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1.
Artigo em Inglês | MEDLINE | ID: mdl-31618376

RESUMO

Dermatophytosis is a cutaneous mycosis caused by a plethora of keratinophilic fungi, but Trichophyton rubrum is the most common etiological agent. Despite its high prevalence worldwide, little is known about the host defense mechanisms in this infection, particularly the in situ immune response. Using an immunohistochemistry approach, we investigated the density of CD1a+, factor XIIIa+ and CD68+ cells in the skin of dermatophytosis patients. Langerhans cells (CD1a+ cells) were significantly decreased in the epidermis of patients, both in affected and unaffected areas. In the dermis, however, no differences in the density of macrophages (CD68+ cells) and dermal dendrocytes (factor XIIIa+ cells) were observed. These results suggest that the decreased number of Langerhans cells may be a risk factor for development of dermatophytosis.


Assuntos
Dermatomicoses/imunologia , Dermatomicoses/patologia , Imunidade Inata/imunologia , Células de Langerhans/imunologia , Células de Langerhans/patologia , Adulto , Estudos de Casos e Controles , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Tinha/imunologia , Tinha/patologia , Adulto Jovem
2.
Toxicol Lett ; 314: 172-180, 2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31404593

RESUMO

Vesicants cause a multitude of cutaneous reactions like erythema, blisters and ulcerations. After exposure to sulfur mustard (SM) and related compounds, patients present dermal symptoms typically known for chemicals categorized as skin sensitizer (e.g. hypersensitivity and flare-up phenomena). However, although some case reports led to the assumption that SM and other alkylating compounds represent sensitizers, a comprehensive investigation of SM-triggered immunological responses has not been conducted so far. Based on a well-structured system of in chemico and in vitro test methods, the Organization for Economic Co-operation and Development (OECD) established procedures to categorize agents on their skin sensitizing abilities. In this study, the skin sensitizing potential of SM and three related alkylating agents (AAs) was assessed following the OECD test guidelines. Besides SM, investigated AAs were chlorambucil (CHL), nitrogen mustard (HN3) and 2-chloroethyl ethyl sulfide (CEES). The methods are described in detail in the EURL ECVAM DataBase service on ALternative Methods to animal experimentation (DB-ALM). In accordance to OECD recommendations, skin sensitization is a pathophysiological process starting with a molecular initiating step and ending with the in vivo outcome of an allergic contact dermatitis. This concept is called adverse outcome pathway (AOP). An AOP links an adverse outcome to various key events which can be assayed by established in chemico and in vitro test methods. Positive outcome in two out of three key events indicates that the chemical can be categorized as a skin sensitizer. In this study, key event 1 "haptenation" (covalent modification of epidermal proteins), key event 2 "activation of epidermal keratinocytes" and key event 3 "activation of dendritic cells" were investigated. Covalent modification of epidermal proteins measured by using the DPRA-assay provided distinct positive results for all tested substances. Same outcome was seen in the KeratinoSens assay, investigating the activation of epidermal keratinocytes. The h-CLAT assay performed to determine the activation of dendritic cells provided positive results for SM and CEES but not for CHL and HN3. Altogether, following OECD requirements, our results suggest the classification of all investigated substances as skin sensitizers. Finally, a tentative AOP for SM-induced skin sensitization is suggested.


Assuntos
Substâncias para a Guerra Química/toxicidade , Irritantes/toxicidade , Gás de Mostarda/toxicidade , Testes de Irritação da Pele/normas , Pele/efeitos dos fármacos , Biomarcadores/metabolismo , Substâncias para a Guerra Química/classificação , Clorambucila/classificação , Clorambucila/toxicidade , Guias como Assunto , Humanos , Irritantes/classificação , Queratinócitos/efeitos dos fármacos , Queratinócitos/imunologia , Queratinócitos/metabolismo , Células de Langerhans/efeitos dos fármacos , Células de Langerhans/imunologia , Células de Langerhans/metabolismo , Mecloretamina/classificação , Mecloretamina/toxicidade , Gás de Mostarda/análogos & derivados , Gás de Mostarda/classificação , Medição de Risco , Pele/imunologia , Pele/metabolismo
3.
J Dermatol ; 46(9): 812-815, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31271447

RESUMO

A 3-month-old boy developed small papules on his trunk. After the papules increased in number, the patient was diagnosed with Langerhans cell histiocytosis based on the pathological findings. He was referred to our department for further examination. Upon initial examination, the papules and nodules were scattered on his back, abdomen and lumbar region. Because he did not present with any organ involvement except the skin, he was diagnosed with single-system and skin-limited Langerhans cell histiocytosis. Skin rashes were treated with a topical steroid and started regressing 3 months after onset. All papules disappeared 6 months after onset. In this boy, the Langerhans cell histiocytosis tumor cells expressed phosphorylated extracellular signal-regulated kinases. In Langerhans cell histiocytosis, BRAF V600E and other genes are known to mutate to act as driver mutations in stem cells of the myeloid dendritic cell lineage. Consequently, extracellular signal-regulated kinases are continuously activated, which contributes to Langerhans cell histiocytosis carcinogenesis.


