigen, migrate to local lymphes, and present that antigen in association with

IL: interleukinLC: Langerhans cellmDCs: myeloid dendritic cellspDCs: plasmacytoid dendritic cellsND: nummular dermatitisplaq 1In addition to lymphocytes and other in-matory cells, it is now evident that psoriatic

DC: dendritic celldDC: dermal dendritic cellIFN: interferonriasis (PSO) have occurred in recent years.

reat advances in the understanding of pso-

Abbreviations used:in DC localization. However, dDCs were significantly increased in PSO by comparison with normal-appearing skin, supporting existing evidence that they are involved in the overall pathogenesis of PSO.( J Am Acad Dermatol 2012;66:98-105.)

Key words: CD11; CD123; CD207; CD303; dendritic cells; psoriasis.Conclusions: The data did not support the hypothewith PSO.

sis that PSO favors extensor skin because of differencesLimitations: We did not study seasonal variationResults: Significant differences in dDC density were not identified between flexural and extensor skin,although extensor skin contained fewer CD11a1 and CD11c1 cells. Compared with normal-appearing skin,cells expressing CD11a, CD11c, CD123, CD303, and CD207 were increased in PSO. ND lesions showedsimilar increases. No significant difference between PSO and ND was evident with the exception ofdecreased S100A61 cells in PSO.

in DC density or assess nonlesional skin from patientsmyeloid dendritic cells (DCs), and plasmacytoid DCs was compared in normal-appearing skin, PSO, and ND.Background: The reason psoriasis (PSO) favors exinvolve extensor skin preferentially because of diff(dDCs) between flexural and extensor skin.

Objective: We sought to compare dDC type andskin, PSO, and nummular dermatitis (ND).

Methods: Using immunohistochemical markers, t0.1016/j.jaad.2010.12.001psoriasis, nummularal-appearing skin

Hennessy, MD,a,b Richard D. Bruggeman, MS,bmacrophages and resemble them morphologically,

icated dDCs in PSO.expressing CD11c1

9 These cells are alsoof patients with PSO,role in the subsequentpart by stimulatingand proliferation.10

y their production ofhave been previouslysis of PSO, includingerferon (IFN)-a, inter-

ic therapies seems to

well. CD1a, an antibohistocompatibility compantigen presentation, isbeen used in routine dCD207/Langerin, a recemembranous C-type lelated ligands found on tand other pathogens.16

dermal LCs, it is also expappear to be distinct fparts.17-20 CD11c, an innormal-appearing/steadflammatory DCs,7 is relasubset of DCs (mDCs

RY

cellsSO)t diffr the

erenappee fouical

d nucontained increased dDCs, includingboth myeloid and plasmacytoidsubtypes. The changes were not sitespecific.

d The results support other datasuggesting dDCs are involved in PSO,but their quantity does not appear toaccount for the predilection of PSO forextensor skin.

J AM ACAD DERMATOLVOLUME 66, NUMBER 1

Clarke et al 99support a role for dDCs in PSO pathogenesis.11

Psoralen plus ultraviolet A decreases dDCs andepidermal T lymphocytes in association with clear-ing of chronic plaque PSO. Efalizumab, a humanmonoclonal antibody directed against lymphocytefunction associated antigen-1 that is efficacious inPSO (although it is no longer available because of anDCs (mDCs); and (3) dermalplasmacytoid DCs (pDCs)6

(Fig 1). During inflammatorystates, a population of in-flammatory mDCs can alsobe detected,7 but it is notclear whether these are adistinct cell type derivedfrom progenitor cells withinthe systemic circulation orsimply mDCs in an activatedstate.

Several studies have implA marked increase in dDCsoccurs in psoriatic plaques.8,

increased in nonlesional skinand they are thought to play adevelopment of plaques9 inT-lymphocyte developmentThis is likely accomplished bcytokines, several of whichimplicated in the pathogenetumor necrosis factor-alfa, intleukin (IL)-23, and IL-15.

