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D O I 1 0 . 1 1 1 1 / j . 1 3 6 5- 2 1 3 3 . 2 0 0 7 . 0 8 2 6 4. x

Immune response profiles in human skinT. Meyer, * E. Stockfleth and E. Christophers

*Institute for Immunology, Clinical Pathology and Molecular Medicine, Lademannbogen 61, 22339 Hamburg, Germany

Department of Dermatology, University of Berlin, HTCC, Chariteplatz 1, 10117 Berlin, Germany

Department of Dermatology, University of Kiel, Schittenhelmstrae 7, 24105 Kiel, Germany

CorrespondenceThomas Meyer.

E-mail: [email protected]

Accepted for publication4 September 2007

Key wordsadaptive immunity, epithelial defense, innate

immunity, TH17 cell, toll-like receptor

Conflicts of interestES acts as a consultant to Meda Pharma. TM and

EC declare no conflicts of interest.

Summary

In addition to the function as a physical barrier human skin has been shown to

be an important immune organ displaying various defense mechanisms, which

can be divided into three major functional compartiments: (i) Epithelial defense,

which is characterized by antimicrobial peptides and proteins (AP) and which

can be induced in inflammatory lesions but also in the absence of inflammation.

(ii) Innate-inflammatory immunity, which involves recognition of microbial

compounds by particular receptors like Toll-like receptors (TLR) and subsequent

activation of signalling pathways resulting in expression of pro-inflammatory

cytokines and interferons, as well as genes of adaptive immunity. Interferon a

(IFNa) produced by plasmacytoid dendritic cells (DC) may stimulate myeloid DC

to produce IL-12 resulting in classical T-cell activation or to produce IL-23 acti-

vating IL-17 producing T-cells (IL-23IL-17 pathway). (iii) Adaptive immunity,

which is based on antigen presenting cells, T-cells and B-cells and which is char-

acterized by specificity and memory. In contrast to epithelial defense and innate-

inflammatory immunity, adaptive immune functions provide slowly reacting pro-

tection. Recent improvements of our knowledge of dysregulated immune path-

ways associated with inflammatory skin diseases represent an important basis of

novel immunomodulatory treatment modalities.

With a surface area of approximately 17.000 cm2 human skin

is one of the largest organs of the body. Located at the inter-

face between environment and living organ systems skin

serves a variety of functions. These include

1 maintaining an effective barrier against loss of body fluids

and protection against chemical and physical injury,

2 protection against UV injury together with adequate radia-

tion damage repair and

3 the capacity for rapid wound healing along with a powerful

defense armentarium against invading microorganisms.

Human skin is covered by the epidermis, which partly con-

sists of 1720 layers of coherent, flattened cells, the Stratum

corneum.1,2 As skin is constantly exposed to the outside world

physical injury is among the most common threats eventually

leading toward lethal outcomes. Thus, during phylogeny avariety of defense systems has emerged which actively serve to

maintain cutaneous integrity and immunity. Players participat-

ing in this scenario consist of protective antimicrobial peptides

(APs) as well as inflammatory cells and signal substances

in conjunction with sessile skin cells forming a skin immune

armentarium. Functionally this consists of three major

compartments:

1 Epithelial defense

2 Innate-inflammatory immunity and

3 Antigen-elicited, adaptive immunity.

Epithelial defense has only recently been discovered in

human skin3 whereas the leukocyte driven inflammatory

response has been known since a long time as an innate (pre-

viously called nonspecific) arm.4

The third arm (adaptive immunity) has by far been given

greatest attention in medicine. With specificity and memory as

outstanding features this system provides powerful, however,

slowly reacting protection of unlimited diversity. In addition,

adaptive immunity is of principal importance in immune sur-

veillance against viruses and transformed cells. On the other

hand in humans this (adaptive) skin immune system5

appears responsible for a greater number of diseases than any

of the other two defense systems.

In the following some aspects of this skin immune system

will be briefly discussed.

Epithelial defense

Chemical protection by peptides and proteins has first been

observed in insects (Drosophila) and plants.6,7 The first antimi-

crobial peptide (AP) found in human skin was Lysozyme.8

At present about ten APs have been detected in human skin

(Table 1) and more of these compounds will be discovered.

