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ARTICLE |
production
CORRESPONDENCE Michel Gilliet: mgilliet{at}mdanderson.org OR Frank O. Nestle: nestle{at}derm.unizh.ch
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–producing cells, infiltrate the skin of psoriatic patients and become activated to produce IFN- early during disease formation. In a xenograft model of human psoriasis, we demonstrate that blocking IFN- signaling or inhibiting the ability of PDCs to produce IFN- prevented the T cell–dependent development of psoriasis. Furthermore, IFN- reconstitution experiments demonstrated that PDC-derived IFN- is essential to drive the development of psoriasis in vivo. These findings uncover a novel innate immune pathway for triggering a common human autoimmune disease and suggest that PDCs and PDC-derived IFN- represent potential early targets for the treatment of psoriasis.
M. Gilliet's present address is Dept. of Immunology, M.D. Anderson Cancer Center, Houston, TX 77030.
Psoriasis is the most common autoimmune disease of the human skin, affecting
2% of the population worldwide (1). Similar to Crohn's disease and rheumatoid arthritis, psoriasis results from an overt self-perpetuating activation of autoimmune T cells (2–4). Through the secretion of Th1 cytokines, these T cells contribute to the epidermal hyperproliferation in genetically predisposed individuals. The initial onset of the lesions is commonly followed by chronic relapses of the disease triggered by infections, mechanical stress, and drugs (5). Although it is still unclear how these environmental factors drive the pathogenic T cell cascade, it has been suggested that innate immune pathways may provide the missing link (6, 7).
Plasmacytoid pre-DCs (PDCs) are a rare cell population in the peripheral blood and secondary lymphoid organs characterized by plasma cell–like morphology and a unique surface phenotype (8). PDCs represent key effectors in innate antiviral immunity because of their unique capacity to secrete large amounts of IFN- in response to viruses (9, 10). Upon viral stimulation, PDCs differentiate into DCs (11, 12) and/or induce an IFN-–dependent maturation of bystander myeloid DCs with the ability to drive Th1 responses (13), thus providing a unique link between innate and adaptive antiviral immunity. During homeostasis, PDCs are encountered exclusively in the blood and lymphoid organs; however, viral infection leads to an active recruitment of PDCs from the blood into peripheral sites of infection (14). Recent studies have shown that PDCs may also accumulate in peripheral tissues during certain noninfectious inflammatory disorders (15–18), including psoriasis (17, 19), although a functional relevance has not been demonstrated.
There are three scientific observations that suggest a role for IFN- in psoriasis. First, psoriatic skin lesions demonstrate an activated IFN- signaling pathway (20–23). Second, continuous excessive IFN-/ß signaling in IFN regulatory factor (IRF)-2–/– mice causes an inflammatory skin disease resembling psoriasis (24). Finally, treatment of psoriasis patients with recombinant IFN- for unrelated conditions (e.g., viral infections or tumors) can exacerbate psoriasis (25–28). We therefore hypothesized that IFN- produced by PDCs may contribute to the pathogenesis of psoriasis.
We show that PDCs infiltrate the normal-appearing skin of psoriatic patients and become activated to produce IFN- early during the development psoriatic skin lesions. Furthermore, we demonstrate that PDC-derived IFN- is essential in driving the local activation and expansion of pathogenic T cells leading to the development of psoriatic skin lesions. Thus, activation of PDCs to produce IFN- in the skin of psoriatic patients represents a key innate immune pathway to initiate the autoimmune T cell cascade leading to psoriasis.