The success of antipsoriatmacrophages lack the complex antigen processingand presenting capabilities of DCs.

Until recently, the Langerhans cells (LCs) of theepidermis were widely regarded as the only cutane-ous antigen-presenting cells. Now, however, itappears that DCs residing within the dermis (dermalDCs [dDCs]) are actually of equal or greater impor-tance in the pathogenesis ofmany skin inflammatory dis-eases. Depending on themethods used to identifythem and the criteria bywhich they are classified, asmany as 5 different subtypesof cutaneous dDCs havebeen described.5 For pur-poses of simplification, how-ever, they may be broadlycategorized into one of 3general subsets: (1) epider-mal LCs; (2) dermal myeloid

CAPSULE SUMMA

d Dermal dendriticrole in psoriasis (Phypothesized thamight account fofor extensor skin.

d No significant diffbetween normal-extensor skin werimmunohistochemHowever, PSO anunacceptably high risk of progressive multifocalleukoencephalopathy), blocks the interactionthe heterodimeric lymphocyte function associatedantigen-1 molecule (CD11a/CD18). Although it isgenerally expressed primarily by T lymphocytes ratherthan DCs, CD11a binds intracellular adhesion mole-cules on DCs and plays a key role in lymphocytetrafficking, antigen presentation, and T-cell costimula-tion. Incontrast tomDCs,pDCsarenegative forCD11c.

Instead, they are recogCD123 and CD303/bloCD34, CD68, and S100. LikefactorXIIIa, however, theyareby no means specific forantigen-presenting cells.

Fortunately, markers withincreased specificity havesince emerged. Althoughsome are suitable only forflow cytometric analysis,many are now available forimmunohistochemistry asdy directed against an majorlex-like molecule involved inhighly specific for LCs and hasiagnostic work for years.14,15

ntly identified LC marker, is actin that recognizes mannosy-he surface of viruses, bacteria,Although it is found on epi-ressed by a subset of DCs thatrom their epidermal counter-tegrin expressed by dDCs iny-state skin and also by in-tively specific for the myeloid). CD11a composes part ofbetween lymphocyte function associated antigen-1 on T cells and intracelluar adhesion molecule-2 onDCs and reduces the density of CD11c1 dDCs.12

Tumor necrosis factor inhibitors have also beenshown to decrease dDCs.

Studies of dDCs are dependent on markers thatallow their reliable identification. In the late 1980s and

early 1990s, markers such asfactor XIIIa were found tolabel dermal cells with den-dritic morphology that werereferred to as dermal den-drocytes.13 The specificity ofthese antibodies for antigen-presenting cells is doubtful,however, because they areusually expressed by macro-phages as well. Numerousother markers are known tolabel dermal cells with den-dritic morphology, including

(dDCs) may play apathogenesis. Weerences in dDCspreference of PSO

ces in dDCsaring flexural andnd usingmarkers for dDCs.mmular dermatitisnized by their expression ofod dendritic cell antigen-2.21

ic ceigraCs aeaseactoractivsmaf typand m

J AM ACAD DERMATOLJANUARY 2012

100 Clarke et alBecause mDCs may also express CD123 in low levels,CD303/blood dendritic cell antigen-2 is currentlyregarded as the most specific marker of pDCs.7

We hypothesized that PSO may involve extensor

Fig 1. Basic subtypes of cutaneous dendritwithin epidermis, but after antigen uptake, mand travel to local lymph nodes. Myeloid Dsteady-state conditions, but they also incrpsoriatic plaques produce tumor necrosis f(iNOS ). In addition, they may stimulate theDCs were named for their resemblance to plalymphocytes. They produce large amounts oIFN stimulates and regulates T lymphocytesskin preferentially because of a difference in thenumber of dDCs between flexural and extensorareas under steady-state (ie, noninflamed) condi-tions. Using immunohistochemistry and routinelyprocessed, formalin-fixed, paraffin-embedded archi-val tissue, we studied a broad panel of DC markers(both specific and nonspecific) in normal-appearing(uninflamed) flexural skin and extensor skin, psori-atic plaques, and nummular dermatitis (ND).

