Cutaneous Dendritic Cells Research Articles

Radiation Therapy for Cutaneous Blastic Plasmacytoid Dendritic Cell Neoplasm: A Case Report and Review of the Literature

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a clinically aggressive hematologic malignancy derived from plasmacytoid dendritic cells. It commonly presents as cutaneous lesions. To date, no standard treatment protocol for BPDCN exists. Traditionally treated similarly to acute leukemia or lymphoma, its prognosis remains poor. Radiation therapy is employed for isolated skin lesions, for patients that are ineligible for chemotherapy due to age or comorbidities and for post-chemotherapy recurrence. However, very limited reports are available on radiotherapy for BPDCN. We present a case involving a 94-year-old BPDCN patient treated with radiation therapy, highlighting an atypical situation of two separate radiotherapy sessions with different dosages for isolated skin lesions. Initially, 45 Gy was administered in 15 fractions (45 Gy/15 Fr), followed by a second session of 30 Gy in 10 fractions (30 Gy/10 Fr) after disease recurrence. This case is unique in detailing radiation therapy for the exceedingly rare BPDCN, particularly dose fractionation. The findings indicate that 45 Gy/15 Fr can provide adequate local control, while even a lower dose of 30 Gy/10 Fr may be effective. This case report contributes to the limited literature by proposing potential therapeutic approaches and dosage guidelines to refine future BPDCN treatment protocols.

Cutaneous clonal mature plasmacytoid dendritic cell dermatosis in patients with myeloid neoplasms

Cutaneous clonal mature plasmacytoid dendritic cell dermatosis in patients with myeloid neoplasms

Cutaneous Manifestations of Myeloid Neoplasms Exhibit Broad and Divergent Morphologic and Immunophenotypic Features but Share Ancestral Clonal Mutations With Bone Marrow

In this study, we performed a comprehensive molecular analysis of paired skin and peripheral blood/bone marrow (BM) samples from 17 patients with cutaneous myeloid or cutaneous histiocytic-dendritic neoplasms. The cutaneous manifestations included 10 patients with cutaneous acute myeloid leukemia (c-AML), 2 patients with full or partial Langerhans cell differentiation, 2 patients with blastic plasmacytoid dendritic cell neoplasms (BPDCN), 1 patient with both Langerhans cell differentiation and BPDCN, and 2 patients with full or partial indeterminate dendritic cell differentiation. Seven of the 10 c-AML patients (70%) exhibited concurrent or subsequent marrow involvement by acute myeloid leukemia, with all 7 cases (100%) demonstrating shared clonal mutations in both the skin and BM. However, clonal relatedness was documented in one additional case that never had any BM involvement. Nevertheless, NPM1 mutations were identified in 7 of the 10 (70%) of these c-AML cases while one had KMT2A rearrangement and one showed inv(16). All 3 patients (100%) with Langerhans cell neoplasms, 2 patients with BPDCN (100%), and one of the 2 patients (50%) with other cutaneous dendritic cell neoplasms also demonstrated shared mutations between the skin and concurrent or subsequent myeloid neoplasms. Both BM and c-AML shared identical founding drivers, with a predominance of NPM1, DNMT3A, and translocations associated with monocytic differentiation, with common cutaneous-only mutations involving genes in the signal transduction and epigenetic pathways. Cutaneous histiocytic-dendritic neoplasms shared founding drivers in ASXL1, TET2, and/or SRSF2. However, in the Langerhans cell histiocytosis or histiocytic sarcoma cases, there exist recurrent secondary RAS pathway hits, whereas cutaneous BPDCN cases exhibit copy number or structural variants. These results enrich and broaden our understanding of clonally related cutaneous manifestations of myeloid neoplasms and further illuminate the highly diverse spectrum of morphologic and immunophenotypic features they exhibit.

