Resident and “inflammatory” dendritic cells in human skin

Lisa C. Zaba1, James G Krueger1, and Michelle A. Lowes1,a1 Laboratory for Investigative Dermatology, The Rockefeller University, New York, New York, U.S.A,10065

AbstractDendritic cells (DCs) are a heterogeneous group of antigen-presenting leukocytes that play animportant role in activation of both the innate and acquired arms of the immune system. While thereare several different DC populations in the body, DCs are globally defined by their capacity for potentantigen presentation and naive T cell activation. In non-inflamed human skin during steady-state,there are three main cutaneous DC populations: epidermal Langerhans cells (LCs), dermal myeloidDCs, and dermal plasmacytoid DCs (pDCs). In psoriasis, a model for cutaneous inflammation, thereis an additional population of myeloid dermal DCs – “inflammatory DCs” – which appear to becritical for disease pathogenesis.

IntroductionThe term “dendritic cell” (DC) was coined in 1973 when DCs in the lymph node werediscovered by Ralph Steinman and Zanvil Cohn (Steinman and Cohn, 1973). These DCs wereidentified as potent antigen presenting cells (APCs) in the mixed leukocyte reaction (MLR).However, it took a number of years for scientists to understand the significance and potentialroles of these cells, and we now know that they are central in generating and regulating immuneresponses. Retrospectively, it was appreciated that Langerhans cells (LCs) described in theepidermis of the skin nearly 140 years ago (Langerhans, 1868), were also DCs.

DCs are a heterogeneous population of cells in the immune system, defined initially by theirappearance, but more specifically by their potent ability to present antigen to T cells.Standardized characterization of human cutaneous DC populations is complicated bypleiomorphic phenotype and function during emigration from the skin for ex vivo study, andby the great number of potential surface and intracellular antigens that are present on theseleukocytes. In addition, there are differences between human and murine DC networks. DCpopulations have been historically classified either spatially (circulating blood DCs, draininglymph node DCs, epidermal DCs, and dermal DCs), by their presumed origin (myeloid DCs,plasmacytoid DCs [pDCs]), by physiological or pathophysiological state (steady-state DCs,inflammatory DCs), or by antigen expression (Langerin, DEC-205 etc.). We review our currentclassification of DC subsets contained within human skin during steady-state and inflammation(Figure 1 and Figure 2). Our main message is that there are three cutaneous DC populationsin the steady-state – epidermal LCs, resident dermal myeloid DCs, and pDCs – and duringinflammation there appears to be an additional population of myeloid dermal “inflammatory”DCs. Understanding these DCs may lead to new therapeutic targets for augmenting orsuppressing inflammation during human disease (Steinman and Banchereau, 2007).

aCorresponding author: lowesm@rockefeller.edu Telephone: 212-327-7576 Fax: 212-327-8232.Conflict Of Interest: The authors state no conflict of interest.

NIH Public AccessAuthor ManuscriptJ Invest Dermatol. Author manuscript; available in PMC 2009 September 18.

Published in final edited form as:J Invest Dermatol. 2009 February ; 129(2): 302–308. doi:10.1038/jid.2008.225.

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Langerhans cellsLCs reside in the suprabasal layers of the epidermis wedged in between, and in close contactwith, keratinocytes. The stellate appearance of these cells led researchers to believe that theywere of neural origin until over 100 years later, when their role in antigen presentation waselucidated (Braathen and Thorsby, 1980). LCs were initially identified by the electron-denseorganelle, the Birbeck granule, which has a unique tennis-racket appearance. The function ofBirbeck granules is still unclear, but likely includes receptor-mediated endocytosis andtransport of cellular materials into the extracellular space (Mc Dermott et al., 2002). The firstmonoclonal antibody that clearly identified LCs bound to CD1a, an MHC-I-like molecule thatpresents microbial lipids to T cells (Barral and Brenner, 2007; Thomas et al., 1984). Morerecently, the monoclonal antibody to Langerin/CD207 has been used to specifically recognizeLCs (Figure 2). Langerin/CD207 is a membranous C-type lectin discovered by Valladeau etal (Valladeau et al., 2000), that recognizes mannosylated ligands found on the surface of awide range of pathogens including viruses, bacteria, fungi, and protozoa (Figdor et al., 2002).Following receptor mediated endocytosis, CD1a and Langerin/CD207 traffic to the Birbeckgranule where they may participate in antigen processing (Stössel et al., 1990).