METHODSTissue selection

Routinely processed, formalin-fixed, paraffin-embedded tissue blocks from patients with PSO,ND, and normal-appearing flexural and extensorskin were retrieved from the files of the Departmentof Pathology at the Penn State University HersheyMedical Center.

Ten specimens from patients aged 20 to 50 years(average age 37.5 years) with PSO on the abdomen,back, or flank were selected, along with 10 age-matched and site-matched specimens from patientswith ND (average age 39.5 years). Also examinedwas histologically normal-appearing skin fromuninvolved (without inflammation or neoplasm) re-gions of surgical excision specimens of benign skintumors (eg, congenital nevi and dermatofibromas).These normal-appearing skin specimens were frompatients 20 to 50 years of age andwere obtained fromthe elbow, knee, antecubital fossa, or popliteal fossa.

lls (DCs). Langerhans cells generally residete into dermis where they enter lymphaticsre present within dermis under normal ordramatically during inflammation and in(TNF ) and inducible nitric oxide synthaseation of Th17 T lymphocytes. Plasmacytoidcells, and they share several features with Be 1 interferon (IFN ) during viral infections.yeloid DCs.A total of 26 normal-appearing skin samples werestudied: 7 elbow and knee specimens, and 6 poplitealfossa and antecubital fossa specimens.

ImmunohistochemistryFormalin-fixed, paraffin-embedded tissue sections

were reacted with mouse monoclonal anti-CD1a(DAKO Corp, Carpinteria, CA), anti-CD11a (Abcam,Cambridge, MA), anti-CD11c (Abcam), anti-CD68(DAKO Corp), anti-CD34 (DAKO Corp), anti-s100A4 (DAKO Corp), anti-s100 A6 (Abcam), anti-CD303/blood dendritic cell antigen-2 (Abcam),anti-CD207/Langerin (Abcam), and anti-CD123(eBioscience, San Diego, CA). Four-micrometer sec-tions were cut and slides were baked for 1 hour at508C. Slides were deparaffinized in xylene and hy-drated through a series of ethanol solutions (100%,100%, 95%,distilledwater). Subsequently, slidesweretreatedwith 0.05% Tween 20 in tris buffered saline for5minutes topermeabilize tissues andwashed twice intris buffered saline. Slideswere heated in a householdvegetable steamer in 1 mmol/L EDTA buffer (pH 8.0)or 10 mmol/L sodium citrate buffer (pH 6.0) for 20minutes for antigen retrieval and treated with 3%hydrogen peroxide for 10 minutes to quench endog-enous peroxidase activity. After washing twice with

J AM ACAD DERMATOLVOLUME 66, NUMBER 1

Clarke et al 101tris buffered saline, the slides were incubated withthe primary antibodies for 30 minutes at roomtemperature. They were then incubated withEnvision1 (DAKO Corp) antirabbit or antimouselabeled polymer conjugated with horseradish per-oxidase for 20 minutes at room temperature, devel-oped using DAB1 (DAKO Corp), and counterstainedwith Meyer modified hematoxylin. All immunohis-tochemical staining procedures were performed onan Autostainer Plus (DAKO Corp).

Assessment of immunohistochemical stainingTo obtain an objective analysis of positivity,

Table I. Average cell counts (per pixel 31000) forcells staining with dendritic cellimmunohistochemical markers in healthy flexuraland extensor skin, psoriasis lesions, and nummulardermatitis lesions

Marker F E PSO ND

CD11a 0.00384 0.00221 0.10809 0.04454CD11c 0.00424 0.00207 0.01402 0.04291CD1a 0.00796 0.01340 0.03035 0.06796CD34 0.30803 0.28319 0.11832 0.17371CD68 0.00459 0.00252 0.02385 0.01489FXIIIa 0.02880 0.04039 0.04297 0.04256S100A4 0.10467 0.12253 0.21546 0.25007S100A6 0.06410 0.06735 0.04034 0.10953CD303 (BDCA-2) 0.00021 0.00845 0.01434 0.1846CD123 0.00010 0.00281 0.01513 0.01421CD207 (Langerin) 0.00021 0.00018 0.01611 0.01458