RNAse 7 and psoriasin (S100A7) represent constitutively

expressed APs, whereas human beta defensin (hBD) 24 as

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well as LL-37 are inducible. As skin is practically soaked with

(mostly keratinocyte derived) defense molecules (within

microgram range per g tissue)4 their immediate availability

provides a powerful chemical shield for instance in wounding.

In fact most of the peptides and proteins are discovered in

inflamed skin, notably in psoriatic scales.9

Interestingly, only few of the APs exhibit broad antimicro-

bial activities (e.g. hBD3), instead the majority is directed

against either gram-negative (e.g. hBD1, hBD2) or gram-posi-

tive bacteria or fungi (Lysozyme, RNAse7, CAP 18LL-37). Adegree of specificity is also seen with psoriasin which primar-

ily acts against E. coli.10

Principal producers of APs are keratinocytes. They respond

to a variety of stimuli including IL-1, TNFa (Tumour necrosis

factor alpha), IGF-1 (Insulin-like growth factor 1) as well as

bacterial membrane substances.3 Recently, IL-22 has been

detected as potent cytokine stimulating keratinocytes to pro-

duce defense molecules, proteases and growth factors (see

below).

While regulatory pathways have become better under-

stood,3 so far receptors for AP induction have been hiding

from detection. One may assume that receptors different from

known innate receptors e.g. Toll-like receptors (TLRs)11 are

active. So far studies have shown induction of hBD2 via

TLR4.12

In certain situations APs may participate in the adaptive

immune response by serving as chemoattractants for immature

dendritic cells (DC) and memory T cells (seen with hBD2 and

hBD3) as well as neutrophils, T cells and monocytes (seen

with LL-37).13,14

Innate (inflammatory) immune response

In order to elicit inflammatory responses innate immunity

employs germline-encoded pattern recognition receptors to

recognize microbial compounds. TLRs have been shown to act

as primary sensors by binding of particular structures present

on bacteria, viruses, fungi as well as protozoa [also called

pathogen associated molecular patterns (PAMPs)15]. There are

10 members of the TLR family in humans (Table 2).

Organ systems exposed to environmental influences e.g.

skin, lung, and intestines show different colonisation with

microbial symbionts. In consequence, gut epithelium as com-

pared to skin or lung shows different defense strategies in

host-bacterial interaction.16 For these nonsterile organs with

permanent contact to micro-organisms it is important to pre-

vent constant activation of innate immune functions, which

would potentially compromise organ function. To maintainhomeostasis several regulatory mechanisms have evolved that

control innate immunity. Due to the heterogeneity of micro-

bial colonization homeostasis is achieved through different,

organ-specific mechanisms involving TLRs. This includes dif-

ferences in TLR activation thresholds, tolerance, and varying

receptor profiles in distinct organs, as well as different expres-

sion of negative regulators of TLR signalling and environmen-

tal molecules regulating TLR function (e.g. IFNa, IL-10 or

TGFb [Transforming growth factor beta]).16

Binding of PAMPs to TLRs reflects early infection with acti-

vation of cellular signalling pathways including transcription

factor NFkB (Nuclear factor kappa B) and activation of MAP

(mitogen-activated protein) kinases p38 and JNK (jun amino

terminal kinase). These factors regulate expression of many

genes involved in inflammation and immunity. Thus, pro-

inflammatory cytokines and interferons, but also adaptive

immune functions such as MHC (major histocompatibility

Table 1 Antimicrobial peptides in human skin

Lysozyme

Human beta defensin 1 (hBD1)

hBD 24

RNAse 7, 8

Psoriasin

CAP 18 LL-37

Dermcidin

Table 2 Toll-like receptors and their ligands

Receptor Ligands

TLR 1 Triacylated lipopeptidesa

TLR 2 Peptidoglycan, bacterial lipoprotein, zymosan, lipoteichoic acid, LPS

(Porphyromonas gingivalis, Leptospira interrogans), GPI-anchor proteins (Trypanosoma cruzi.)