Assuntos
MAP Quinases Reguladas por Sinal Extracelular/imunologia , Histiocitose de Células de Langerhans/imunologia , Regressão Neoplásica Espontânea/imunologia , Neoplasias Cutâneas/imunologia , Administração Cutânea , Biópsia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Glucocorticoides/administração & dosagem , Histiocitose de Células de Langerhans/congênito , Histiocitose de Células de Langerhans/tratamento farmacológico , Histiocitose de Células de Langerhans/patologia , Humanos , Lactente , Células de Langerhans/imunologia , Células de Langerhans/patologia , Masculino , Fosforilação/imunologia , Pele/citologia , Pele/imunologia , Pele/patologia , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/patologia
4.
J Dermatol ; 46(7): 610-614, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31166031

RESUMO

Primary cicatricial alopecia (PCA) is a group of poorly understood mechanisms in which the destruction of hair follicles leads to permanent hair loss. Lichen planopilaris (LPP) is a type of lymphocytic PCA and it has been known for epidermal Langerhans cells (LC) to disappear in the scar of LPP. We also found that epidermal LC also disappeared in the scar of folliculitis decalvans (FD), a type of neutrophilic PCA. Of note was that epidermal LC did not disappear in the scar of discoid lupus erythematosus, another type of lymphocytic PCA, suggesting that LC disappearance in the scar was not always a common feature of PCA. We found that the expression of integrin (ITG)-αvß6 in scar epidermis was significantly diminished in LPP and FD, but not in other PCA and disorders accompanied with scar formation. We also found that exogenous interleukin-1ß and α-interferon downregulated ITG-αvß6 expression in normal human epidermal keratinocytes. These data suggest that downregulation of ITG-αvß6 may be one of the causes of LC disappearance in the scar of LPP and FD.


Assuntos
Alopecia/patologia , Antígenos de Neoplasias/metabolismo , Cicatriz/patologia , Foliculite/patologia , Integrinas/metabolismo , Células de Langerhans/imunologia , Líquen Plano/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Alopecia/imunologia , Antígenos de Neoplasias/imunologia , Cicatriz/imunologia , Regulação para Baixo , Células Epidérmicas/imunologia , Epiderme/imunologia , Epiderme/patologia , Feminino , Foliculite/imunologia , Folículo Piloso/imunologia , Folículo Piloso/patologia , Humanos , Integrinas/imunologia , Queratinócitos , Líquen Plano/imunologia , Masculino , Pessoa de Meia-Idade
5.
mBio ; 10(3)2019 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-31088921

RESUMO

Staphylococcus aureus is a major cause of skin and soft tissue infections and aggravator of the inflammatory skin disease atopic dermatitis (AD [eczema]). Epicutaneous exposure to S. aureus induces Th17 responses through skin Langerhans cells (LCs), which paradoxically contribute to host defense but also to AD pathogenesis. The molecular mechanisms underlying the interaction between S. aureus and LCs are poorly understood. Here we demonstrate that human LCs directly interact with S. aureus through the pattern recognition receptor langerin (CD207). Human, but not mouse, langerin interacts with S. aureus through the conserved ß-N-acetylglucosamine (GlcNAc) modifications on wall teichoic acid (WTA), thereby discriminating S. aureus from other staphylococcal species. Importantly, the specific S. aureus WTA glycoprofile strongly influences the level of proinflammatory cytokines that are produced by in vitro-generated LCs. Finally, in a murine epicutaneous infection model, S. aureus strongly upregulated transcripts of Cxcl1, Il6, and Il17, which required the presence of both human langerin and WTA ß-GlcNAc. Our findings provide molecular insight into the unique proinflammatory capacities of S. aureus in relation to skin inflammation.IMPORTANCE The bacterium Staphylococcus aureus is an important cause of skin infections and is also associated with the occurrence and severity of eczema. Langerhans cells (LCs), a specific subset of skin immune cells, participate in the immune response to S. aureus, but it is yet unclear how LCs recognize S. aureus Therefore, we investigated the molecular mechanism underlying the interaction between LCs and S. aureus We identified that wall teichoic acid, an abundant polymer on the S. aureus surface, is recognized by langerin, a receptor unique to LCs. This interaction allows LCs to discriminate S. aureus from other related staphylococcal species and initiates a proinflammatory response similar to that observed in patients with eczema. Our data therefore provide important new insights into the relationship between S. aureus, LCs, and eczema.


Assuntos
Antígenos CD/genética , Antígenos de Superfície/genética , Células de Langerhans/imunologia , Lectinas Tipo C/genética , Lectinas de Ligação a Manose/genética , Infecções Estafilocócicas/imunologia , Ácidos Teicoicos/imunologia , Acetilglucosamina , Animais , Antígenos CD/imunologia , Antígenos de Superfície/imunologia , Células Cultivadas , Citocinas/genética , Citocinas/imunologia , Humanos , Inflamação , Interleucina-17/genética , Interleucina-17/imunologia , Lectinas Tipo C/imunologia , Lectinas de Ligação a Manose/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Pele/imunologia , Pele/microbiologia , Staphylococcus aureus
6.
J Cutan Med Surg ; 23(4): 370-379, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31010295