Atopic dermatitis – Perspectives and unmet medical needs

Atopic dermatitis (AD) is a chronic inflammatory skin disease for which many new insights have been gained in recent years through a better understanding of pathophysiology, concomitant diseases and therapeutics in particular. In this review, new and practice-relevant results from current research are presented. Many studies have been performed on the diagnosis of AD and on different subtypes, yet no diagnostic biomarker or clinical predictor of treatment response has been established. For topical treatment, some agents such as Janus kinase (JAK) inhibitors are in advanced stages of clinical trials or already approved in some countries, which will be available in Europe for the treatment of certain eczema subtypes in the foreseeable future. Current systemic therapies in Europe include two antibodies for inhibition of the interleukin (IL)-4/13 signaling cascades and three oral JAK inhibitors with somewhat different efficacy and safety profiles. Among the antibody therapies for AD already advanced in development, promising new targets include blockade of IL-31, of neurokinin-1 receptor on sensory neurons, and inhibition of the OX40/OX40L axis for cutaneous dendritic cell and T lymphocyte interaction. Primary prevention and modulation of sequential disease progression as well as effects on concomitant diseases by early therapeutic intervention will be important questions in future research on AD.

Exploring the roles of prostanoids, leukotriens, and dietary fatty acids in cutaneous inflammatory diseases: Insights from pharmacological and genetic approaches.

Prostanoids and leukotrienes (LTs) are representative of ω6 fatty acid-derived metabolites that exert their actions through specific receptors on the cell surface. These lipid mediators, being unstable in vivo, act locally at their production sites; thus, their physiological functions remain unclear. However, recent pharmacological and genetic approaches using experimental murine models have provided significant insights into the roles of these lipid mediators in various pathophysiological conditions, including cutaneous inflammatory diseases. These lipid mediators act not only through signaling by themselves but also by potentiating the signaling of other chemical mediators, such as cytokines and chemokines. For instance, prostaglandin E2 -EP4 and LTB4 -BLT1 signaling on cutaneous dendritic cells substantially facilitate their chemokine-induced migration ability into the skin and play critical roles in the priming and/or activation of antigen-specific effector T cells in the skin. In addition to these ω6 fatty acid-derived metabolites, various ω3 fatty acid-derived metabolites regulate skin immune cell functions, and some exert potent anti-inflammatory functions. Lipid mediators act as modulators of cutaneous immune responses, and manipulating the signaling from lipid mediators has the potential as a novel therapeutic approach for human skin diseases.

006 Conventional dendritic cell 2 as an activator for cytotoxic T lymphocytes in the elicitation phase of murine contact hypersensitivity

Cytotoxic T lymphocyte (CTL) has been found to be activated by cutaneous dendritic cell (DC) in inducible skin-associated lymphoid tissue (iSALT) in a murine contact hypersensitivity (CHS) model. Cutaneous DCs are classified into Langerhans cell (LC), conventional DC1 (cDC1), conventional DC2 (cDC2) and monocyte-derived DC (MoDC); however, which DC subsets activate CTL within iSALT during the elicitation phase of CHS has remained unclear. To clarify this, we used Langerin-diphtheria toxin receptor (DTR), XCR1-DTR and CD301b-DTR mice to deplete LC, cDC1 and cDC2, respectively.

A population of dermal Langerin+ dendritic cells promote the inflammation in mouse model of atopic dermatitis.

Cutaneous dendritic cells (DCs) have been implicated in the pathogenesis of atopic dermatitis (AD). However, the specific role of different subsets of DCs has not been well defined. This study aimed to investigate the contributions of Langerhans cells (LCs), resident dermal Langerin+ DCs (r-Langerin+ dDCs), and newly infiltrated inflammatory dermal Langerin+ DCs (i-Langerin+ dDCs) in an AD mouse model induced by the topical application of MC903. The result showed that depletion of i-Langerin+ dDCs in DTR mice after multiple diphtheria toxin (DT) injection significantly reduced thymic stromal lymphopoietin (TSLP) production in lesions and skin inflammation alleviation. However, depletion of LCs or r-Langerin+ dDCs didn’t resulted in significant changes in skin inflammation of DTA or single DT injection-treated DTR mice compared with the wild-type (WT) mice. DT-treated DTR-WT chimeric mice with the depletion of bone marrow (BM)-derived i-Langerin+ dDCs resulted in markedly decreased skin inflammation than controls, while PBS-treated chimeric mice (DTR-WT) with only the depletion of r-Langerin+ dDCs showed inflammation comparable to that in WT mice. Furthermore, TSLP contributed to the upregulation of Langerin expression in BM-derived DCs and promoted the maturation of Langerin+ DCs. In summary, the present study demonstrated that the newly infiltrated inflammatory dermal Langerin+ DCs were essential for AD development and local TSLP production, and TSLP further promoted the production of BM-derived i-Langerin+ dDCs, which might maintain AD inflammation.