TLR 3 ds RNA

TLR 4 LPS (gram-negative bacteria), F-Protein (RSV), Hsp60, Fibronectin domain ATLR 5 Flagellin

TLR 6 MALP-2 (Mycoplsma)b, phenol-soluble modulin (Staphylococcus epidermidis)b

TLR 7 ssRNA, Loxoribine, Bropirimine, Guanosine analogs, Imiquimod, Resiquimod

TLR 8 ss RNA, Resiquimod, Loxoribine, Bropirimine

TLR 9 Unmethylated CpG-DNA (bacteria and viruses)

TLR10 No ligands found yet

LPS, Lipopolysaccharid; GPI, glycosylphosphatidylinositol; MALP, macrophage activating

lipopeptide.aLigands recognized by TLR1 + TLR2bLigands recognized by TLR2 + TLR6

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2 Immune response profiles in human skin, T. Meyer et al.


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complex)-proteins, co-stimulatory signals and adhesion mole-

cules become activated.17,18

Furthermore, signal transduction induced upon ligand bind-

ing to TLR favours a complex interplay of a growing number

of adaptor proteins.19 MyD88 was the first adaptor molecule

identified. TLR and MyD88 associate via common Toll-IL1-

receptor domain, which results in recruitment of kinases

(IRAK1 and IRAK4). Phosphorylated IRAK1 then leads to acti-

vation of protein kinase TAK1 (TGF-activated kinase) which

finally liberates NFkB from the Inhibitor of NFkB kinase com-

plex. This pathway of NFkB activation has been seen with

IL1R, but also represents the main pathway of TLR signalling,

except for TLR3.

Next to MyD88 several other adaptor proteins like MyD88

adaptor-like, TIR-related adaptor protein inducing interferon

(TRIF) and TRIF-related adaptor molecule have been identified

to be involved in TLR signalling. Importantly, different TLRs

signal through different combinations of adaptors, resulting in

activation of different transcription factors and diverse gene

induction (see Fig. 1).

Within the context of this report it is of relevance that

ligand binding to intracellular receptors TLR7 and TLR 9

mainly results in activation of IRF7 and induction of IFNa, an

important factor for antiviral defense and as shown below in acertain group of diseases.20

Toll-like receptor expression in different cellsand tissues

Expression of TLRs has been detected in various human tissues

with varying expression levels.21 In general, organs involved in

immune response or exposed to environment, e.g. spleen, skin

and lungs were found to have significantly higher TLR expres-

sion, than for instance the brain, liver and skeletal muscles.21

TLR expression is also increased in peripheral blood mono-

nuclear cells with large differences of TLR expression levels

between different cell types. For example, TLR 2, 4 and 8 are

expressed predominantly in monocytes and macrophages22,23

with the highest level shown for TLR2 in monocytes. Blood-

derived myeloid dendritic cells (mDC) express TLR 2, 3, 4, 5

and 8,2325 while TLR 7, 9 and 10 were found mainly on

plasmacytoid dendritic cells (pDC) and B-cells.22,26 Of impor-

tance pDCs are the primary class I IFN producing cells.27

Interestingly, Imiquimod and Resiquimod act as TLR7 agon-

ists28 and were shown to induce IFNa and IFNx in pDCs iso-

lated from blood.29

In human skin TLRs are expressed in both DC and keratino-

cytes. Human keratinocytes constitutively express mRNA of

TLR 1, 2, 3, 4, 5, 6, 9 and 10 not, however, of TLR 7 and

8.3032 Functionality was also shown for TLR 2, 3, 4, 5 and

9.30,31,33 Langerhans cells (LC) were also shown to express

TLR 1, 2, 3, 5, 6, and 10.34

In another study LCs also respond to TLR 4, TLR 7 and TLR

9 ligands.35 Among DCs, however, TLR 8 is usually expressed

in mDCs, while TLR 7 was found predominantly in pDCs.23

Recently, the accumulation of pDC-like cells has been

described in the dermis of mice topically treated with TLR 7

agonist Imiquimod.36

pDCs were also identified in psoriaticskin lesion.37 Importantly, topical application of TLR7 agonist

Imiquimod exacerbates the psoriatic lesion,38 indicating that

pDCs are major effector cells of the immune response induced

by Imiquimod.

