RESUMO
BACKGROUND: The prevalence of infections by nontuberculous mycobacteria (NTM) has steadily increased over the past decades, especially in immunocompromised patients. CASE PRESENTATION: We present a patient with IgA-deficiency and mixed cutaneous infection by two slowly growing mycobacteria, Mycobacterium (M.) haemophilum and M. kansasii. CONCLUSIONS: Cutaneous M. haemophilum infections most often result from HIV or transplantation-associated immunosuppression. Rarely, M. haemophilum may also infect healthy patients or iatrogenically immunosuppressed patients without transplantation. M. kansasii is one of the most frequent NTM and large awareness exists about its involvement in human diseases. Mycobacterial diagnosis of cutaneous infections should be considered in long-lasting skin lesions.
Assuntos
Deficiência de IgA/complicações , Infecções por Mycobacterium não Tuberculosas/complicações , Infecções por Mycobacterium/complicações , Mycobacterium haemophilum/isolamento & purificação , Mycobacterium kansasii/isolamento & purificação , Dermatopatias Bacterianas/complicações , Antibacterianos/uso terapêutico , Biópsia , Claritromicina/administração & dosagem , Claritromicina/uso terapêutico , Quimioterapia Combinada , Etambutol/administração & dosagem , Etambutol/uso terapêutico , Humanos , Hospedeiro Imunocomprometido , Masculino , Pessoa de Meia-Idade , Infecções por Mycobacterium/imunologia , Infecções por Mycobacterium/microbiologia , Infecções por Mycobacterium/patologia , Infecções por Mycobacterium não Tuberculosas/tratamento farmacológico , Infecções por Mycobacterium não Tuberculosas/imunologia , Infecções por Mycobacterium não Tuberculosas/microbiologia , Infecções por Mycobacterium não Tuberculosas/patologia , Mycobacterium haemophilum/crescimento & desenvolvimento , Mycobacterium kansasii/crescimento & desenvolvimento , Rifabutina/administração & dosagem , Rifabutina/uso terapêutico , Dermatopatias Bacterianas/tratamento farmacológico , Dermatopatias Bacterianas/imunologia , Dermatopatias Bacterianas/microbiologia , Dermatopatias Bacterianas/patologiaRESUMO
Antimicrobial peptides and proteins (AMPs) are tools of the innate immune system employed at injury sites to protect the host from invading microbes and to promote wound repair. In this issue, Roupé et al. characterize epidermal innate immune responses induced by skin injury and the involvement of EGFR for distinct AMPs and IL-8 induction.
Assuntos
Peptídeos Catiônicos Antimicrobianos/metabolismo , Receptores ErbB/metabolismo , Interleucina-8/metabolismo , Pele/imunologia , Pele/lesões , Humanos , Pele/metabolismo , Cicatrização/imunologiaRESUMO
Tumor surveillance requires the interaction of multiple molecules and cells that participate in innate and the adaptive immunity. Cathelicidin was initially identified as an antimicrobial peptide, although it is now clear that it fulfills a variety of immune functions beyond microbial killing. Recent data have suggested contrasting roles for cathelicidin in tumor development. Because its role in tumor surveillance is not well understood, we investigated the requirement of cathelicidin in controlling transplantable tumors in mice. Cathelicidin was observed to be abundant in tumor-infiltrating NK1.1(+) cells in mice. The importance of this finding was demonstrated by the fact that cathelicidin knockout mice (Camp(-/-)) permitted faster tumor growth than wild type controls in two different xenograft tumor mouse models (B16.F10 and RMA-S). Functional in vitro analyses found that NK cells derived from Camp(-/-) versus wild type mice showed impaired cytotoxic activity toward tumor targets. These findings could not be solely attributed to an observed perforin deficiency in freshly isolated Camp(-/-) NK cells, because this deficiency could be partially restored by IL-2 treatment, whereas cytotoxic activity was still defective in IL-2-activated Camp(-/-) NK cells. Thus, we demonstrate a previously unrecognized role of cathelicidin in NK cell antitumor function.