Type 2 immunity plays an essential role for murine model of allergic contact dermatitis with mixed type 1/type 2 immune response

BackgroundBoth human and mouse allergic contact dermatitis (ACD) frequently demonstrates a combined type 1 and type 2 immune response. However, the relative importance of type 2 immunity in this setting has been incompletely understood yet. ObjectiveTo explore an effector function of type 2 immunity in ACD with mixed type 1/type 2 immune response. MethodsGene expression characteristics of contact hypersensitivity (CHS) model was examined by quantitative polymerase chain reaction. Cytokine profile of T cells was analyzed by flow cytometry. The involvement of type 2 immunity was assessed by antibody-mediated cytokine neutralization and cell depletion. The role of specific subset of cutaneous dendritic cells was evaluated using diphtheria toxin-induced cell-depleting mouse strains. ResultsOxazolone-induced CHS revealed a combination of type 1/type 2 gene expression. The severity of oxazolone-induced CHS was ameliorated by neutralization of IL-4 but not of IFN-γ, indicating that type 2 immunity plays a dominant effector function in this mixed type 1/type 2 model. Mechanistically, type 2 effector immunity was mounted by CD301b+Langeirn− dermal dendritic cells in part through thymic stromal lymphopoietin-interleukin 7 receptor alpha signaling-dependent manner. ConclusionOur findings suggest the clinical rationale for targeting type 2 immunity as a relevant therapeutic strategy for the mixed immune phenotype of ACD.

In vivo Function of Differential Subsets of Cutaneous Dendritic Cells to Induce Th17 Immunity in Intradermal Candida albicans Infection.

The skin is the outermost barrier organ in the body, which contains several types of dendritic cells (DCs), a group of professional antigen-presenting cells. When the skin encounters invading pathogens, different cutaneous DCs initiate a distinct T cell immune response to protect the body. Among the invading pathogens, fungal infection specifically drives a protective interleukin-17-producing Th17 immune response. A protocol was developed to efficiently differentiate Th17 cells by intradermal Candida albicans infection to investigate a subset of cutaneous DCs responsible for inducing Th17 immunity. Flow cytometry and gene expression analyses revealed a prominent induction of Th17 immune response in skin-draining lymph nodes and infected skin. Using diphtheria toxin-induced DC subset-depleting mouse strains, CD301b+ dermal DCs were found to be responsible for mounting optimal Th17 differentiation in this model. Thus, this protocol provides a valuable method to study in vivo function of differential subsets of cutaneous DCs to determine Th17 immunity against deep skin fungal infection.

Single-cell analysis of human skin identifies CD14+ type 3 dendritic cells co-producing IL1B and IL23A in psoriasis.

Inflammatory skin diseases including atopic dermatitis (AD) and psoriasis (PSO) are underpinned by dendritic cell (DC)-mediated T cell responses. Currently, the heterogeneous human cutaneous DC population is incompletely characterized, and its contribution to these diseases remains unclear. Here, we performed index-sorted single-cell flow cytometry and RNA sequencing of lesional and nonlesional AD and PSO skin to identify macrophages and all DC subsets, including the newly described mature LAMP3+BIRC3+ DCs enriched in immunoregulatory molecules (mregDC) and CD14+ DC3. By integrating our indexed data with published skin datasets, we generated a myeloid cell universe of DC and macrophage subsets in healthy and diseased skin. Importantly, we found that CD14+ DC3s increased in PSO lesional skin and co-produced IL1B and IL23A, which are pathological in PSO. Our study comprehensively describes the molecular characteristics of macrophages and DC subsets in AD and PSO at single-cell resolution, and identifies CD14+ DC3s as potential promoters of inflammation in PSO.