RESUMO

BACKGROUND: 5-aminolevulinic acid photodynamic therapy (PDT) for genital warts is effective, safe, and can prevent recurrence. It is believed that PDT can induce immune responses, but the mechanism is not completely understood. OBJECTIVES: The objectives of this article are to confirm the effect of PDT for genital warts on local immunity and to investigate the recruitment and significance of immune cells in tissues. METHODS: Local immune changes in T lymphocytes (CD3+, CD4+, CD8+), plasmacytoid dendritic cells (pDCs) (CD123+), and myeloid dendritic cells (CD1a+) after PDT in patients were evaluated by immunohistochemistry staining. Changes in mRNA levels of IFN-γ, IFN-α, IFN-ß, interferon-stimulated gene 15 kDa (ISG-15), Mx2, Toll-like receptor 9 (TLR9), and interferon regulatory factor 7 (IRF7) were analyzed by real-time quantitative polymerase chain reaction. RESULTS: At 4 hours after PDT, CD4+ increased, accompanied by increased levels of mRNA expression of IFN-γ, but CD4+ and mRNA expression levels of IFN-γ were decreased at 24 hours after PDT. CD123+ pDCs showed an increasing trend. CD1a+ LCs in the epidermis gradually decreased, and DCs in the epidermis gradually increased. CD3+ infiltrated and migrated to the superficial dermis, but CD8+ did not change significantly after PDT. The mRNA expression levels of IFN-α, IFN-ß, ISG-15, Mx2, TLR9, and IRF7 showed an increasing trend after PDT. As compared with the patients without significantly increased IFN-α and IFN-ß after PDT sessions, patients with significant increases needed fewer sessions of PDT for remission. CONCLUSIONS: PDT for genital warts can activate T lymphocyte-mediated, DC-related, and pDC-related immunity. The clinical efficacy of PDT for genital warts may be related to the increased levels of IFN-α and IFN-ß after treatment.


Assuntos
Ácido Aminolevulínico/farmacologia , Condiloma Acuminado/tratamento farmacológico , Epiderme/imunologia , Células de Langerhans/imunologia , Fotoquimioterapia , Fármacos Fotossensibilizantes/farmacologia , Adulto , Ácido Aminolevulínico/uso terapêutico , Antígenos CD1/metabolismo , Complexo CD3/metabolismo , Contagem de Linfócito CD4 , Linfócitos T CD8-Positivos/imunologia , Citocinas/genética , Epiderme/metabolismo , Feminino , Expressão Gênica/efeitos dos fármacos , Humanos , Fator Regulador 7 de Interferon/genética , Interferon-alfa/genética , Interferon beta/genética , Interferon gama/genética , Subunidade alfa de Receptor de Interleucina-3/metabolismo , Células de Langerhans/efeitos dos fármacos , Células de Langerhans/metabolismo , Masculino , Pessoa de Meia-Idade , Proteínas de Resistência a Myxovirus/genética , Fármacos Fotossensibilizantes/uso terapêutico , RNA Mensageiro/metabolismo , Receptor Toll-Like 9/genética , Ubiquitinas/genética , Adulto Jovem
7.
J Int AIDS Soc ; 22(3): e25268, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30932366

RESUMO

INTRODUCTION: The significant rise in incidence of Hepatitis C virus (HCV) infection among men-who-have-sex-with-men (MSM) living with HIV-1 suggests that HCV under specific circumstances is transmitted via sexual contact. During sexual transmission HCV has to cross the epithelial barrier to either directly enter the blood stream or indirectly via mucosal immune cells. However, the mechanisms of sexual transmission of HCV remain unclear. We investigated the role of Langerhans cells (LCs) in HCV susceptibility during sexual contact as LCs are among the first cells in mucosal tissues to encounter invading viruses. METHODS: We investigated the phenotype of primary LCs in anal biopsies from MSM living with HIV-1. To investigate the role of primary LCs in HCV infection and transmission, we have used both isolated primary skin LCs and the ex vivo tissue transmission model. RESULTS: Our data identified an important role for mucosal LCs in facilitating HCV transmission after HIV-1 exposure or immune activation. LCs were detected within mucosal anal tissues obtained from HIV-1 positive MSM biopsies. In order to perform functional studies, we used primary LCs from skin, which have a similar phenotype as mucosal LCs. Immature LCs were neither infected nor transmitted HCV to hepatocytes. Notably, exposure to HIV-1 significantly increased HCV transmission by LCs in the ex vivo transmission model. HIV-1 replication was crucial for the increased HCV transmission as HIV-1 inhibitors significantly reduced HIV-1-induced HCV transmission. Moreover, tissue immune activation of LCs also increased HCV transmission to target cells. CONCLUSIONS: Thus, our data strongly indicate that HIV-1 or immune activation in MSM leads to capture of HCV by mucosal LCs, which might facilitate transmission to other cells or allow entry of HCV into the blood. This novel transmission mechanism by LCs also implicates that the activation state of LCs is an important cellular determinant for HCV susceptibility after sexual contact.