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is expressed early and transiently during the development of psoriasis on activation, we sought to analyze IFN- expression in psoriatic skin. Initial investigations did not reveal substantial up-regulation of IFN- mRNA in primary psoriatic plaque lesions compared with the normal skin of healthy individuals. However, psoriatic plaque lesions, but not uninvolved skin or normal skin, consistently demonstrated a significantly increased expression of IRF-7, an IFN-–inducible gene (P < 0.0001; references 32 and 33; Fig. 3 a), and the presence of MxA protein, a marker for IFN- activity (references 34 and 35; Fig. S3, available at http://www.jem.org/cgi/content/full/jem.20050500/DC1). Given the presence of an IFN- signature in the absence of detectable levels of the IFN- cytokine, we questioned whether IFN- had been produced earlier during the development of the psoriatic plaque lesion. To analyze the early stages of psoriasis development, we took advantage of a xenograft model of human psoriasis developed in our laboratory in which the uninvolved (prepsoriatic) skin of psoriasis patients spontaneously converts into a full-fledged psoriatic skin lesion on transplantion onto AGR–/– mice within 35 d (36). This model system depends on the activation and proliferation of autoimmune T cells derived from the engrafted prepsoriatic skin (36) and allows temporal analyses of psoriasis development. Human IFN- mRNA expression levels in skin grafts increased as early as day 7 after transplantation and reached a peak at day 14 before rapidly declining (Fig. 3 b, top left), whereas its signature, detected by increased IRF-7 expression levels, persisted throughout the 35-d development of the psoriatic plaque (Fig. 3 b, top right). It is noteworthy that skin grafts of control mice transplanted with the normal skin of healthy donors did not develop an IFN- signature within 35 d (unpublished data). The early induction of IFN- in engrafted prepsoriatic skin was paralleled by the activation and expansion of pathogenic T cells (Fig. 3 b, bottom). In contrast, the psoriatic phenotype, defined by the typical epidermal hyperplasia involving a thickening of the epidermis (acanthosis), as well as the elongation of the epidermal rete ridges (reflected in the papillomatosis index), showed delayed kinetics starting at day 21 after transplantation and reaching complete development at day 35 (Fig. 3 b, bottom). These data indicate that IFN- expression is an early and transient event during the development of the psoriatic phenotype and precedes a completely activated epidermal compartment. During this early wave of IFN- secretion, MxA expression was confined to cells of the dermal compartment and involvement of cells of the epidermal compartment occurred at later time points (after day 14 of engraftment; unpublished data), indicating that IFN- originates in cells of the dermal compartment.
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–producing cells in developing psoriasis, we sampled the margin zone of spreading psoriatic plaque lesions as a surrogate for early developmental disease stages in psoriasis patients (37). Intracellular staining of dermal single cell suspensions demonstrated that IFN- protein was expressed in developing psoriatic skin lesions and was confined to BDCA-2+ PDCs (Fig. 4). In contrast, IFN- was not detectable in PDCs or other cells derived from uninvolved skin (Fig. 4) or peripheral blood (unpublished data) of the same psoriasis patient. These data indicate that PDCs represent the principal IFN-–producing cell in developing psoriasis.
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/ß signaling inhibits the development of psoriasis in the development of psoriasis, we sought to block IFN- signaling in vivo during the spontaneous conversion of uninvolved skin into psoriatic skin lesions in the AGR–/– xenograft model perviously described (36). Transplanted mice were treated with either neutralizing antibodies to IFN-/ß receptor (38) or an isotype-matched control antibody, and histological analyses of grafts were performed at day 35. Whereas skin grafts from mice receiving the isotype-matched control antibodies developed into full-fledged psoriatic lesions, with T cell numbers and epidermal hyperplasia reaching similar levels to those of primary psoriatic plaques of the graft donor, treatment with neutralizing anti–IFN-/ß receptor antibody completely inhibited both the activation and expansion of pathogenic T cells (Fig. 5 a) and the development of the psoriatic phenotype (Fig. 5 b and Fig. S4, available at http://www.jem.org/cgi/content/full/jem.20050500/DC1). These data indicate a requirement for IFN-/ß signaling for the T cell–dependent development of psoriasis.