Th17-induced inflammation

Recently, further differentiation of immune defense has been

elaborated.39,40 This arm involves cytokines as well a distinct

set of lymphocyte subpopulations. Central role in this pathway

TIR

TLR4

TLR7,8,9TIR

TIR

TRIFMyD88

MyD88

MyD88

TLR2MD2/CD14

LPS (E. coli)

MAL

TRAM

MAL

LPS (P. gingivalis)

PG (S. aureus)

NFkB

ssRNA, CpG-DNA

Imiquimod, Resiquimod

IRF7

TNF, IL1, IL6, IL12IL8, MIP1a RANTESCD40, CD80, CD86

TNF, IL1, IL6, IL12IL8, MIP1a RANTESCD40, CD80, CD86

IFN

TIR

TLR3

TRIF

dsRNA

IFN

IRF3NFkB

IKK complex IKK complexTBK-1 IRAK-1Fig 1. Differential gene expression of TLR-

signalling. LPS, Lipopolysaccharid; PG,

Proteoglycan; TIR, Toll-IL1-receptor; MAL,

MyD88 adaptor-like; TRIF, TIR-related adaptor

protein inducing interferon; TRAM, TRIF-

related adaptor molecule; IKK, Inhibitor of

NFkB kinase; TBK, TANK-binding kinase;

IRAK, Interleukin-1 receptor associated kinase;

IRF, Interferon regulatory factor.

2007 The Authors


Immune response profiles in human skin, T. Meyer et al. 3


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is played by pDC and a new T cell subtype called Th17.40

As shown by Nestle et al.37 pDC can be activated by a variety

of ligands including virus RNA, HSP (Heat shock protein) or

bacterial products to produce IFNa with production being

1000 times higher compared to any other cell. The responder

cell for this excess IFNa is noted as mDC.

Following stimulation via IFNa these latter cells produce

IL-12, whereby classical T cell activation, marked by secretion

of IFNc, granzyme and preforin and others, proceeds.41 mDC

are also seen to produce IL-23 which is structurally related to

IL-12, sharing a common subunit (p40). IL-12 is known as

the key promoter of naive T cells to multiply and differentiate

into Th1 cells and cytotoxic T cells, while IL-23 causes activa-

tion of a IL-17 producing T cell, which is hence called

Th17.39,40

Recent evidence suggests that under the co-stimulatory

effect of TGFb and IL6 Th17 cells develop from nave T cells.

Th17 cells once activated by IL-23 become important actors in

the ensuing inflammatory program in that IL-17 stimulates

various cells to produce pro-inflammatory cytokines: under

the stimulus of IL-17 stromal cells, endothelial cells and others

produce IL-1, TNFa, IL-6, IL-8 and GM-CSF [Granulocyte-

macrophage colony stimulating factor].42 These mediators are

chemokines themselves (e.g. IL-8) or powerful stimulators of

leukocyte activation and migration.43

The IL-23IL-17 pathway represents an important pro-inflammatory arm of the innate defense with leukocyte infil-

tration and phagocytosis as ultimate goals. It bears relevance

to psoriasis and it has been suggested that psoriasis rather than

being a Th1 disease actually is a Th17 disease.40

Th17 cells have recently been shown also to produce IL-22

and further, a receptor for IL-22 is expressed by keratinocytes

and other epithelial cell e.g. in the gut.4446 This ligand-recep-

tor binding in keratinocytes causes up-regulation of defense

molecules (e.g. defensins), but also proteases, S100 proteins

and chemokines.4749

Apparently by these two arms of the innate defense armen-tarium (IL-17 and IL-22) not only inflammation is initiated

but also keratinocytes become active players (see Fig. 2). In

this context keratinocytes not only respond to environmental

pathogens by producing antimicrobial defense molecules and

also, via the IL-22 receptor, interact with endogenous den-

dritic cell derived signals.

One of the key TLRs capable for sensing viral nucleotides

on pDCs is TLR7, which also binds Imiquimod. Several reports

have shown that Imiquimod applied to skin can exacerbate

psoriasis.50,51 As IL-23 and IL-17 are found to be up-regulated

in psoriasis52,53 this IL-17 regulated pathway could play a sig-

nificant role in initiating psoriatic lesions.