Assuntos
Infecções por HIV/complicações , Hepacivirus/fisiologia , Hepatite C/transmissão , Células de Langerhans/virologia , Doenças Sexualmente Transmissíveis/transmissão , Adulto , Células Cultivadas , Infecções por HIV/epidemiologia , Infecções por HIV/virologia , HIV-1/genética , HIV-1/isolamento & purificação , HIV-1/fisiologia , Hepacivirus/genética , Hepacivirus/isolamento & purificação , Hepatite C/epidemiologia , Hepatite C/imunologia , Hepatite C/virologia , Humanos , Células de Langerhans/imunologia , Masculino , Membrana Mucosa/imunologia , Membrana Mucosa/virologia , Doenças Sexualmente Transmissíveis/imunologia , Doenças Sexualmente Transmissíveis/virologia
8.
J Immunol Res ; 2019: 5143635, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30944833

RESUMO

Ideal agents for the topical treatment of skin wounds should have antimicrobial efficacy without negative influence on wound healing. Octenidine (OCT) has become a widely used antiseptic in professional wound care, but its influence on several components of the wound healing process remains unclear. In the present study, we have used a superficial wound model using tape stripping on human full-thickness skin ex vivo to investigate the influence of OCT on epidermal Langerhans cells (LCs) and cytokine secretion pattern of skin cells during wound healing in a model without disruption of the normal skin structure. Histological and immunofluorescence studies showed that OCT neither altered human skin architecture nor the viability of skin cells upon 48 hours of culture in unwounded or wounded skin. The epidermis of explants and LCs remained morphologically intact throughout the whole culture period upon OCT treatment. OCT inhibited the upregulation of the maturation marker CD83 on LCs and prevented their emigration in wounded skin. Furthermore, OCT reduced both pro- and anti-inflammatory mediators (IL-8, IL-33, and IL-10), while angiogenesis and growth factor mediators (VEGF and TGF-ß1) remained unchanged in skin explant cultures. Our data provide novel insights into the host response to OCT in the biologically relevant environment of viable human (wounded) skin.


Assuntos
Anti-Infecciosos/farmacologia , Citocinas/genética , Epiderme/efeitos dos fármacos , Células de Langerhans/efeitos dos fármacos , Células de Langerhans/imunologia , Piridinas/farmacologia , Cicatrização/efeitos dos fármacos , Adulto , Citocinas/imunologia , Células Epidérmicas/efeitos dos fármacos , Células Epidérmicas/imunologia , Humanos , Pessoa de Meia-Idade , Modelos Biológicos , Pele/efeitos dos fármacos , Pele/imunologia , Pele/patologia , Fita Cirúrgica , Cicatrização/imunologia , Ferimentos e Lesões/tratamento farmacológico , Ferimentos e Lesões/imunologia , Adulto Jovem
9.
J Immunol ; 202(10): 2999-3007, 2019 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-30952816

RESUMO

The lymphatic vasculature is an important route for dendritic cell (DC) or tumor cell migration from peripheral tissues to draining lymph nodes (DLNs). However, the underlying molecular and cellular mechanisms remain poorly understood. In this study, using conventional bone marrow chimeric mice and additional UVB radiation, we found that deficiency of LIGHT but not lymphotoxin (LT) α1ß2, likely on radioresistant Langerhans cells (LCs), resulted in impaired skin DC migration to DLNs during LPS-induced inflammation. In addition, LT ß receptor (LTßR), but not herpes virus entry mediator, was found to be the receptor of LIGHT controlling DC migration. Furthermore, conditional deficiency of LTßR in Tie2 cre or Lyve1 cre mice, but not in LTßR-deficient bone marrow chimeric mice, impaired DC migration, suggesting an important role of LTßR in radioresistant lymphatic endothelial cells (LECs), although the role of LTßR in blood endothelial cells remains intriguing. Mechanistically, the gene expression of both CCL21 and CCL19 was found to be reduced in skin LECs isolated from LC-LIGHT-conditionally deficient or Lyve1 cre Ltbr fl/fl mice compared with their controls upon LPS stimulation. Soluble recombinant LIGHT was able to upregulate CCL21 and CCL19 gene expression on SVEC4-10 endothelial cells. Doxycycline, an inhibitor of soluble LIGHT release in the inflamed skin, impaired skin CCL21 and CCL19 expression and DC migration. In addition, melanoma cell metastasis to DLNs was also inhibited in LC-LIGHT-conditionally deficient or Lyve1 cre Ltbr fl/fl mice. Together, our data suggest, to our knowledge, a previously unrecognized scenario in which LCs activate LECs via the LIGHT-LTßR signaling axis to promote DC migration or tumor cell metastasis.