Elegant studies by Merad et al. have recently shed light on the origin and trafficking of LCsduring steady-state and inflammation (Merad et al., 2004; Merad et al., 2002). It now seemsclear that epidermal LCs are continuously replaced from a resident precursor pool (perhaps byself-renewal) throughout life under steady-state conditions (Merad et al., 2002). Howeverfollowing inflammation, LCs are repopulated by blood precursors, most likely monocytes(Ginhoux et al., 2006). In human psoriasis vulgaris, there are variable reports of the numberand arrangement of LCs in the epidermis adjacent to non-inflamed epidermis. This may be dueto different staining and counting methods used for analysis, or non-equivalent patientpopulations. In our studies on stable plaque psoriasis, we have found that LCs in lesional andnon-lesional epidermis are of similar number per linear surface, with a redistribution to theupper layers of the thickened psoriatic epidermis, and express comparable antigen markers(unpublished data). These observations are supported by studies showing that LC migration inpsoriasis is impaired, leading to retention of LCs in psoriatic inflammation (Cumberbatch etal., 2006). Further studies need to be performed to evaluate LCs during human disease statesusing these new markers.

Interest in LCs has increased with three key observations. Firstly, in mice, there is a newlydiscovered population of Langerin+ DCs in the dermis and skin draining lymph nodes (Burschet al., 2007; Ginhoux et al., 2007; Poulin et al., 2007). These epidermal and dermal LCpopulations have distinct phenotypic and mitotic capacities, and the dermal Langerin+ LCs donot appear to be simply epidermal LCs en route to the draining lymph node (Douillard et al.,2005; Stoitzner et al., 2003; Stoitzner et al., 2005). Epidermal LCs areLangerin+CCR6+CCR7+/-, radioresistant, slowly self-replicating (Merad et al., 2002), and arehighly responsive to CCR6 agonist macrophage inflammatory protein (MIP)-3alpha (CCL20)(Larregina et al., 2001). In contrast, dermal LCs are Langerin+CCR2+CCR7+/-, radiosensitive,rapidly self-replicating, and are responsive to CCR2 agonist monocyte chemoattractant protein(MCP)-1 (CCL2) (Bursch et al., 2007; Ginhoux et al., 2007; Poulin et al., 2007), althoughCCR6 expression and responsiveness to CCL20 have not yet been investigated in these dermalLangerin+ CCR2+ cells. Langerin+CD1a+ dermal LCs may also exist in human skin (Angel etal., 2006), although we have not been able to identify many dermal LCs in normal or psoriaticskin in situ (unpublished data and (Lowes et al., 2005b)).

Secondly, there is much debate concerning the pathophysiologial role of LCs. Until recentlyit was assumed that cutaneous antigens were locally processed by epidermal LCs which thenmigrate out of the skin into the draining lymph node for efficient antigen presentation to T

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cells. During this journey to the lymph node, the LCs change their surface phenotype and“mature”, simultaneously down-regulating antigen-processing and acquiring improved abilityfor T cell co-stimulation (Larregina and Falo, 2005). Recent studies have questioned thebiological significance of this pathway as antigen-specific T cell activation remains intact inLC deficient murine models (Bennett et al., 2005; Kaplan et al., 2005; Kissenpfennig et al.,2005a; Mommaas et al., 1994; Ritter et al., 2004; Zhao et al., 2003). However, inconsistentresults were obtained in these studies, which may be due to many factors, such as the mode ofLC depletion (constitutive or induced), the site of challenge (epidermis versus epidermis anddermis), the dose of antigen, and the timing of contact hypersensitivity schedules. To date, nomodel claiming to show the redundancy of LCs in the induction of immunity has used a strictlyepidermotropic pathogen, e.g papillomavirus. Thirdly, another group recently published anovel role for these cells, describing how LCs expressing ligands for cytotoxic T cellsunexpectedly promoted murine carcinogenesis (Strid et al., 2008).