Assuntos
Peptídeos Catiônicos Antimicrobianos/imunologia , Vigilância Imunológica/imunologia , Células Matadoras Naturais/imunologia , Melanoma Experimental/imunologia , Animais , Peptídeos Catiônicos Antimicrobianos/genética , Western Blotting , Imunofluorescência , Humanos , Imuno-Histoquímica , Camundongos , Camundongos Knockout , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Ensaios Antitumorais Modelo de Xenoenxerto , CatelicidinasRESUMO
Antimicrobial peptides (AMPs) are strongly expressed in lesional skin in psoriasis and play an important role as proinflammatory "alarmins" in this chronic skin disease. Vitamin D analogs like calcipotriol have antipsoriatic effects and might mediate this effect by changing AMP expression. In this study, keratinocytes in lesional psoriatic plaques showed decreased expression of the AMPs beta-defensin (HBD) 2 and HBD3 after topical treatment with calcipotriol. At the same time, calcipotriol normalized the proinflammatory cytokine milieu and decreased interleukin (IL)-17A, IL-17F and IL-8 transcript abundance in lesional psoriatic skin. In contrast, cathelicidin antimicrobial peptide expression was increased by calcipotriol while psoriasin expression remained unchanged. In cultured human epidermal keratinocytes the effect of different vitamin D analogs on the expression of AMPs was further analyzed. All vitamin D analogs tested blocked IL-17A induced HBD2 expression by increasing IkappaB-alpha protein and inhibition of NF-kappaB signaling. At the same time vitamin D analogs induced cathelicidin through activation of the vitamin D receptor and MEK/ERK signaling. These studies suggest that vitamin D analogs differentially alter AMP expression in lesional psoriatic skin and cultured keratinocytes. Balancing AMP "alarmin" expression might be a novel goal in treatment of chronic inflammatory skin diseases.
Assuntos
Anti-Infecciosos/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Peptídeos/metabolismo , Psoríase/metabolismo , Vitamina D/farmacologia , Peptídeos Catiônicos Antimicrobianos/genética , Western Blotting , Células Cultivadas , Genes Reporter , Humanos , Interleucina-17/genética , Interleucina-8/genética , Sistema de Sinalização das MAP Quinases , Peptídeos/genética , Reação em Cadeia da Polimerase , Interferência de RNA , Receptores de Calcitriol/metabolismo , Vitamina D/análogos & derivados , CatelicidinasRESUMO
Innate immune responses involve the production of antimicrobial peptides (AMPs), chemokines, and cytokines. We report here the identification of B-cell leukemia (Bcl)-3 as a modulator of innate immune signaling in keratinocytes. In this study, it is shown that Bcl-3 is inducible by the Th2 cytokines IL-4 and IL-13 and is overexpressed in lesional skin of atopic dermatitis (AD) patients. Bcl-3 was shown to be important to cutaneous innate immune responses as silencing of Bcl-3 by small-interfering RNA (siRNA) reversed the downregulatory effect of IL-4 on the HBD3 expression. Bcl-3 silencing enhanced vitamin D3 (1,25D3)-induced gene expression of cathelicidin AMP in keratinocytes, suggesting a negative regulatory function on cathelicidin transcription. Furthermore, 1,25D3 suppressed Bcl-3 expression in vitro and in vivo. This study identified Bcl-3 as an important modulator of cutaneous innate immune responses and its possible therapeutic role in AD.
Assuntos
Imunidade Inata , Queratinócitos/imunologia , Proteínas Proto-Oncogênicas/fisiologia , Fatores de Transcrição/fisiologia , Sequência de Aminoácidos , Peptídeos Catiônicos Antimicrobianos/genética , Peptídeos Catiônicos Antimicrobianos/fisiologia , Proteína 3 do Linfoma de Células B , Células Cultivadas , Colecalciferol/análogos & derivados , Colecalciferol/farmacologia , Dermatite Atópica/imunologia , Humanos , Interleucina-13/farmacologia , Interleucina-4/farmacologia , Interleucina-6/biossíntese , Interleucina-8/biossíntese , Dados de Sequência Molecular , Subunidade p50 de NF-kappa B/fisiologia , CatelicidinasRESUMO
Calcineurin inhibitors are potent inhibitors of T-cell-receptor mediated activation of the adaptive immune system. The effects of this class of drug on the innate immune response system are not known. Keratinocytes are essential to innate immunity in skin and rely on toll-like receptors (TLRs) and antimicrobial peptides to appropriately recognize and respond to injury or microbes. In this study we examined the response of cultured human keratinocytes to pimecrolimus. We observed that pimecrolimus enhances distinct expression of cathelicidin, CD14, and human beta-defensin-2 and beta-defensin-3 in response to TLR2/6 ligands. Some of these responses were further enhanced by 1,25 vitamin D3. Pimecrolimus also increased the functional capacity of keratinocytes to inhibit growth of Staphylococcus aureus and decreased TLR2/6-induced expression of IL-10 and IL-1beta. Furthermore, pimecrolimus inhibited nuclear translocation of NFAT and NF-kappaB in keratinocytes. These observations uncover a previously unreported function for pimecrolimus in cutaneous innate host defense.