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is essential for the development of psoriasis in developing psoriatic lesions, we next sought to determine whether psoriasis development was mediated by PDC-derived IFN-. For this purpose, we took advantage of the anti–BDCA-2 monoclonal antibody that specifically binds to human PDCs and suppresses their ability to secrete IFN- (29). Given that human cells derived from the transplanted skin do not recirculate in the AGR–/– mice (36), in vivo treatment with anti–BDCA-2 selectively targets human PDCs present in engrafted prepsoriatic skin. Intravenous injection of anti–BDCA-2 antibody led to a >90% reduction of IFN- expression in engrafted skin at day 13 after transplantation (Fig. 6 a), confirming that PDCs represented the principal IFN-–producing cells in the engrafted skin. Anti–BDCA-2 antibody injections completely inhibited the activation and expansion of pathogenic T cells and the development of a psoriatic phenotype (Fig. 6, b and c; and Fig. S5, available at http://www.jem.org/cgi/content/full/jem.20050500/DC1). To test whether IFN- was sufficient to reverse the anti–BDCA-2–mediated inhibition of psoriasis development, we administered recombinant human IFN- during anti–BDCA-2 antibody treatment. In contrast to the anti–BDCA-2 treatment alone, the addition of IFN- induced a strong activation and expansion of pathogenic T cells and the development of a full-fledged psoriatic plaque lesion (Fig. 6, b–d), demonstrating that PDC-derived IFN- was not only necessary but also sufficient to drive psoriasis development from prepsoriatic skin. In contrast, IFN- was not able to induce T cell expansion and psoriasis development in normal skin transplanted onto AGR mice, suggesting that factors already present in normal-appearing prepsoriatic skin are a prerequisite for the IFN-–mediated induction of the pathogenic T cell cascade leading to psoriasis (Fig. 6, b and c).
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early during disease development. Furthermore, we demonstrate that, through the production of IFN-, PDCs drive the activation and expansion of autoimmune T cells in prepsoriatic skin, leading to the development of psoriasis. Thus, our findings revise the current immunopathogenic understanding of psoriasis by identifying a key proximal event based on the presence of PDCs in psoriatic skin and their innate activation to produce IFN-.
PDCs represent a unique cell type in antiviral immunity because of their unique ability to secrete large amounts of IFN- on viral stimulation through toll-like receptor (TLR)-7 and TLR-9 (39, 40). PDCs have also been found in the inflamed tissue of autoimmune diseases, including lupus erythematosus (15), rheumatoid arthritis (41), and psoriasis (17, 19), although a functional relevance had not been demonstrated. We provide the first direct evidence that PDCs play a key role in the elicitation of a common autoimmune disease. We show that PDCs are increased in the normal-appearing prepsoriatic skin of psoriasis patients compared with the skin of healthy controls and demonstrate that this accumulation represents a conditioning factor for future flares of the disease. Through their ability to secrete IFN- in response to innate activation signals, PDCs in prepsoriatic skin determine the onset of local autoimmune inflammation leading to disease formation. Because injury to the skin is a well known elicitation factor for psoriasis (42), PDC activation may result from the release of skin-derived products on infectious or mechanical stress (simulated in the AGR–/– model by the transplantation procedure). In psoriatic skin, potential activation signals may include pathogen- or self-derived single-stranded RNA, recently identified as potent IFN- inducers in PDCs through TLR-7 (43). Accordingly, we have observed that psoriasis can be exacerbated by topical application of imiquimod, a synthetic TLR-7 agonist (19). Furthermore, it has been recently demonstrated that TLR-mediated inflammation of the peripheral target organ is a prerequisite for the conversion of T cell autoreactivity into overt autoimmune disease (44).
Our study defines IFN- as the molecular mediator of PDC function in eliciting psoriasis. PDC-derived IFN- may drive the "quiescent" autoimmune T cells in prepsoriatic skin into activated pathogenic effectors through the induction of myeloid DC activation/maturation. An unabated activation of myeloid DCs through IFN- with the consequent activation of autoimmune T cells has been recognized as a key pathogenic event in SLE (13, 45). In line with these findings, we have previously shown that myeloid DCs in psoriatic skin are also activated and have the ability to stimulate autoimmune T cells (46). The presence of high levels of lesional IFN- might favor cross-presentation of sequestered tissue-specific autoantigens by myeloid DCs (47). PDC-derived IFN- may also enhance the survival and expansion of T cells through the induction of IL-15 (48) or may act directly on T cells by promoting their expression of T-bet and IL12-Rß2 (49), thus potentiating the Th1 cell bias of pathogenic T cells in psoriasis.