These new observations suggest that there is steady-state migration of LCs to skin-draininglymph nodes, perhaps to induce and maintain tolerance to cutaneous antigens (Steinman andNussenzweig, 2002). Thus a working hypothesis is emerging whereby DCs that reside in thedermis may be essential for the process of cutaneous immune activation while LCs may playa more important role in sustaining cutanous immunological tolerance.

Dermal DCsThe population of DCs that reside in the dermis of the skin are known as dermal DCs, and theseare considered analogous to “interstitial DCs” found in the connective tissue and stroma ofother organs (Nestle et al., 1993; Lenz et al., 1993; Shortman and Naik, 2007). These importantcells have the capacity to take up cutaneous antigens, mature and migrate to draining locallymph nodes, and present these antigens to T cells and B cells (Dubois et al., 1998;Kissenpfennig et al., 2005b; Nestle et al., 1998). This process may be essential during skininfections, such as herpes simplex, as blockade of dermal DC migration from skin to lymphnode may prevent effective cytotoxic T cell activation (Allan et al., 2006).

Because culture methods change the surface cellular phenotype, the purest phenotypicclassification of dermal DCs is best performed in situ, followed by ex vivo functionalverification of antigen presenting capacity. Unfortunately, there is no single or specific markerfor these cells, although the integrin CD11c is probably the best tool we currently have toidentify them. For many years, antibodies to Factor XIIIA (FXIIIA) clotting factor were usedto identify a dermal population of cells which have multiple dendritic processes protrudingfrom a stellate-shaped cell body, and were thus called “dermal dendrocytes” (Headington,1986). In 1993 Meunier et al. described a small population of HLA-DR+CD11c+CD1c+FXIIIA+ cells from cultured normal human dermis that had the capacity tostimulate T cells in an MLR (Meunier et al., 1993). In addition, Nestle et al showed thatimmunostimulatory dermal DC populations were present from psoriatic skin (Nestle et al.,1994). However, it has recently been demonstrated that FXIIIA is induced with culture and isactually a macrophage marker, rather than a specific DC marker (Töröcsik et al., 2005; Zabaet al., 2007b). Thus, more work needs to be performed to re-evaluate the body of literatureclassifying dermal APCs as FXIIIA+.

Resident dermal DCsIn order to understand dermal DCs and to develop working models to study these cells, we andothers have developed the concept that there is a resident population of dermal DCs, as wellas an additional group of DCs that appear or develop during inflammation (“inflammatory”dermal DCs) (Shortman and Naik, 2007). A proportion of resident murine steady-state dermalDCs (CD11c+) appear to be able to proliferate in situ to maintain the baseline population

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(Bogunovic et al., 2006). The major resident population in normal dermis is identifiedphenotypically with a single monoclonal antibody, CD1c, which is also known as blooddendritic cell antigen (BDCA)-1 (Figure 2). Anti-BDCA antibodies -1 (CD1c), -2 (CD303),-3 (CD141), and -4 (CD304/ neuropilin-1) recognize proteins that were first used to identifycirculating DCs (Dzionek et al., 2000; MacDonald et al., 2002). In steady-state, CD1c+

(BDCA-1) DCs are relatively immature with modest T cell stimulatory ability, but theirimmunostimulatory capacity can be greatly increased with DC maturing stimuli (Zaba et al.,2007b). These CD1c+ (BDCA-1) DCs are also CD11c+HLA-DR+CD45+CD14-, are mostlydendritic cell-specific ICAM-3-grabbing non-integrin (DC-SIGN)/CD209+, and by flowcytometric analysis, are approximately 50% CD1a+ (unpublished data). CD1c+CD14-CD1a+

dermal DCs from normal skin are also CCR7+ and are responsive to the lymph node chemokineCCL19, suggesting that these cells can migrate to draining lymph nodes for antigenpresentation (Angel et al., 2006). Prior to these experiments, it had been previously shown thatdermal DCs associating with T cells in normal skin display an activated phenotype (McLellanet al., 1999; Pope et al., 1995). It is possible that these immature CD1c+ (BDCA-1) residentDCs are tolerogenic in steady-state, analogous to epidermal Langerhans cells.