Assuntos
Peptídeos Catiônicos Antimicrobianos/metabolismo , Imunossupressores/farmacologia , Queratinócitos/metabolismo , Tacrolimo/análogos & derivados , Receptor 2 Toll-Like/metabolismo , Receptor 6 Toll-Like/metabolismo , beta-Defensinas/metabolismo , Calcitriol/farmacologia , Células Cultivadas , Relação Dose-Resposta a Droga , Humanos , Queratinócitos/efeitos dos fármacos , Lipopeptídeos , Receptores de Lipopolissacarídeos/metabolismo , NF-kappa B/metabolismo , Fatores de Transcrição NFATC/metabolismo , Oligopeptídeos/farmacologia , Tacrolimo/farmacologia , CatelicidinasRESUMO
Hormonally active vitamin D(3)-1,25-dihydroxyvitamin D(3) (1,25D3)-acts as a signaling molecule in cutaneous immunity by increasing pattern recognition through Toll-like receptor-2 (TLR2), and increasing the expression and function of antimicrobial peptides. Here we show that the actions of 1,25D3 on keratinocyte innate immune responses are influenced by histone acetylation and require the steroid receptor coactivator 3 (SRC3), which mediates inherent histone acetyltransferase (HAT) activity. SRC3 was detected in the suprabasal and granular layer of the skin, similar to cathelicidin expression. HAT activity was important to keratinocyte cathelicidin expression as the combination of histone deacetylase inhibitors (HDACi) (butyrate or trichostatin A) and 1,25D3 increased cathelicidin and CD14 expression and enhanced the antimicrobial function of keratinocytes against Staphylococcus aureus. This treatment, or activation of TLR2, also directly increased acetylation of histone 4. Small interfering RNA silencing of the vitamin D receptor or SRC3 blocked the induction of cathelicidin and CD14 by 1,25D3. HDACi could not reverse this effect or influence cathelicidin in the absence of 1,25D3, suggesting that both are necessary for function. These studies demonstrate that the epigenetic control of gene transcription by histone acetylation is important for 1,25D3-regulated antimicrobial and TLR function of keratinocytes, essential elements of the innate immune response of the skin.
Assuntos
Peptídeos Catiônicos Antimicrobianos/genética , Calcitriol/fisiologia , Epigênese Genética , Histonas/metabolismo , Queratinócitos/imunologia , Receptores de Lipopolissacarídeos/genética , Pele/imunologia , Acetilação , Butiratos/farmacologia , Calcitriol/farmacologia , Linhagem Celular , Inibidores Enzimáticos/farmacologia , Histona Acetiltransferases/análise , Histona Acetiltransferases/antagonistas & inibidores , Histona Acetiltransferases/metabolismo , Humanos , Ácidos Hidroxâmicos/farmacologia , Imunidade Inata/genética , Queratinócitos/efeitos dos fármacos , Queratinócitos/microbiologia , Coativador 3 de Receptor Nuclear , RNA Interferente Pequeno/farmacologia , Receptores de Calcitriol/antagonistas & inibidores , Pele/efeitos dos fármacos , Pele/microbiologia , Staphylococcus aureus/imunologia , Receptor 2 Toll-Like/agonistas , Transativadores/análise , Transativadores/antagonistas & inibidores , Transativadores/metabolismo , CatelicidinasRESUMO
Psoriasis is a chronic inflammatory disorder that is mediated by elements of the innate and adaptive immune systems. Its characteristic features in the skin consist of inflammatory changes in both dermis and epidermis, with abnormal keratinocyte differentiation and proliferation. Despite the elucidation of many aspects of psoriasis pathogenesis, some puzzling questions remain to be answered. A major question currently debated is whether psoriasis is a primary abnormality of the epidermal keratinocyte or a reflection of dysregulated bone marrow-derived immunocytes. In this review we will focus on understanding the role of the innate immune system in psoriasis and how this provides a rational solution to address the origin of this multifactorial disease. Innate immunity is nonspecific and genetically based. It protects the body against the constant risk of pathogens through the use of rapidly mobilized defenses that are able to recognize and kill a variety of threats (bacteria, fungi, viruses, etc). The key mechanisms of innate immune responses are the existence of receptors to recognize pathogens and the production of factors that kill pathogens, such as antimicrobial peptides and proteins. Any combination of excessive sensitivity of the innate detection system, or dysregulation of the response system, can manifest both an epidermal phenotype and an abnormal T-cell function. Thus, the multidimensional action of the innate immune system, its triggers, and its recently understood role in T-cell function argue for an important role for innate mechanisms of recognition and response in the pathogenesis of psoriasis.