Our data provides the direct evidence that IFN- is a master cytokine in psoriasis development. In contrast to TNF-, a validated therapeutic target for psoriasis expressed throughout psoriatic inflammation (36, 50–52), production of IFN- is a tightly regulated, transient event occurring early during the development of psoriasis. Furthermore, in contrast to the broad expression of TNF- by a variety of cells, including myeloid DCs, T cells, and keratinocytes, the production of IFN- in psoriatic skin seems to be confined to dermal PDCs. This may reflect the specialization of PDCs to recognize distinct TLR ligands (39, 40), as well as their extraordinary ability to produce large amounts of IFN-, because of a prolonged endosomal retention of TLR ligands with consequent sustained MyD88/IRF-7 signaling (53). We therefore propose a spatial and temporal view of psoriasis development in which PDC-derived IFN- represents an early upstream event preceding autoimmune inflammation and the development of psoriasis.
Increasing evidence indicates that IFN- plays a pivotal role in the pathogenesis of other autoimmune disorders such as SLE, insulin-dependent diabetes mellitus (IDDM), and rheumatoid arthritis (for review see reference 54). As for psoriasis, IFN- treatment for unrelated conditions can induce or exacerbate these autoimmune diseases (55–57). Evidence for a pathogenic role of IFN- in SLE was provided by the finding that SLE patients have increased serum levels of IFN- that coincide with exacerbations of the disease (58, 59). In addition, large numbers of PDCs are found in the skin lesions of SLE and may be activated to produce IFN- by immune complexes consisting of anti–double-stranded DNA antibodies and DNA derived from apoptotic cells (60). Patients with IDDM demonstrate increased levels of IFN- in the serum and in the pancreas (61). In addition, convincing evidence for a role of IFN- in the pathogenesis of IDDM has been obtained from murine studies (44, 62). IFN- signature has also been detected in the synovium of rheumatoid arthritis patients and has been correlated with the infiltration and activation of PDCs (63). Thus, the organ-specific accumulation of PDCs and their innate activation to produce IFN- may represent a common proximal pathway that drives the efferent arm of immune responses leading to exacerbation of the underlying autoimmune diseases in susceptible individuals.
In conclusion, this study identifies PDCs and PDC-derived IFN- as being important upstream initiators of psoriasis development. Given the side effects and limitations of current antipsoriatic therapies, including TNF- blockers for long term disease control (64), we propose that new strategies targeting PDCs and PDC-derived IFN- should be considered both for prevention and early therapeutic intervention in psoriasis and, potentially, other related autoimmune diseases.
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Isolation of dermal cells and flow cytometry analysis.
Skin keratome biopsies (20 x 20 x 0.4 mm) of plaque psoriasis lesions and uninvolved skin (normal-appearing skin at a distance of 
0.5 cm from the lesion) were taken from the buttocks or upper thigh of patients with confirmed plaque-type psoriasis as described previously (46). Patients did not receive topical or systemic therapy for at least 4 wk before the study. For analysis of developing psoriasis lesions, biopsies were taken across the margin zone (immediately inside and outside of the clinical edge) of spreading psoriatic lesions as defined clinically (37). Dermal sheets were separated from epidermal sheets, cut into small pieces (1–5 mm), and carefully enzymatically digested to yield single cell suspensions as previously described (46). Three-color staining was performed by using anti–BDCA-2 FITC, CD123 APCs (Miltenyi Biotech), and PE-labeled CD3, CD4, CD11b, CD11c, CD14, CD20, CD56, CD80, CD86, CD83, and HLA-DR (all obtained from Becton Dickinson) or their corresponding isotype controls. For intracellular IFN- detection, cells were first surface stained with anti–BDCA-2 FITC, followed by permeabilization and incubation with PE-labeled anti–human IFN-2 mAb (Chromaprobe Inc.) or IgG2b isotype control. Cells were analyzed using a flow cytometer (FACSCalibur; Becton Dickinson) and data were processed using CellQuestPro (Becton Dickinson).