Assuntos
Células Endoteliais/imunologia , Células de Langerhans/imunologia , Vasos Linfáticos/imunologia , Receptor beta de Linfotoxina/imunologia , Transdução de Sinais/imunologia , Membro 14 da Superfamília de Ligantes de Fatores de Necrose Tumoral/imunologia , Animais , Células Endoteliais/patologia , Inflamação/induzido quimicamente , Inflamação/genética , Inflamação/imunologia , Inflamação/patologia , Células de Langerhans/patologia , Lipopolissacarídeos/toxicidade , Vasos Linfáticos/patologia , Receptor beta de Linfotoxina/genética , Camundongos , Camundongos Transgênicos , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Membro 14 da Superfamília de Ligantes de Fatores de Necrose Tumoral/genética
11.
J Immunol ; 202(3): 653-663, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30598513

RESUMO

CD4+ T cell responses are crucial for the control of many intracellular pathogens, yet the requirements for their induction are not fully understood. To better understand the role that various dendritic cell (DC) subtypes play in CD4+ T cell priming, we compared in vivo T cell responses to skin inoculation of mice with infectious or UV-inactivated HSV type 1. Localized infection elicited a Th1 response that was primed in skin-draining lymph nodes involving Ag presentation by migratory dermal and lymph node-resident DC. However, expansion and Th1 differentiation was impaired in response to UV-inactivated virus (UV-HSV), and this defect correlated with a restriction of Ag presentation to migratory CD103- dermal DC. A similar differentiation defect was seen in infected mice lacking CD8α+ and CD103+ classical type 1 DC (cDC1). Finally, Th1 differentiation after UV-HSV inoculation was rescued by targeted Ag delivery to CD8α+ and CD103+ cDC1 using an anti-Clec9A Ab construct. This suggests that Ag presentation by cDC1 is crucial for optimal Th1 immunity to HSV type 1 infection and potentially other pathogens of the skin.


Assuntos
Apresentação do Antígeno , Células Dendríticas/imunologia , Herpes Simples/imunologia , Células de Langerhans/imunologia , Dermatopatias Virais/imunologia , Células Th1/imunologia , Animais , Linfócitos T CD8-Positivos/imunologia , Diferenciação Celular , Feminino , Herpesvirus Humano 1/efeitos da radiação , Linfonodos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Raios Ultravioleta , Inativação de Vírus/efeitos da radiação
12.
J Dermatol Sci ; 93(2): 82-91, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30514663

RESUMO

BACKGROUND: Psoriasis is an inflammatory disease associated with aberrant crosstalk between the epidermis and immune system. However, the role of Langerhans cells (LCs) in psoriasis remains controversial. OBJECTIVES: To elucidate whether LCs are functionally involved in the development of psoriasis using a mouse model. METHODS: Two lines of transgenic mice were used and crossed. They included K5.Stat3C, the psoriasis-model mouse and langerin DTR knock-in (KI) mouse. We performed immunofluorescence staining for LCs in psoriatic lesion of human and model mice. Flow cytometric analyses were performed to compare between dendritic cells (DCs) and LCs in the epidermis and skin-draining lymph nodes (sDLNs). To assess cytokine/chemokine expression in the skin lesion or primary cultured keratinocytes, we performed RT-PCR, microarray analysis or intracellular staining on the flow cytometer. RESULTS: LCs were activated in psoriatic lesion of patients with psoriasis and K5.Stat3C mice. Compared with non-transgenic mice, K5.Stat3C mice constitutively showed an increased number of LCs in the sDLNs before psoriasis-like lesion developed. Stat3C transgenic keratinocytes expressed an elevated level of IL-1α. Psoriasis-like lesion in K5.Stat3C mice were attenuated in the absence of LCs, indicating that LCs were essential to the development of psoriasis-like lesion. Furthermore, we also recognized that epidermal LCs in psoriatic lesion of not only K5.Stat3C mice but also psoriasis patients produced IL-23. CONCLUSIONS: Our study suggests that Stat3 activation in keratinocytes may impact on LC activation in situ via IL-1α stimulation, at least in part, and that their presence may be essential for the pathogenesis of psoriasis through producing IL-23.


Assuntos
Interleucina-23/imunologia , Queratinócitos/patologia , Células de Langerhans/imunologia , Psoríase/imunologia , Fator de Transcrição STAT3/metabolismo , Animais , Antígenos de Superfície/genética , Antígenos de Superfície/metabolismo , Biópsia , Células Cultivadas , Modelos Animais de Doenças , Voluntários Saudáveis , Humanos , Interleucina-1alfa/imunologia , Interleucina-1alfa/metabolismo , Interleucina-23/metabolismo , Queratinócitos/imunologia , Lectinas Tipo C/genética , Lectinas Tipo C/metabolismo , Lectinas de Ligação a Manose/genética , Lectinas de Ligação a Manose/metabolismo , Camundongos , Camundongos Transgênicos , Cultura Primária de Células , Psoríase/patologia , Pele/citologia , Pele/patologia
13.
J Invest Dermatol ; 139(2): 422-429, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30296420