CD1a has also been used to specifically identify immunostimulatory dermal DCs in normalskin (Angel et al., 2006; Angel et al., 2007; Lenz et al., 1993; Nestle et al., 1993) and inpsoriasis (Nestle et al., 1994). In normal skin, dermal CD1a+ cells appear to be CD1c+

(BDCA-1) in situ and also in single cell suspensions (unpublished data). This suggests thatdermal CD1a+ cells may be a subset of the resident myeloid DCs, but CD1c+ (BDCA-1+) maybe a more useful marker of these cells as it co-localizes with nearly all the CD11c+ cells.Secondly, there are reports of an additional population of dermal antigen-presenting cellsidentified by CD14+ (Angel et al., 2007; Morelli et al., 2005). In our studies, there are fewCD14+ cells in normal skin in situ (unpublished data) and it is not yet clear if these are indeeddermal residents. When the skin is cultured to produce dermal single cell suspensions, it ispossible that there are contaminating monocytes present. Future studies are required to clarifythe CD14+ dermal population and the role of the CD1a+CD1c+ dermal DC subset.

While most of these CD1c+ (BDCA-1) cells are relatively immature, there is a small subgroup(∼5%) expressing mature DC markers (Zaba et al., 2007b). This includes dendritic cell-lysosomal-membrane associated protein (DC-LAMP)/CD208, and endocytic receptorDEC-205/CD205, which is present on immature DCs, but markedly upregulated on maturation(Butler et al., 2007; Guo et al., 2000). These rare, phenotypically mature cells often aggregatetogether in dermal clusters, but their scarcity prevents detailed functional analysis. Perhapsnormal skin requires a small population of mature DCs for fast antigen presentation to local Tcells, or for ongoing “micro” immune responses.

In normal skin, there is also a population of dermal DCs identified by CD141 (BDCA-3). TheseCD141+ (BDCA-3) cells constitute approximately 10% of all CD11c+ dermal DCs and do notoverlap with CD1c+ (BDCA-1) DCs (Zaba et al., 2007b). Again, functional analysis has notbeen performed on dermal CD141+ (BDCA-3) cells due to their low frequency. However, ithas been established that CD141+ (BDCA-3) DCs in blood are non-overlapping with bloodCD1c+ (BDCA-1) DCs and are the least immunostimulatory myeloid blood DC population(MacDonald et al., 2002).

“Inflammatory” dermal DCsPsoriatic inflammation induces dramatic changes in dermal DC populations, most obviouslya 30-fold increase in CD11c+ DCs in the dermis (approximately equal to T cell numbers) (Zabaet al., 2007a) (Figure 2). These DCs return to normal or non-lesional levels with effectivetreatment (Lowes et al., 2005b; Zaba et al., 2007a). Characterization of these cells duringinflammation is not yet complete, but our preliminary studies suggest that they are not

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CD1c+ (BDCA-1), that is, these “inflammatory” myeloid dermal DCs are CD11c+CD1c-. Thisindicates that they may be derived from circulating DC- precursors migrating into the skin dueto inflammatory and chemotactic signals. Potential precursors include circulatinghematopoietic precursor cells (Massberg et al., 2007; Svensson and Kaye, 2006), circulating“pre-DCs” (CD11c+ HLA-DRhi, CD16+) (Piccioli et al., 2007; Randolph et al., 2002; Tackeand Randolph, 2006), monocytes (Serbina et al., 2003), or resident DCs.