BDCA, Blood dendritic cell antigen-2; E, extensor skin; F, flexural

skin; ND, nummular dermatitis; PSO, psoriasis.automated scoring of immunohistochemical expres-sion was conducted using image analysis as follows:photomicrographs of a field of standardized size,limited to the dermis, were obtained at 3200 mag-nification for each glass slide and imported intoAdobe Photoshop Version CS3 Extended (AdobeSystems Inc, San Jose, CA). Using the Image Analysisfeature in the software, DAB1 (DAKO Corp) (ie,brown) pixels were identified and counted for eachimage. Results were tabulated as positive (brown)pixels per total pixels (ie, the total field size). Theresults were confirmed by review of each slide byexperienced dermatopathologists.

Statistical analysisDifferences among the groups were analyzed

using a repeated measures rank analysis of covari-ance model. P values equal to or less than .001 wereconsidered significant.

RESULTSThe results are summarized in Tables I to III.Normal-appearing flexural versus extensorskin

Normal-appearing extensor skin contained fewerdermal CD11a1 and CD11c1 cells than flexural skin(Table I), but this difference did not achieve statis-tical significance, nor did differences between any ofthe other markers. Overall, very few cells expressedany of the markers studied (Figs 2 and 3).

Psoriatic plaques versus normal-appearingskin

In PSO, CD11a1 cells were significantly increasedwhen compared with normal-appearing skin (Fig 4).CD11c1 DCs were also increased in PSO (Fig 5), butmuch more so in comparison with healthy extensorskin, where the difference reached statistical signif-icance. Cells expressing CD123, CD303, and dermalCD207/Langerin were also significantly increased in

Table II. P values for pairwise comparisons fromrepeated measures rank analysis of covariancemodel

Marker F vs E F vs ND F vs PSO E vs ND E vs PSO ND vs PSO

CD11a .52 \.001 \.001 \.001 \.001 .22CD11c .27 \.001 .067 \.001 \.001 .037CD1a .7 \.001 .033 \.001 .037 .11CD34 .63 .015 \.001 .022 \.001 .15CD68 .29 .005 \.001 \.001 \.001 .15S100A4 .59 \.001 .011 \.001 .02 .21S100A6 .80 .3 .031 .15 .029 .001CD303 .26 \.001 \.001 \.001 \.001 .450CD207 .26 \.001 \.001 \.001 \.001 .664CD123 .23 .03 \.001 \.001 \.001 .256

E, Extensor skin (normal-appearing); F, flexural skin (normal-

appearing); ND, nummular dermatitis; PSO, psoriasis.PSO (Figs 6 to 8). CD681 cells in PSO biopsyspecimens were also significantly increased relativeto normal-appearing skin. CD341 cells were signif-icantly decreased in PSO compared with normal-appearing skin. S100A41 cells and S100A61 cellswere not significantly different between PSO andnormal-appearing skin.

ND versus normal-appearing skinND showed significantly greater numbers of

cells that expressed CD11a, CD11c, CD1a, CD68,and S100A4 by comparison with normal-appearingskin. Cells that expressed CD123, CD303, andCD207/Langerin were also significantly increased(Figs 9 to 11).

Psoriatic plaques versus NDThe density of dDCs in PSO and ND was similar

overall with no significant differences between any

rmat

68

ase*ase*

een P

each

*Statistically significant changes by comparison with normal-appearing

J AM ACAD DERMATOLJANUARY 2012

102 Clarke et alTable III. Comparison of psoriasis and nummular de

CD11a CD11c CD1a CD34 CD

PSO Increase* Increase* Increase Decrease* IncreND Increase* Increase* Increase* Decrease Incre

Differences in S100A61 cells were not significantly different betw

(although they approached significance). However, compared with

PSO versus ND (P = .001).