RESUMO

Dendritic cells (DCs) are important inducers and regulators of T-cell responses. They are able to activate and modulate the differentiation of CD4+ and CD8+ T cells. In the skin, there are at least five phenotypically distinct DC subpopulations that can be distinguished by differential expression of the cell surface markers CD207, CD103, and CD11b. Previous studies have suggested that dermal CD11b-CD207+ conventional type 1 DCs are indispensable for the priming of a skin homing cytotoxic T-lymphocyte response. However, conventional type 1 DCs are also the only skin DC subset capable of cross-presenting exogenous antigens on major histocompatibility complex class I. Thus, it remained unclear whether for antigens that do not require cross-presentation, such as viruses that infect DCs, other DC subtypes in the skin can contribute to cytotoxic T-lymphocyte priming. To address this question, we used a transgenic mouse model that allows inducible expression and presentation of a model antigen on selected subsets of dermal DCs. We show that for antigens presented via the conventional major histocompatibility complex class I presentation pathway, CD207- dermal DCs are fully competent to prime a skin homing cytotoxic T-lymphocyte response that is capable of protection against a local virus challenge and gives rise to skin resident memory CD8+ T cells.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Apresentação Cruzada , Células de Langerhans/imunologia , Pele/imunologia , Linfócitos T Citotóxicos/imunologia , Animais , Modelos Animais de Doenças , Epitopos de Linfócito T/genética , Epitopos de Linfócito T/imunologia , Epitopos de Linfócito T/metabolismo , Antígenos de Histocompatibilidade Classe I/imunologia , Antígenos de Histocompatibilidade Classe I/metabolismo , Humanos , Memória Imunológica , Células de Langerhans/metabolismo , Camundongos , Camundongos Transgênicos , Pele/citologia , Dermatopatias Virais/imunologia , Dermatopatias Virais/virologia , Linfócitos T Citotóxicos/metabolismo , Vírus Vaccinia/imunologia
14.
Nat Commun ; 9(1): 5238, 2018 12 07.
Artigo em Inglês | MEDLINE | ID: mdl-30531969

RESUMO

The skin immune system must discriminate between innocuous antigens and pathogens. Antigen applied topically using a Viaskin® patch elicits immune tolerance that can suppress colitis and food allergy. Here we show how topical antigen is acquired and presented by dendritic cells in the skin. Topical antigen is acquired by Langerhans cells (LC) and CD11b+ cDC2s but not cDC1s, and both  LCs and CD11b+ cDC2s reaching the lymph node can prime T cells and expand LAP+ Tregs. However, LCs are neither required nor sufficient for T cell priming, and have no role in tolerance induction. Conversely, IRF-4-dependent cDC2s are required for T cell priming. Acquisition of antigen in the dermis, delivery to the draining lymph node, and generation of tolerance are all absent in hairless mice. These results indicate an important function for hair follicle niche and CD11b+ cDC2s in antigen acquisition, and in generation of primary immune tolerance to topical antigens.


Assuntos
Antígenos/imunologia , Células Dendríticas/imunologia , Folículo Piloso/imunologia , Linfócitos T Reguladores/imunologia , Animais , Apresentação do Antígeno/imunologia , Antígeno CD11b/imunologia , Antígeno CD11b/metabolismo , Células Dendríticas/metabolismo , Derme/citologia , Derme/imunologia , Derme/metabolismo , Folículo Piloso/metabolismo , Células de Langerhans/imunologia , Células de Langerhans/metabolismo , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Peptídeos/imunologia , Peptídeos/metabolismo , Proteína 2 Ligante de Morte Celular Programada 1/imunologia , Proteína 2 Ligante de Morte Celular Programada 1/metabolismo , Precursores de Proteínas/imunologia , Precursores de Proteínas/metabolismo , Pele/imunologia , Pele/metabolismo , Linfócitos T Reguladores/metabolismo , Fator de Crescimento Transformador beta/imunologia , Fator de Crescimento Transformador beta/metabolismo
15.
Cancer Treat Rev ; 71: 88-101, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30390423

RESUMO

The field of cancer immunotherapy has been revolutionized with the use of immune checkpoint blockade antibodies such as anti-programmed cell death 1 protein (PD-1) and chimeric antigen receptor T cells. Significant clinical benefits are observed in different cancer types with these treatments. While considerable efforts are made in augmenting tumor-specific T cell responses with these therapies, other immunotherapies that actively stimulate endogenous anti-tumor T cells and generating long-term memory have received less attention. Given the high cost of cancer immunotherapies especially with chimeric antigen receptor T cells, not many patients will have access to such treatments. The next-generation of cancer immunotherapy could entail in vivo cancer vaccination to activate both the innate and adaptive anti-tumor responses. This could potentially be achieved via in vivo targeting of dendritic cells which are an indispensable link between the innate and adaptive immunities. Dendritic cells highly expressed toll-like receptors for recognizing and eliminating pathogens. Synthetic toll-like receptors agonists could be synthesized at a low cost and have shown promise in preclinical and clinical trials. As different subsets of human dendritic cells exist in the immune system, activation with different toll-like receptor agonists could exert profound effects on the quality and magnitude of anti-tumor T cell responses. Here, we reviewed the different subsets of human dendritic cells. Using published preclinical and clinical cancers studies available on PubMed, we discussed the use of clinically approved and emerging toll-like receptor agonists to activate dendritic cells in vivo for cancer immunotherapy. Finally, we searched www.clinicaltrials.gov and summarized the active cancer trials evaluating toll-like receptor agonists as an adjuvant.