In psoriasis, we have been able to determine that dermal DCs produce mediators TNF andintracellular nitric oxide synthase (iNOS), and these have been termed TNF and iNOS-producing DCs (Tip-DCs) (Lowes et al., 2005a). It is likely that these Tip-DCs are containedwithin the CD11c+CD1c- population of “inflammatory” myeloid DCs in psoriasis lesions. Tip-DCs were first described in a murine model of Listeria monocytogenes infection (Serbina etal., 2003) and have also been found in murine E.coli bladder infection (Engel et al., 2006). Inhumans, the location and functions of Tip-DCs are emerging: they are present in the laminapropria of the gut where they may be important for IgA production (Tezuka et al., 2007), andthey appear to be induced by topical imiquimod treatment of basal cell carcinoma (Stary etal., 2007), so they may participate in tumor rejection. Pathogenicity of these Tip-DCs inpsoriasis is suggested by the rapid downmodulation of Tip-DC products TNF, iNOS, IL-20,and IL-23 during treatment with effective therapies (Haider et al., 2008; Zaba et al., 2007a).Tip-DCs can also stimulate the differentiation and activation of Th17 T cells (unpublisheddata), which are a new set of T cells associated with autoimmune inflammation in many diseasemodels (Zaba et al., 2007a). The potential role of these DCs as sources of inflammatorymediators is in contrast to the classic role of DCs as antigen-presenting cells, and warrantsfurther attention. Because these DCs may actually be the key target of a variety of anti-inflammatory therapies, and may be broadly involved in “autoimmune” inflammation of manydifferent human diseases, we need to better understand the development and activation of thesecells.

In another common skin disease, atopic dermatitis, a population of inflammatory DCs havealso been described. These cells were initially termed inflammatory dendritic epidermal cells(IDECs) based on flow cytometric analysis of cells from epidermal cell suspensions (Novakand Bieber, 2005; Wollenberg et al., 1996; Wollenberg et al., 2002). IDECs were defined bythe following: HLA-DR+Lin-CD11c+CD1a+ and these DCs co-express CD206/macrophagemannose receptor (MMR), CD36, FceRI, IgE, CD1b/c, CD11b, as well as DC-SIGN/CD209(Guttman-Yassky et al., 2007). There is now appreciation that these DCs are also located inthe dermis and appear to produce a different array of cytokines and chemokines (Th2chemokines CCL17 and CCL18) than do psoriatic inflammatory DCs, and do not have an iNOSsignature (Guttman-Yassky et al., 2007). Thus the cutaneous inflammatory milleau may drivethe differentiation of different types of inflammatory DCs that contribute specifically to thedisease process and even clinical phenotype.

Plasmacytoid DCsPDCs are an additional unique population of resident cutaneous DCs initially described bytheir morphology, which is similar to a plasma cell (Corcoran et al., 2003). There areconsiderable phenotypic and functional differences of PDCs in humans and mice, which maycontribute to the confusion in the literature as to their precise role in immune responses(Valladeau and Saeland, 2005). PDCs share many characteristics with B cells, includingdependence on a B cell transcription factor (SPI-B), and immunoglobulin gene rearrangements.It now appears that both PDCs and myeloid DCs may actually arise from a bone marrow-derived common DC precursor (Naik et al., 2007; Onai et al., 2007). While both myeloid andplasmacytoid DCs express high levels of HLA-DR and have the capacity to present antigen,pDCs are characterized by their ability to produce large amounts of type 1 interferon (IFN)

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(IFN-α, β, ω) during viral infection – 10,000 fold more IFN than any other cell type (Ito etal., 2004; Kadowaki et al., 2000). This potent IFN production is induced by viral RNA andDNA containing repeated unmethylated CG nucleotides (CpG) binding to Toll-like receptor(TLR) 7 and TLR9 endosomal receptors, and the CpG class determines the level of IFNproduced (Rothenfusser et al., 2002). IFN-α, the most studied of the Type I IFNs, modulatesdevelopment and maturation of many immune cells, including T cells and myeloid DCs, bybinding to abundantly expressed IFN receptor (Theofilopoulos et al., 2005). In addition,different stimulation conditions (eg influenza virus and CpG) may induce distinct activationstates in pDC (Iparraguirre et al., 2008). The pleiotropic effects of pDC activation arecomplicated and not fully understood.

Monoclonal antibodies for pDC identification are well developed and include CD123/IL-3R,BDCA-2, and BDCA-4. BDCA-2 is the only marker that is exclusive to pDCs, as myeloid DCscan express low levels of CD123 and BDCA-4 (Liu, 2005). Thus, a common phenotypicdefinition of blood and tissue pDCs is HLA-DR+CD11c-CD123hiBDCA-2+. Research on thefunction of human pDCs during steady-state and disease is limited by low frequency andtransitory expression of IFNα (Nestle and Gilliet, 2005).