Attraction of pDCs, which are almost absent in normal skin,

to inflamed skin areas is mediated by chemotactic peptides like

IL8 and complement split products, like C5a and its desarginated

form C5a-des-Arg. These act as powerful chemoattractants and

are present in increased amounts in psoriatic skin lesions.54,55

The complement cascade consists of a set of proteolytic

enzymes and represents a component of the humoral innate

immune system. Complement can be activated by three sepa-

rate pathways (classical antibody-mediated, alternate proper-

dine-induced, and lectinMASP (Mannose binding lectin-

associated serine protease)-mediated).56 Activation finally leads

to formation of membrane attack complex, which kills bacte-

ria by cell lysis. During complement activation the split prod-ucts C3a and C5a are generated, which have anaphylactic and

chemotactic properties. In serum both are des-arginated by

carboxypeptidase N to less potent fragments C3a-des-Arg and

C5a-des-Arg. C5a-des-Arg, like C5a binds to C5a receptor

(C5aR).57 Recently, expression of C5aR and C3aR was shown

in immature pDCs of skin lesions from patients with LE and

contact dermatitis.58 Considering significant amounts of C5a

and C5a-des-Arg in psoriatic skin lesions complement medi-

ated attraction might be relevant for infiltration of pDCs in

psoriatic skin.

Th1

Th17

PMN

KC KCMP

G-CSF, IL8, NO

TNF, IL1, IL6

pDC mDC

IL23, TGF, IL6

IL12

APsProteases

IFN

IFN

IL17IL22

FG-CSF

E

EC

Fig 2. The IL-23 Th17 pathway in

inflammation. pDC, plasmacytoid dendritic

cell; mDC, myeloid dendritic cell; Th17,

IL-17 producing T cell; EC, endothelial cell;

PMN, polymorphonuclear cell; MP,

macrophage; F, fibroblast; E, epithelial cell;

KC, keratinocyte; APs, antimicrobial peptides.

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Induction of adaptive immune functions

A crucial step of the induction of adaptive immune reactions

is reflected by activation of DC, which are professional antigen

processing and presenting cells. In skin epidermal LC and der-

mal dendritic cells (DDC) represent the most important types

of DC. Resident epidermal LCs are characterized by expression

of CD1a, CD1c, Langerin, E-cadherin and membrane ATPase

and by the presence of Birbeck granules. These rod-shaped

membrane structures are absent in resident DDC. Also, in con-

trast to LC, DDC do not express Langerin, E-cadherin, and

membrane ATPase, but do express clotting factor FXIIIa, as

well as CD1b and CD1c.59

Dendritic cells take up and process peripheral antigens, and

after migration to lymphoid organs, present them to nave T

cells. In addition binding of PAMPs to TLRs results in activa-

tion of DC by NFkB-induced expression of chemokines, cyto-

kines, MHC class I and II antigens, co-stimulatory signals, and

adhesion molecules.19

Migration of skin DCs to draining lymph nodes through

afferent lymphatics is associated with functional and pheno-typic changes. While migrating centrally LCs loose their Bir-