Assuntos
Peptídeos Catiônicos Antimicrobianos/metabolismo , Imunidade Inata , Psoríase/imunologia , Proteínas S100/metabolismo , Receptores Toll-Like/metabolismo , Peptídeos Catiônicos Antimicrobianos/imunologia , Infecções Bacterianas/imunologia , Citocinas/imunologia , Citocinas/metabolismo , Humanos , Imunidade Ativa , Imunidade Celular , Psoríase/metabolismo , Proteínas S100/imunologia , Pele/imunologia , Receptores Toll-Like/imunologiaRESUMO
The human calcium-binding protein (hS100A15) was first identified in inflamed hyperplastic psoriatic skin, where the S100A15 gene is transcribed into two mRNA splice variants, hS100A15-S and hS100A15-L. To compare the contribution of the human S100A15 (hS100A15) isoforms in skin inflammation and differentiation, we determined the expression, distribution and regulation of hS100A15-S and hS100A15-L in psoriasis and chronic atopic eczema compared with normal skin. We found that both hS100A15 transcripts were mainly distributed in the epidermis of normal and inflamed skin with hS100A15-L being the predominantly expressed mRNA isoform in both psoriasis and atopic eczema. In cultured keratinocytes, IL-1beta and Th1 cytokines significantly induced hS100A15-L compared with hS100A15-S. In contrast, Th2-derived cytokines had no influence on the expression of either hS100A15 splice variant. Differentiation of human keratinocytes induced by 1.2 mm calcium resulted in the upregulation of both hS100A15 mRNA isoforms. Our data show that both hS100A15 splice variants are differentially regulated and expressed with epidermal differentiation and skin inflammation. Overexpression of hS100A15 in chronic inflammatory skin diseases and regulation by inflammatory cytokines and calcium suggest that hS100A15 is involved in Th1-associated epithelial responses and epidermal maturation in normal and diseased human skin.
Assuntos
Dermatite Atópica/imunologia , Isoformas de Proteínas/imunologia , Psoríase/imunologia , Proteínas S100/genética , Células Th1/imunologia , Cálcio/metabolismo , Células Cultivadas , Dermatite Atópica/metabolismo , Epiderme/imunologia , Epiderme/metabolismo , Regulação da Expressão Gênica/imunologia , Humanos , Interleucina-1beta/metabolismo , Queratinócitos/citologia , Queratinócitos/imunologia , Isoformas de Proteínas/metabolismo , Psoríase/metabolismo , RNA Mensageiro/metabolismo , Proteína A7 Ligante de Cálcio S100 , Proteínas S100/metabolismoRESUMO
E. coli is a gram-negative bacterium rarely found on human skin. We investigated whether direct interaction of E. coli with keratinocytes might induce an innate immune response through recognition by pattern recognition receptors. The capacity of E. coli to activate innate immune responses and IL-8 induction was investigated. We found that E. coli significantly induced human S100A7 and S100A15 transcript abundance and IL-8 release in cultured primary human keratinocytes. S100A15 is a member of the S100 protein family with previously unknown function. E. coli induced effects could be inhibited by neutralizing Toll-like receptor 4 (TLR4) antibodies, suggesting that E. coli-induced IL-8 and S100A15 expression in human keratinocytes are TLR4 dependent. TLR4-/- mice lacked elevated mS100A15 expression after infection with E. coli in contrast to wild-type mice. In vitro, human S100A15 displayed antimicrobial activity against E. coli. Our findings suggest that E. coli modulates S100A15 and IL-8 expression of keratinocytes by recognition through TLR4.
Assuntos
Escherichia coli/fisiologia , Queratinócitos/metabolismo , Proteínas S100/metabolismo , Receptor 4 Toll-Like/metabolismo , Animais , Anticorpos/imunologia , Anticorpos/farmacologia , Proteínas de Ligação ao Cálcio/metabolismo , Células Cultivadas , Feminino , Regulação da Expressão Gênica/fisiologia , Humanos , Imunidade Inata/imunologia , Interleucina-8/genética , Interleucina-8/metabolismo , Queratinócitos/citologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteína A7 Ligante de Cálcio S100 , Proteínas S100/genética , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/imunologiaRESUMO
An essential element of the innate immune response to injury is the capacity to recognize microbial invasion and stimulate production of antimicrobial peptides. We investigated how this process is controlled in the epidermis. Keratinocytes surrounding a wound increased expression of the genes coding for the microbial pattern recognition receptors CD14 and TLR2, complementing an increase in cathelicidin antimicrobial peptide expression. These genes were induced by 1,25(OH)2 vitamin D3 (1,25D3; its active form), suggesting a role for vitamin D3 in this process. How 1,25D3 could participate in the injury response was explained by findings that the levels of CYP27B1, which converts 25OH vitamin D3 (25D3) to active 1,25D3, were increased in wounds and induced in keratinocytes in response to TGF-beta1. Blocking the vitamin D receptor, inhibiting CYP27B1, or limiting 25D3 availability prevented TGF-beta1 from inducing cathelicidin, CD14, or TLR2 in human keratinocytes, while CYP27B1-deficient mice failed to increase CD14 expression following wounding. The functional consequence of these observations was confirmed by demonstrating that 1,25D3 enabled keratinocytes to recognize microbial components through TLR2 and respond by cathelicidin production. Thus, we demonstrate what we believe to be a previously unexpected role for vitamin D3 in innate immunity, enabling keratinocytes to recognize and respond to microbes and to protect wounds against infection.