Fate mapping analysis reveals a novel murine dermal migratory Langerhans-like cell population.

Dendritic cells residing in the skin represent a large family of antigen-presenting cells, ranging from long-lived Langerhans cells (LC) in the epidermis to various distinct classical dendritic cell subsets in the dermis. Through genetic fate mapping analysis and single-cell RNA-sequencing, we have identified a novel separate population of LC-independent CD207+CD326+ LClike cells in the dermis that homed at a slow rate to the lymph nodes (LNs). These LClike cells are long-lived and radio-resistant but, unlike LCs, they are gradually replenished by bone marrow-derived precursors under steady state. LClike cells together with cDC1s are the main migratory CD207+CD326+ cell fractions present in the LN and not, as currently assumed, LCs, which are barely detectable, if at all. Cutaneous tolerance to haptens depends on LClike cells, whereas LCs suppress effector CD8+ T-cell functions and inflammation locally in the skin during contact hypersensitivity. These findings bring new insights into the dynamism of cutaneous dendritic cells and their function opening novel avenues in the development of treatments to cure inflammatory skin disorders.

Pituitary adenylate cyclase-activating polypeptide promotes cutaneous dendritic cell functions in contact hypersensitivity

Sensory nerves regulate cutaneous local inflammation indirectly through induction of pruritus and directly by acting on local immune cells. The underlying mechanisms for how sensory nerves influence cutaneous acquired immune responses remain to be clarified. This study aimed to explore the effect of peripheral nerves on cutaneous immune cells in cutaneous acquired immune responses. We analyzed contact hypersensitivity (CHS) responses as a murine model of delayed-type hypersensitivity in absence or presence of resiniferatoxin-induced sensory nerve denervation. We conducted ear thickness measurements, flow cytometric analyses, and mRNA expression analyses in CHS. CHS responses were attenuated in mice that were denervated during the sensitization phase of CHS. By screening neuropeptides, we found that pituitary adenylate cyclase-activating polypeptide (PACAP) mRNA expression was decreased in the dorsal root ganglia after denervation. Administration of PACAP restored attenuated CHS response in resiniferatoxin-treated mice, and pharmacological inhibition of PACAP suppressed CHS. Flow cytometric analysis of skin-draining lymph nodes showed that cutaneous dendritic cell migration and maturation were reduced in both denervated mice and PACAP antagonist-treated mice. The expression of chemokine receptors CCR7 and CXCR4 of dendritic cell s was enhanced by addition of PACAP invitro. These findings indicate that a neuropeptide PACAP promotes the development of CHS responses by inducing cutaneous dendritic cell functions during the sensitization phase.

Improvement of clinical and immunological parameters after allergen-specific immunotherapy in atopic dermatitis.

Allergen immunotherapy (AIT) is considered a curative treatment in some atopic diseases, but in AD contradictory clinical results exist and the action of AIT has not been elucidated. In the literature, there is no evidence for parallel investigations of permeability barrier, cutaneous and blood immune responses after AIT in AD. The objective was to investigate immune parameters in the blood and skin and to detect clinical and barrier changes after AIT in AD. Mild-to-moderate AD patients (n=14) with concomitant allergic rhinitis to house dust mites were selected. All patients received topical treatment, while eight patients were randomly selected for adjuvant AIT also. At baseline and after 6months, clinical, barrier and immunological investigations (serum and skin tests) were performed. In selected patients, biopsies from atopy patch tests (APTs) were analysed by immunohistochemistry for AD-relevant immune cells and mediators. In the adjuvant AIT group, clinical parameters and barrier functions improved significantly. Blood immune parameters displayed no significant changes. Post-AIT APT became negative in all patients in the AIT group, but remained positive in the non-AIT group. Cutaneous dendritic cell and T-cell recruitment decreased significantly after allergen challenge in the AIT group, but no significant changes in skin or serum immunoglobulin E levels or prick test (SPT) reactivity were detected. Allergen immunotherapy is a beneficial adjuvant treatment for sensitized AD patients. AIT improves not only clinical symptoms, but also permeability barrier functions. The effect of AIT on sensitization should be detected by APT, not by SPT.