beck granules and downregulate CD1, langerin and E-

cadherin. In contrast, due to TLR activation, surface proteins

important for T-cell activation like MHC-proteins, CD40,

CD58, ICAM-1, CD80, and CD86, are induced.59

During interaction with nave CD4 T-cells, which have

entered the lymph nodes through high endothelial venules,

DCs can induce differentiation of these cells. Usually, differen-

tiation into two subsets is distinguished: Th1, induced by IL-

12 and promoting cellular immunity and Th2, induced by IL-

4 and promoting humoral immunity.41

Two pathways of antigen presentation in DCs have been

described: an endocytic pathway, which results in binding of

exogenous antigens into MHC II molecules for presentation to

CD4+ T cells, and an endogenous pathway which results in

association of endogenous antigens to MHC I molecules for

presentation to CD8+ T cells.60 Moreover, a third pathway of

antigen uptake and presentation exists, which depends on

cross presentation and represents an important mechanism for

presentation of exogenous antigens to CD8 T cells through a

process called cross priming.61 In addition, nonprotein anti-

gens (mycobacterial glycolipids) can be internalized after

binding to langerin. After loading to CD1 molecules in Bir-

beck granules glycolipids are recycled to cell membrane and

presented to CD4 and CD8 T cells and NK (Natural Killer)cells.62,63

In addition to immunostimulatory functions of LCs and

DDCs in response to potential pathogens skin DCs exert regu-

latory functions to maintain homeostasis of the skin and to

prevent excessive inflammatory reactions.64,65 In the absence

of danger signals under steady state conditions, LCs take up

epidermal antigens and transport them to local lymph nodes.

Here they act as promoters of peripheral tolerance to skin

antigens by inducing anergy or apoptosis of nave T cells or

by stimulation of regulatory T cells (Treg, CD4+, CD25+).66

Effectors of adaptive immunity

T cells become activated by interaction with DC in local drain-

ing lymph nodes. Only nave T cells with TCRs, specific for

the antigens presented, are stimulated. In addition to TCR-

MHC-antigen interaction (tri-molecular complex) co-stimula-

tory signals are necessary to induce clonal expansion of appro-

priate T cells (defined by antigen specificity). Co-stimulatory

signals are represented by interactions of surface molecules,

like CD40-CD40L, CD28-CD8086 and CD2-CD58, as well as

cytokines (IL-1, IL-6 TNFa). Absence of these secondary sig-

nals results in nonreactivity (anergy) to the respective antigens.

Activated T cells leave the lymph node and enter the skin

by interaction with specific homing receptors. Most important

is the interaction of CLA (cutaneous lymphocyte antigen) with

E-selectin expressed on endothelial cells of inflamed skin. CLA

is not expressed in nave T cells, but found in about 30% of

circulating memory T cells and T cells in inflamed skin are

mainly CD45Ro- and CLA-positive.67,68 Next to CLA, several

chemokine receptors (CCR4, CCR10) are also associated with

skin homing of T cells.69,70

Among T cells, subpopulations with different functions are

distinguished. CD4+ T cells (T helper cells) are mainly

involved in immune responses to foreign antigens, while

CD8+ T cells (cytotoxic T cells) provide antiviral and antitu-

mor immune reactions. According to the cytokines produced,

T helper cells were divided into Th1 and Th2 cells: Th1 cells

produce IL-2, TNFa and IFNc and induce cell mediated

immune responses. Th2 cells produce IL-4, IL-5, IL-10 and IL-

13 and promote humoral immune responses, as well as growth

of eosinophils and IgE production. Th2 responses are fre-

quently associated with allergic diseases, like atopic dermatitis.

Th17 cells represent another subset of CD4 and CD8 T cells,

which are generated different from Th1 and Th2 cells, as

described above. As shown Th17 cells were suggested to be

involved in the pathogenesis of psoriasis and other autoim-

mune diseases.46,71

Other populations of T cells with suppressiveregulatory

properties, important to control autoreactive immune

responses, were recently identified. CD4+ CD25+ regulatory T

cells (Tregs) have suppressive effects and induce anergy and

tolerance by cell contacts probably via membrane-bound fac-

tors. The exact mechanism is still unknown, but does not

require soluble suppressive cytokines. Th3 and type 1 T regu-

latory cells (Tr1) are also immunosuppressive, which, in con-

trast to Tregs, depends on production of immunosuppressivecytokines (IL-10, TGFb).72

Outlook

In human approximately 2000 separate disease entities are

presently recognized and nearly half of these are inflamma-

tory. Thus the identification of inflammatory pathways in

skinincluding innate and adaptive, as well as stimulatory

and regulatoryhas been revolutionized by the rapidly

increasing knowledge especially of innate immunity. All of

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this makes the skin an appropriate target for immunomodula-

tory therapy. As our knowledge of underlying immune dysre-

gulations in skin diseases is improving, activation or

suppression of distinct immune functions by topical applica-

tion of immune response modifiers (the number of which is

steadily increasing) will provide extending treatment modali-

ties in near time.

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