Assuntos
Células Dendríticas/imunologia , Imunoterapia/métodos , Terapia de Alvo Molecular/métodos , Neoplasias/terapia , Receptores Toll-Like/agonistas , Animais , Antineoplásicos/imunologia , Antineoplásicos/farmacologia , Vacinas Anticâncer , Humanos , Imiquimode/farmacologia , Células de Langerhans/citologia , Células de Langerhans/efeitos dos fármacos , Células de Langerhans/imunologia , Lectinas Tipo C/metabolismo , Glicoproteínas de Membrana/metabolismo , Receptores Imunológicos/metabolismo , Pele/citologia , Receptor 3 Toll-Like/agonistas , Receptor 3 Toll-Like/imunologia , Receptor 7 Toll-Like/agonistas , Receptor 7 Toll-Like/imunologia , Receptor 8 Toll-Like/agonistas , Receptor 8 Toll-Like/imunologia , Receptor Toll-Like 9/agonistas , Receptor Toll-Like 9/imunologia
16.
J Immunol ; 201(10): 3006-3016, 2018 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-30322965

RESUMO

Human mucosal tissues and skin contain two distinct types of dendritic cell (DC) subsets, epidermal Langerhans cells (LCs) and dermal DCs, which can be distinguished by the expression of C-type lectin receptors, Langerin and DC-SIGN, respectively. Although peripheral blood monocytes differentiate into these distinct subsets, monocyte-derived LCs (moLCs) induced by coculture with GM-CSF, IL-4, and TGF-ß1 coexpress both Langerin and DC-SIGN, suggesting that the environmental cues remain unclear. In this study, we show that LC differentiation is TGF-ß1 dependent and that cofactors such as IL-4 and TNF-α promote TGF-ß1-dependent LC differentiation into Langerin+DC-SIGN- moLCs but continuous exposure to IL-4 blocks differentiation. Steroids such as dexamethasone greatly enhanced TNF-α-induced moLC differentiation and blocked DC-SIGN expression. Consistent with primary LCs, dexamethasone-treated moLCs express CD1a, whereas monocyte-derived DCs (moDCs) express CD1b, CD1c, and CD1d. moDCs but not moLCs produced inflammatory cytokines after stimulation with CD1b and CD1d ligands mycolic acid and α-galactosylceramide, respectively. Strikingly, CD1a triggering with squalene on moLCs but not moDCs induced strong IL-22-producing CD4+ helper T cell responses. As IL-22 is an important cytokine in the maintenance of skin homeostasis, these data suggest that CD1a on LCs is involved in maintaining the immune barrier in the skin.


Assuntos
Diferenciação Celular/imunologia , Células de Langerhans/imunologia , Monócitos/imunologia , Pele/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Antígenos CD1/imunologia , Células Cultivadas , Células Dendríticas/imunologia , Humanos , Interleucinas/imunologia , Células de Langerhans/citologia , Ativação Linfocitária/imunologia , Monócitos/citologia , Pele/citologia
17.
Trends Immunol ; 39(10): 788-800, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30219310

RESUMO

Langerhans cells (LCs) are classically viewed as unique antigen-presenting cells (APCs) that originate from embryonic precursors and maintain themselves independently in the epidermis. However, recent studies have demonstrated that murine LCs in mucosal epithelia arise and are continuously replenished from circulating bone marrow (BM) precursors. This has led to the emergence of a novel perspective proposing that LCs can evolve from various origins. Because both embryonic and BM precursors differentiate into LCs only after entering the epithelium, this highlights its crucial role in nurturing LC development to perfectly comply with the physiological functions of the tissue. Thus, current evidence suggests plasticity of LC differentiation, revealing novel developmental mechanisms that are controlled by environmental cues.


Assuntos
Células da Medula Óssea/fisiologia , Células de Langerhans/imunologia , Membrana Mucosa/imunologia , Pele/citologia , Animais , Apresentação do Antígeno , Diferenciação Celular , Plasticidade Celular , Humanos , Camundongos
18.
Front Immunol ; 9: 1951, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30233572

RESUMO

The skin is a major immunologic organ that may induce protection, sensitization or tolerance. Epicutaneous immunotherapy (EPIT) has been proposed as an attractive strategy to actively treat food allergy and has been shown to induce tolerance in sensitized mice through the induction of Foxp3+ regulatory T cells (Tregs), especially CD62L+ Tregs. Among immune cells in the skin, dendritic cells are key players in antigen-specific immune activation or regulation. The role of different populations of skin DCs in tolerance induction remains to be elucidated. Using OVA-sensitized BALB/c mice, we demonstrated that the application of a patch containing OVA-A647 to the skin resulted in allergen uptake by Langerhans cells (LCs) and CD11b+ dermal cDC2 and subsequent migration into skin draining lymph nodes. These 2 populations induced Foxp3 expression in CD4+ cells in vitro. Only LCs induced LAP+ cells and CD62L+ Tregs. Using Langerin-eGFP-DTR mice, we analyzed the role of LCs in the mechanisms of tolerance induction by EPIT in vivo. Following complete depletion of LCs, a dramatic decrease in the number of OVA+ DCs and OVA+ CD11b+ dermal cDC2 was observed in skin draining lymph nodes 48 h after epicutaneous application. Likewise, 2 weeks of EPIT in non-depleted mice induced Foxp3+ Tregs, especially CD62L+, and LAP+ Tregs in skin draining lymph nodes and spleen, whereas no induction of Tregs was observed in LC-depleted mice. Following 8 weeks of treatment, EPIT-treated mice showed significant protection against anaphylaxis accompanied by a significant increase of Foxp3+ Tregs, especially CD62L+ Tregs, which was not seen in the absence of LCs. In summary, although both LCs and CD11b+ dermal cDC2s could induce regulatory T cells, the absence of LCs during EPIT impaired treatment efficacy, indicating their crucial role in skin-induced tolerance.