Real-time quantitative PCR.
Total RNA from homogenized skin specimens was extracted and reverse transcribed as previously described (36). Complementary DNA was quantitatively analyzed for the expression of IFN- and IRF-7 transcripts by real-time PCR using primers designed against most human IFN- sequences and against human IRF-7 (left, 5'-TCCCCACGCTATACCATCTACCT-3'; right, 5'-ACAGCCAGGGTTCCAGCTT-3'; Applied Biosystems). 18S ribosomal RNA was used for normalization. In the AGR model, IFN- was quantified in transplanted skin by using a primer kit recognizing most human IFN- genes and that did not recognize its mouse counterpart (Search-LC). Human GAPDH mRNA levels were quantified using human-specific primers (left, 5'-ATTGCCCTCAACGACCACTTTG-3'; right, 5'-TTGATGGTACATGAAAGGTGAGG-3') and used for normalization as previously described (36).
Animals and transplantation procedure.
Animal studies were approved by the Kantonale Veterinaersamt of Zurich. AGR129 mice, deficient in type I (A) and type II (G) IFN receptors, in addition to being RAG-2–/–, were kept pathogen free throughout the study. Keratomes of uninvolved prepsoriatic or normal skin (a gift of S. Baldi, University Hospital of Zurich, Zurich Switzerland) as controls were transplanted to the back of mice using an absorbable tissue seal as previously described (36). 35 d after engraftment, transplanted skin was removed and snap frozen for histological or mRNA expression analysis. CD3+ T cell counts, acanthosis, and papillomatosis index were determined histologically as previously described (36). CD3+ T cell values represent the mean cell count of three random fields assessed at 400x by two independent investigators. The indicated papillomatosis and acanthosis values represent the mean of 10 random areas of each sample.
Neutralization studies.
Dosage and schedule of antibody administration were deduced based on previous data with anti–human mAbs against other cell surface molecules (36) and administered as follows: (a) i.v. injection of 30 µg neutralizing anti–human IFN-/ß Receptor Chain 2 (CD118) mAb (clone MMHAR-2; PBL Biomedical Laboratories) twice weekly for 35 d, starting at day 0 after transplantation; and (b) i.v. injection of 30 µg anti–BDCA-2 mAb (reference 29; provided by J. Schmitz, Miltenyi Biotec, Bergisch-Gladbach, Germany) twice weekly for 35 d, starting at day 0 after transplantation. For IFN- reconstitution experiments, 30,000 IU recombinant human IFN-2a (Roferon A; Roche) were administered systemically by s.c. injections three times a week for 35 d. Dosage corresponds to the therapeutic dose of 8 Mio IU used in humans and was deduced by an allometric approach as previously described (36).
Online supplemental material.
Fig. S1 shows absent expression of BDCA-2 in normal skin and atopic dermatitis skin. Fig. S2 shows plasmacytoid morphology and the classical phenotype of PDCs in psoriatic lesions. Fig. S3 shows IFN- activity in psoriatic plaque lesions but not the uninvolved skin of psoriatic patients, normal skin of healthy individuals, or skin lesions of atopic dermatitis patients. Figs. S4 and S5 show induction and inhibition of psoriasis development in the AGR model as measured by the epidermal acanthosis index. Online supplemental material is available at http://www.jem.org/cgi/content/full/jem.20050500/DC1.
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Acknowledgments |
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This work was funded by a grant from the Swiss National Science Foundation (32-100833/1) to M. Gilliet and F.O. Nestle.
The authors have no conflicting financial interests.
Submitted: 9 March 2005
Accepted: 25 May 2005
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