ND, Nummular dermatitis; PSO, psoriasis.of the markers studied, the one exception being asignificant decrease in S100A61 cells in PSO versusND (Figs 12 and 13) (Table III).

DISCUSSIONIn light of many recent studies proposing a role for

dDCs in the pathogenesis of PSO, we hypothesizedthat the disease may involve extensor skin preferen-tially because of a difference in the number or type ofdDCs between flexural and extensor areas understeady-state (ie, noninflamed) conditions. This hy-pothesis was not confirmed by our study. Althoughextensor skin contained fewer CD11a1 and CD11c1

cells than flexural skin, the difference did not achieve

Fig 2. CD11a in normal-appearing extensor skin. (Orig-inal magnification: 3100.)

Fig 3. CD11c in normal-appearing extensor skin. (Origi-nal magnification: 3100.)itis with normal-appearing skin

S100A4 S100A6 CD303 CD207 CD123

Increase Decrease Increase* Increase* Increase*Increase* Increase Increase* Increase* Increase*

SO and normal-appearing skin or ND and normal-appearing skin

other, there was significant difference, with decreased numbers in

skin.statistical significance as evaluated by pairwise com-parisons in a repeated measures rank analysis ofcovariance model, nor did differences in any of theother dDCmarkers that we included (Table II). Theseresults, however, do not exclude dDCs as a factor indisease localization. Nestle et al10 demonstrated anincrease in pDCs in uninvolved (nonlesional) skin ofpatients with PSO, whereas we studied only normaltissue from subjects without the disease (tissue fromuninvolved skin from patients with PSO was notavailable to us). It is possible these differences existonly in patients predisposed to PSO.

Wedid find, however, that cells expressing CD11c,CD11a, CD123, CD303, and CD207/Langerin weresignificantly increased in PSO as compared withnormal-appearing skin. As noted in the introduction,

Fig 4. CD11a in psoriasis. (Original magnification:3100.)

Fig 5. CD11c in psoriasis. (Original magnification:3100.)

J AM ACAD DERMATOLVOLUME 66, NUMBER 1

Clarke et al 103increases in CD11c1 myeloid dDCs in psoriaticplaques have been well documented by other inves-tigators.22 Results of studies pertaining to pDCs inPSO, however, have beenmixed. AlthoughGuttman-Yassky et al23 found no significant increase in pDCs inchronic large plaque PSO, a study by Nestle et al9 didshow an increased density of these cells. It may bethat density of pDCs varies with the age of a lesion,but we found that even established plaques con-tained numerous pDCs.

Our data indicating an increase in both subsets ofdDCs make sense in light of what is now knownabout the interactions of these two populations. Ithas been shown that proliferation of CD11c1 dDCs isinduced by IFN-a, and high levels of IFN-a are foundin psoriatic plaques.24 Recently, pDCs have beenidentified as major producers of IFN-a9 in responseto viruses,25 bacterial products, and antibody

Fig 6. CD123 in psoriasis. (Original magnification:3100.)

Fig 7. CD303 in psoriasis. (Original magnification:3100.)complexes. Cutaneous injury and/or infection mayinduce keratinocyte expression of the antimicrobialpeptide LL37 (cathelicidin), which is known to beexpressed at increased levels in PSO lesions. LL37forms complexes with human self-DNA to activatepDCs and elicit INF-a secretion in psoriatic pla-ques.26 Extensor skin surfaces that are exposed togreater trauma than flexural surfaces may producemore LL37 that in turn leads to the activation of pDCs,the subsequent secretion of IFN-a, and the down-stream effects of IFN-a including activation and pro-liferation of T cells and CD11c1 dDCs. Thismechanism has also been proposed to explain theautoimmune inflammatory activity in cutaneous lupuserythematosus and dermatomyositis lesions.27 Alongthe same lines, we also found increased CD11a1 cellsin PSO compared with normal-appearing skin.