Assuntos
Alérgenos/imunologia , Apresentação do Antígeno , Dessensibilização Imunológica , Hipersensibilidade/terapia , Células de Langerhans/imunologia , Pele/imunologia , Linfócitos T Reguladores/imunologia , Animais , Hipersensibilidade/imunologia , Hipersensibilidade/patologia , Células de Langerhans/patologia , Camundongos Endogâmicos BALB C , Camundongos Transgênicos , Ovalbumina/imunologia , Pele/patologia , Linfócitos T Reguladores/patologia
19.
Front Immunol ; 9: 1768, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30105033

RESUMO

The identity of Langerhans cells (LCs) has been called into question of late due to the increasing evidence that LCs originate from macrophage lineage instead of dendritic cell (DC) lineage as previously thought. For many years, LCs have been assumed to be DCs due to its migratory capabilities. However, recent studies have demonstrated that LCs are from macrophage lineage of the adult fetal liver (FL) progenitor. Bona fide LCs are now considered tissue-resident macrophages as they originate from the FL as shown by fate mapping models. In recent years, studies have shown that there are three types of antigen-presenting cells present in the epidermis, such as LCs, monocyte-derived LC-like cells, and inflammatory dendritic epidermal cells (IDECs). Of these, LC-like cells have been characterized in both human and mouse studies, while IDECs have only been described in human studies. This has shed a new light on the area of epidermal macrophages, suggesting that there might be a misidentification and misclassification of LCs. IDECs and LC-like cells have been shown to be present in both steady state and inflammatory state, but they are present in more significant amounts under inflammatory conditions such as atopic dermatitis, ultra violet injury, and psoriasis. In this review, we discuss what is already known and discuss the possible roles of LCs, LC-like cells, and IDECs during inflammation. Most intriguingly, we discuss the possibility of LCs having a dual identity as both a macrophage and a DC. This is shown as LCs are the only tissue-resident macrophage to have shown migratory property-like DCs.


Assuntos
Células Dendríticas/imunologia , Células Epidérmicas/imunologia , Epiderme/imunologia , Células de Langerhans/imunologia , Animais , Células Apresentadoras de Antígenos/imunologia , Células Apresentadoras de Antígenos/metabolismo , Diferenciação Celular , Movimento Celular/imunologia , Células Dendríticas/metabolismo , Dermatite/etiologia , Dermatite/metabolismo , Dermatite/patologia , Suscetibilidade a Doenças , Células Epidérmicas/metabolismo , Epiderme/metabolismo , Humanos , Células de Langerhans/citologia , Células de Langerhans/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Monócitos/citologia , Monócitos/imunologia , Monócitos/metabolismo , Fenótipo
20.
J Dermatol ; 45(11): 1271-1277, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30144155

RESUMO

Exposure to arsenic is a global health issue. Long-term arsenic exposure may associate with various cancers and many other pathological effects. Over 100 million people worldwide are exposed to arsenic particularly in countries such as Bangladesh, Chile, China, India, Mexico, Taiwan and the USA. Drinking of water contaminated with arsenic is the major route of human exposure. Skin lesions are considered to be the most common adverse effects associated with chronic arsenic exposure. Skin lesions usually develop with the latency period spanning more than 20 years from first exposure. Arsenic-induced Bowen's disease, the most frequently encountered carcinoma in situ resulting from chronic arsenic exposure, is characterized by multiple and recrudescent lesions. Long-term arsenic exposure results in impaired immunity in susceptible individuals. In the prenatal stage, enhanced placental inflammatory responses and reduced placental T cells by arsenic may result in decreased thymic size and functions in newborns. In childhood, arsenic exposure may reduce peripheral CD4+ cells and interleukin-2 secretion which leads to susceptibility to opportunistic infections. There was an impairment of macrophage function and oxidative DNA damage of peripheral polymorphonuclear leukocytes in adults with skin lesions. In arsenic-induced Bowen's disease lesions, a decrease in the number and functions of Langerhans cells and, in parallel, a selective CD4+ cell apoptosis was noticed. These findings provide scientific evidence for understanding the phenomenon of arsenic-induced immune escape in the early stage of carcinogenesis and a reasonable explanation for multiple and recrudescent arsenic cancers in the skin.


Assuntos
Arsênico/toxicidade , Doença de Bowen/induzido quimicamente , Exposição Ambiental/efeitos adversos , Imunidade Inata/efeitos dos fármacos , Neoplasias Cutâneas/induzido quimicamente , Apoptose/efeitos dos fármacos , Doença de Bowen/imunologia , Doença de Bowen/patologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/patologia , Doença Crônica , Dano ao DNA/efeitos dos fármacos , Humanos , Células de Langerhans/efeitos dos fármacos , Células de Langerhans/imunologia , Células de Langerhans/patologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/patologia , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Neutrófilos/patologia , Pele/citologia , Pele/efeitos dos fármacos , Pele/imunologia , Pele/patologia , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/patologia
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