Primary cutaneous blastic plasmacytoid dendritic cell neoplasm in a child: A challenging diagnosis and management

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive malignancy of the skin and hematopoietic system. There are few pediatric cases reported in the literature. Management of primary cutaneous BPDCN is challenging because, despite an apparently indolent clinical presentation, rapid dissemination with high mortality can occur. We describe a child with isolated cutaneous involvement who had a good response to chemotherapy as first-line treatmentof BPDCN.

Abstract 1417: Development of a miRNA-based prediction tool to discriminate cutaneous blastic plasmacytoid dendritic cell neoplasm from cutaneous myeloid sarcoma

Abstract Background Blastic plasmacytoid dendritic cell neoplasm (BPDCN) and myeloid sarcoma (MS) are two extremely rare and aggressive hematological diseases. Both malignancies most commonly arise with skin lesions with or without extramedullary organ involvement before leukemic dissemination. Given its rarity and less known biology, in some cases with defective/ambiguous phenotype distinguish between these two entities may be challenging for pathologists and clinicians.1 Can the machine learning predictive model help to solve this diagnostic question? Here we performed the first study of microRNA (miRNA) profiling of BPDCN and MS in order to 1) Discover new molecular features selectively driving BPDCN respect to MS 2) Develop a machine learning based-prediction tool useful for discriminating BPDCN and MS. Methods We performed miRNA profiling (NanoString Technologies) of cutaneous biopsies of 16 BPDCN and 23 MS cases. Using Supervised Analysis, we identified 49 miRNAs differentially expressed that were randomly validated by qRT-PCR and next interrogated by functional enrichment analysis. Finally, a machine learning algorithm based on Linear Discriminant Analysis2 was applied to identify candidate miRNAs able to discriminate BPDCN from MS cases. Results In line with the overlapping clinical features of BPDCN and MS, the molecular profiling of these two diseases was proved to be extremely similar. Unsupervised Analysis well demonstrated that the miRNA profiles of the two malignancies are closely related and indeed, BPDCN and MS cases cluster together. When a Supervised Analysis was applied, we identified a set of 49 miRNAs differentially expressed in BPDCN respect to MS, 25 down- and 24 up-regulated. Of relevance, down-regulated miRNAs were predicted to be markedly involved in the apoptosis regulation of BPDCN. Machine learning predictive model identified a set of 12 miRNAs (5 up and 7 down) able to discriminate cutaneous BPDCN from MS. Conclusion This is the first miRNA profiling study in BPDCN and MS that showed how strongly these two diseases overlap at molecular level. Despite their similarity, BPDCN cases displayed a set of miRNAs significantly down-regulated when compared to MS, with possible dysregulation of cell death pathway. Of practical interest, we designed a machine learning predictive model based on the expression of 12 miRNAs, which alone may be applied to distinguish between the two hematological diseases. This tool, if validated in a larger set of cases, may help to differentiate BPDCN and MS in cases with defective/ambiguous phenotype.