Fig 8. CD207 in psoriasis. (Original magnification:3100.)

Fig 9. CD123 in nummular dermatitis. (Original magnifi-cation: 3100.)

J AM ACAD DERMATOLJANUARY 2012

104 Clarke et alBlockade of CD11a via the humanized anti-CD11aantibody efalizumab results in a reduction in thenumber of CD11c1 dDCs and clinical improvementin patients with PSO28 (because of the risk ofprogressive multifocal leukoencephalopathy, efalizu-mab was withdrawn from the US pharmaceuticalmarket in 2009).

Of uncertain significance is our finding that CD341

cells are significantly decreased in PSO when com-paredwith normal-appearing skin. CD34 is expressedby monocytes and DC precursors, and it is lost asthese cells mature. Therefore, it is possible that theobserved decrease is a consequence of acceleratedmaturation of immature CD341 dDCs in PSO lesions.

Relatively little is known about S100 protein sub-sets in terms of their expression by cutaneous cells

Fig 10. CD303 in nummular dermatitis. (Original magni-fication: 3100.)

Fig 11. CD207 in nummular dermatitis. (Original magni-fication: 3100.)other than LCs and melanocytes, but DCs also

Fig 12. S100A6 inpsoriasis. (Originalmagnification:3100.)

Fig 13. S100A6 in nummular dermatitis. (Original magni-fication: 3100.)express S100 protein subtypes. We chose to analyzethe S100 A6 and A4 subtypes in this study becausewehad observed variability in their expression indendritic-appearing dermal cells incidentally duringthe course of an unrelated study, and some evidencesuggests S100 proteins are involved in PSO29-31 andthat their expression may differ among PSO, normal-appearing skin, and other inflammatory conditionsincluding contact dermatitis.32,33 Although the valuesapproached significance, S100A61 cells were notsignificantly different between PSO and normal-appearing skin or between ND and normal-appearing skin. Comparedwith each other, however,there was a significant difference, with decreasednumbers in PSO versus ND. This was the onlymarkerstudied that showed a statistically significant differ-ence between PSO and ND (although CD11c alsoapproached significance). The role of S1001 DCs ininflammatory skin disorders has not been well char-acterized, but the data suggest that further study inthis area might be warranted.

Finally, although CD1231 and CD3031 cells weresignificantly increased in PSO as compared withnormal-appearing skin, we found no significant dif-ference in the number of CD1231 and CD3031 pDCsbetween lesions of PSO and ND. In addition, therewas no difference in CD207/Langerin1 DCs. Thismay suggest someoverlap in thepathogenesis of PSO

15. Zajonc DM, Crispin MD, Bowden TA, Young DC, Cheng TY,

J AM ACAD DERMATOLVOLUME 66, NUMBER 1

Clarke et al 105Hu J, et al. Molecular mechanism of lipopeptide presentation

by CD1a. Immunity 2005;22:209-19.

16. Valladeau J, Ravel O, Dezutter-Dambuyant C, Moore K,

Kleijmeer M, Liu Y, et al. Langerin, a novel C-type lectin specific

to Langerhans cells, is an endocytic receptor that induces

the formation of Birbeck granules. Immunity 2000;12:71-81.

17. Stoitzner P, Tripp CH, Douillard P, Saeland S, Romani N.

Migratory Langerhans cells in mouse lymph nodes in steadyand ND diseases. Because pDCs have been impli-cated in other inflammatory skin diseases,34 it may bethat their role in the pathogenesis of PSO is notparticularly distinctive. Alternatively, it is possiblethat it is not a difference in the quantity of pDCs but adifference in their function that is unique to PSO.

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Dermal dendritic cells in psoriasis, nummular dermatitis, and normal-appearing skin Methods Tissue selection Immunohistochemistry Assessment of immunohistochemical staining Statistical analysis

Results Normal-appearing flexural versus extensor skin Psoriatic plaques versus normal-appearing skin ND versus normal-appearing skin Psoriatic plaques versus ND

Discussion References