In studies of normal skin, there are a small number of pDCs (Ebner et al., 2004; Zaba et al.,2007b), and there does not appear to be any marked increase in the frequency of these cells inchronic large plaque psoriasis (Guttman-Yassky et al., 2007), although others have found anincrease of these cells in psoriasis (Nestle et al., 2005). However, two recent observationssupport a role for pDCs during the initiation phase of psoriasis. Firstly, in xenotransplantexperiments of non-lesional skin from patients with psoriasis grafted onto immunosuppressedmice, the stress of transplantation is sufficient for psoriasis to develop spontaneously in thegraft (Nestle and Nickoloff, 2005). Blockade of IFN-α prevented development of psoriasis,implicating pDCs as they are the primary source of IFN-α in the skin. Secondly, keratinocytepeptide LL37 (also known as cathelicidin or cathelicidin antimicrobial peptide [CAMP]), bindsto self-DNA and TLR9 in pDCs, and induces IFN-α (Lande et al., 2007). Expression of thisantimicrobial peptide is increased during inflammation such as psoriasis, and downstreameffects of this increased IFN-α production may be activation of myeloid DCs and initiation ofpsoriasis (Nestle and Gilliet, 2005). Patients with psorasis may have pDCs that are particularlysensitive to LL37 and respond in an exaggerated manner with increased IFN-α induction, thussetting in motion psoriatic inflammation.

SummaryDC heterogeneity and complexity has made them difficult to understand, but we are currentlydeveloping better tools and models to study these cells. DCs are central orchestrators of innateand cellular immune responses, either by secretion of bioactive cytokines or inflammatorymediators that modulate stromal and local cutaneous immunocytes, or by their ability to directlyactivate T cells. Currently, we do not know the relative contribution or temporal involvementof DC subsets, T cells, and keratinocytes in initiating and maintaining skin inflammation. Thedata summarized here indicate that DCs play an important role in cutaneous homeostasis andare likely very central to pathogenic processes in the skin. This information from the skin mayalso be applicable to other organs, systems, and diseases. Further studies on cutaneous DCsare essential if we are to tap into the enormous therapeutic potential of these fascinating cells.

AcknowledgmentsResearch was supported by NIH grants R01 AI-49572, AI-49832, and UL1 RR024143. MAL is supported by 1 K23AR052404-01A1, and LZ is supported by NIH MSTP grant GM07739. The authors would like to thank Dr RalphSteinman for his continued support and inspiration.

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AbbreviationsDC

dendritic cell

LC Langerhans cell

PDC plasmacytoid dendritic cell

APC antigen presenting cell

MLR mixed leukocyte reaction

MCP-1 monocyte chemotactic protein-1

FXIIIA factor XIIIA

BDCA blood dendritic cell antigen

DC-SIGN dendritic cell-specific ICAM-3-grabbing nonintegrin

DC-LAMP DC-lysosomal-associated membrane protein

INOS inducible nitric oxide synthase

Tip-DC TNF-iNOS producing DC

IDEC inflammatory dendritic epidermal cells

MMR macrophage mannose receptor

IFN interferon

TLR toll-like receptor

CAMP cyclic adenosine monophosphate

MIP-3α macrophage inflammatory protein-3alpha

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Figure 1. Dendritic cell and macrophage populations in human skin during steady-state andinflammationNon-inflamed skin contains epidermal Langerhans cells, CD1c/ BDCA-1+ resident dermalDCs, plasmacytoid DCs, and macrophages. In addition, inflamed skin contains a largepopulation of myeloid “inflammatory” DCs. Common markers used to identify these leukocytepopulations are indicated.

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Figure 2. Dendritic cell populations in non-lesional and lesional psoriatic skinH&E staining demonstrates characteristic features of psoriasis (right), with epidermalacanthosis, elongation of rete ridges, parakeratosis (retention of nuclei in stratum corneum),enlarged blood vessels, and marked leukocytic dermal infiltrate. Immunohistochemistry ofnon-lesional and lesional psoriatic skin for Langerhans cells (Langerin), resident dermal DCs(CD1c/ BDCA-1+), resident and inflammatory myeloid DCs (CD11c), and plasmacytoid DCs(BDCA-2). Insert is a high power magnification of each cell type and is approximately 60μmlength. Size bar = 100μm.

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