Lysosomotropic beta blockers induce oxidative stress and IL23A production in Langerhans cells

ABSTRACT Oxidative stress and Th17 cytokines are important mediators of inflammation. Treatment with beta-adrenoceptor (ADRB) antagonists (beta-blockers) is associated with induction or aggravation of psoriasis-like skin inflammation, yet the underlying mechanisms are poorly understood. Herein, we identify lysosomotropic beta-blockers as critical inducers of IL23A in human monocyte-derived Langerhans-like cells under sterile-inflammatory conditions. Cytokine release was not mediated by cAMP, suggesting the involvement of ADRB-independent pathways. NFKB/NF-κB and MAPK14/p38 activation was required for propranolol-induced IL23A secretion whereas the NLRP3 inflammasome was dispensable. MAPK14 regulated recruitment of RELB to IL23A promoter regions. Without affecting the ubiquitin-proteasome pathway, propranolol increased lysosomal pH and induced a late-stage block in macroautophagy/autophagy. Propranolol specifically induced reactive oxygen species production, which was critical for IL23A secretion, in Langerhans-like cells. Our findings provide insight into a potentially crucial immunoregulatory mechanism in cutaneous dendritic cells that may explain how lysosomotropic drugs regulate inflammatory responses. Abbreviations ATF: activating transcription factor; DC: dendritic cell; ChIP: chromatin immunoprecipitation; gDNA: genomic DNA; IL: interleukin; LAMP1: lysosomal associated membrane protein 1; LC: Langerhans cell; LPS: lipopolysaccharide; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MAPK: mitogen-activated protein kinase; MoDC: monocyte-derived DC; MoLC: monocyte-derived Langerhans-like cell; mtDNA: mitochondrial DNA; NAC: N-acetyl-L-cysteine; NLRP3: NLR family pyrin domain containing 3; PBMC: peripheral blood mononuclear cell; PI: propidium iodide; PYCARD/ASC: PYD and CARD domain containing; qRT-PCR: quantitative real-time PCR; ROS: reactive oxygen species; SQSTM1/p62: sequestosome 1; TLR: Toll-like receptor; TRAF6: TNF receptor associated factor 6; TNF: tumor necrosis factor; Ub: ubiquitin.

Percutaneous sensitization is limited by in situ inhibition of cutaneous dendritic cell migration through skin-resident regulatory T cells

Percutaneous sensitization is associated with various allergic diseases, including asthma and food allergies. However, the immunologic mechanisms underlying how the skin regulates percutaneous sensitization are still unclear. We aimed to investigate whether and how CD4+Foxp3+ regulatory T (Treg) cells residing in the skin regulate percutaneous sensitization in the skin. Selective reduction of numbers of cutaneous Treg cells was achieved by means of intradermal injection of diphtheria toxin into the ear skin of Foxp3DTR mice, in which Treg cells specifically express the diphtheria toxin receptor fused with green fluorescent protein. Thirty percent to 40% of cutaneous Treg cells were capable of IL-10 production in both mice and human subjects. Selective reduction of cutaneous Treg cells at the sensitization site promoted migration of antigen-bearing dendritic cells (DCs) to the draining lymph nodes (dLNs). Accordingly, sensitization through the skin with reduced numbers of Treg cells led to enhanced antigen-specific immune responses in the dLNs, including both effector T-cell differentiation and T cell-dependent B-cell responses, such as the development of germinal center B cells expressing IgG1 and IgE. Furthermore, antigen-bearing cutaneous DC migration was enhanced in mice with IL-10 deficiency restricted to the cutaneous Treg cell compartment, suggesting an important role of cutaneous IL-10+ Treg cells in limiting percutaneous sensitization. Treg cells with a skin-homing phenotype in skin dLNs expressed high levels of IL-10, suggesting that they contribute to renewal and maintenance of the cutaneous IL-10+ Treg cell population. Skin-resident Treg cells limit percutaneous sensitization by suppressing antigen-bearing DC migration through in situ IL-10 production.

Silencing of PD-L2/B7-DC by Topical Application of Small Interfering RNA Inhibits Elicitation of Contact Hypersensitivity

Abstract PD-L2 is a ligand for the immune checkpoint receptor PD-1, however, its regulatory function is unclear. We previously reported that silencing of CD86 in cutaneous dendritic cells (DCs) by topical siRNA application inhibits the elicitation of contact hypersensitivity (CHS). Here we investigated the effects of topical PD-L2 siRNA application on allergic skin disease. PD-L2 was induced in DCs concurrently with the elevation of MHC class II and CD86 expression. Topical PD-L2 siRNA application inhibited elicitation of CHS by suppressing early proinflammatory cytokine expression and migration of hapten-carrying DCs into lymph nodes. Local injection of neutralizing anti-PD-L2 mAb comparably inhibited CHS. PD-L2 siRNA treatment inhibited the CHS in PD-1/PD-L1 double-knockout mice and in the sensitized T-cell-transferred skin. These results suggest that the effects of PD-L2 silencing are independent of PD-1 but dependent on local memory T cells. Most of the inhibitory effects of PD-L2 and CD86 silencing on CHS were comparable, but PD-L2 siRNA treatment did not inhibit atopic disease-like manifestations and Th2 responses in NC/Nga mice. Our results suggest that PD-L2 in cutaneous DCs acts as a costimulator rather than a regulator. Local PD-L2 silencing by topical siRNA application represents a new therapeutic approach for contact allergy.

Silencing of PD-L2/B7-DC by Topical Application of Small Interfering RNA Inhibits Elicitation of Contact Hypersensitivity

PD-L2 is a ligand for the immune checkpoint receptor PD-1; however, its regulatory function is unclear. We previously reported that silencing of CD86 in cutaneous dendritic cells by topical application of small interfering RNA (siRNA) inhibits the elicitation of contact hypersensitivity (CHS). Here, we investigated the effects of topical application of PD-L2 siRNA on allergic skin disease. PD-L2 was induced in dendritic cells concurrently with the elevation of major histocompatibility complex class II and CD86 expression. Topical application of PD-L2 siRNA inhibited the elicitation of CHS by suppressing early proinflammatory cytokine expression and migration of hapten-carrying dendritic cells into lymph nodes. Local injection of neutralizing anti-PD-L2 mAb inhibited CHS to the same extent. PD-L2 siRNA treatment inhibited CHS in PD-1/PD-L1 double knockout mice and in the sensitized T-cell-transferred skin. These results suggest that the effects of PD-L2 silencing are independent of PD-1 but dependent on local memory T cells. Most of the inhibitory effects of PD-L2 and CD86 silencing on CHS were comparable, but PD-L2 siRNA treatment did not inhibit atopic disease-like manifestations and T helper type 2 responses in NC/Nga mice. Our results suggest that PD-L2 in cutaneous dendritic cells acts as a costimulator rather than a regulator. Local PD-L2 silencing by topical application of siRNA represents a therapeutic approach for contact allergy.

Dendritic cell distribution in mycosis fungoides vs. inflammatory dermatosis and other T-cell skin lymphoma.

Dendritic cells (DCs) are antigen-presenting cells with an important role in the innate and adaptive immune system. In skin lesions, cutaneous DCs (Langerhans cells, dermal DCs and plasmacytoid DCs) are involved in immune activation in inflammatory benign lesions, as well as in malignant lymphoid proliferations. Density and distribution of DCs in the dermal infiltrate can be helpful to differentiate benign, reactive infiltrate from malignant nature of the lymphoid population. We performed a retrospective study including 149 patients: 35 with mycosis fungoides, 35 with spongiotic dermatitis, 35 with psoriasis, 35 with lupus and 9 with cutaneous T-cell lymphomas (other than mycosis fungoides), diagnosed using histopathological and immunohistochemical stains. Density and distribution of DCs were evaluated using specific markers (CD1a, CD11c and langerin). In all cases, numerous DCs were identified in the dermal infiltrate. Their number was significantly increased in mycosis fungoides and T-cell lymphomas and moderately increased in inflammatory lesions. Variable patterns of distribution were identified such as clusters of DCs with arachnoid extension in mycosis fungoides, nodular pattern in inflammatory lesions and dispersed distribution with peripheric accumulation in T-skin lymphomas. Therefore, immunohistochemical characterization of DC distribution can be an adjuvant tool in differential diagnosis in inflammatory dermatosis and skin lymphomas.