Innate immunity and effector and regulatory mechanisms involved in allergic contact dermatitis

Abstract: Skin's innate immunity is the initial activator of immune response mechanisms, influencing the development of adaptive immunity. Some contact allergens are detected by Toll-like receptors (TLRs) and inflammasome NLR3. Keratinocytes participate in innate immunity and, in addition to functioning as an anatomical barrier, secrete cytokines, such as TNF, IL-1β, and IL-18, contributing to the development of Allergic Contact Dermatitis. Dendritic cells recognize and process antigenic peptides into T cells. Neutrophils cause pro-inflammatory reactions, mast cells induce migration/maturation of skin DCs, the natural killer cells have natural cytotoxic capacity, the γδ T cells favor contact with hapten during the sensitization phase, and the innate lymphoid cells act in the early stages by secreting cytokines, as well as act in inflammation and tissue homeostasis. The antigen-specific inflammation is mediated by T cells, and each subtype of T cells (Th1/Tc1, Th2/Tc2, and Th17/Tc17) activates resident skin cells, thus contributing to inflammation. Skin's regulatory T cells have a strong ability to inhibit the proliferation of hapten-specific T cells, acting at the end of the Allergic Contact Dermatitis response and in the control of systemic immune responses. In this review, we report how cutaneous innate immunity is the first line of defense and focus its role in the activation of the adaptive immune response, with effector response induction and its regulation.

Reconhecimento de Candida albicans por fibroblastos murinos: envolvimento de receptores de reconhecimento de patógenos (TLR2 e CD14) e a proteína adaptadora MyD88 / The recognition of Candida albicans by fibroblasts: Toll like receptors pathogens (TLR2 and CD14) abt the MyD88 protein evaluation

Os tecidos pulpar e periodontal são frequentemente agredidos por fatores ambientais como calor, trauma mecânico e micro-organismos, sendo estes considerados o fator etiológico principal das periodontopatias e periapicopatias. Dentre as células residentes desses tecidos, especial atenção tem sido dada ao papel dos fibroblastos no desenvolvimento da resposta imune. Fibroblastos são células que respondem à estímulos microbianos e existem evidências do papel de receptores do tipo Toll (TLR) no reconhecimento desses estímulos. Dessa forma, o presente trabalho teve como objetivo principal avaliar o reconhecimento de Candida albicans por fibroblastos gengivais e pulpares. Para tal, fibroblastos isolados a partir de tecido gengival e pulpar de camundongos do grupo controle e deficientes de TLR2, CD14 e MyD88 foram avaliados quanto à expressão de TLRs e moléculas de superfície, resposta proliferativa e produção de citocinas (TGF-β, IL-1β, TNF-α, IL-13 e IL-6), após a estimulação com agonistas de TLR2, TLR4 e C. albicans. Fibroblastos gengivais e pulpares, apesar de provenientes de tecidos diferentes, apresentaram características morfológicas semelhantes. Contudo, a cinética de crescimento dos fibroblastos gengivais deficientes de MyD88 foi mais lenta, e fibroblastos pulpares demoraram mais tempo para surgir a partir dos fragmentos de tecido. A ausência de TLR2 e da molécula adaptadora MyD88 não afetaram a produção de colágeno Tipo I pelos fibroblastos gengivais. Entretanto, fibroblastos deficientes de CD14 apresentaram baixa produção de colágeno. Ademais, os fibroblastos gengivais expressaram TLR2, TLR3, TLR4, assim como as moléculas de adesão ICAM-1 e CD44. A ausência de TLR2 e CD14 interferiu na resposta proliferativa de fibroblastos gengivais e pulpares, respectivamente. O reconhecimento de C. albicans por fibroblastos gengivais e pulpares modulou a produção das citocinas. A produção de TNF-α foi...

Pulpal and periapical tissue are frequently injured by heat, mechanical trauma and microorganisms, which are considered the main etiological factor of periodontal and endodontic diseases. Among these tissue resident cells, special attention has been given to fibroblasts in the immune response. Fibroblasts are cells that recognize pathogens through Toll like receptors (TLR). The aim of this study was to evaluate the recognition of Candida albicans by pulpal and gingival fibroblasts from TLR2, CD14, MyD88 knockout mice and control group mice. The results were analyzed concerning the expression of TLR(s) and surface molecules, proliferative response and citokynes production (TGF-β, IL-1β, TNF-α, IL-13 e IL-6) after the cells stimulation with TLR2, TLR4 and C.albicans agonists. Gingival and Pulpal fibroblasts, even isolated from different tissue, showed morphological similarities; however, gingival fibroblast deficient of MyD88 show lower proliferative response and pulpa l fibroblasts needed more time to detach from tissue fragments. The production of Type I collagen was affected in gingival cells deficient of CD14. Gingival fibroblasts expressed TLR2, TLR3, TLR4, and the adhesion molecules (ICAM-1 and CD44). The absence of TLR2 and CD14 interfered with the proliferative response of pulpal and gingival fibroblasts, respectively. The recognition of C. albicans by gingival and pulpal fibroblasts modulated the citokynes production. TNF-α production after the recognition of C. albicans was dependent from MyD88, CD14 and TLR2 molecules, whereas the production of IL-1β and IL-13 was dependent of TLR2.

Expression of non-TLR pattern recognition receptors in the spleen of BALB/c mice infected with Plasmodium yoelii and Plasmodium chabaudi chabaudi AS

The spleen plays a crucial role in the development of immunity to malaria, but the role of pattern recognition receptors (PRRs) in splenic effector cells during malaria infection is poorly understood. In the present study, we analysed the expression of selected PRRs in splenic effector cells from BALB/c mice infected with the lethal and non-lethal Plasmodium yoelii strains 17XL and 17X, respectively, and the non-lethal Plasmodium chabaudi chabaudi AS strain. The results of these experiments showed fewer significant changes in the expression of PRRs in AS-infected mice than in 17X and 17XL-infected mice. Mannose receptor C type 2 (MRC2) expression increased with parasitemia, whereas Toll-like receptors and sialoadhesin (Sn) decreased in mice infected with P. chabaudi AS. In contrast, MRC type 1 (MRC1), MRC2 and EGF-like module containing mucin-like hormone receptor-like sequence 1 (F4/80) expression decreased with parasitemia in mice infected with 17X, whereas MRC1 an MRC2 increased and F4/80 decreased in mice infected with 17XL. Furthermore, macrophage receptor with collagenous structure and CD68 declined rapidly after initial parasitemia. SIGNR1 and Sn expression demonstrated minor variations in the spleens of mice infected with either strain. Notably, macrophage scavenger receptor (Msr1) and dendritic cell-associated C-type lectin 2 expression increased at both the transcript and protein levels in 17XL-infected mice with 50% parasitemia. Furthermore, the increased lethality of 17X infection in Msr1 -/- mice demonstrated a protective role for Msr1. Our results suggest a dual role for these receptors in parasite clearance and protection in 17X infection and lethality in 17XL infection.

Toll-like receptors in autoimmunity with special reference to systemic lupus erythematosus.

The Toll-like receptor (TLR) family plays a fundamental role in host innate immunity by mounting a rapid and potent inflammatory response to pathogen infection. TLRs recognize distinct microbial components and activate intracellular signaling pathways that induce expression of host inflammatory genes. Several studies have indicated that TLRs are implicated in many inflammatory and immune disorders. Extensive research in the past decade to understand TLR-mediated mechanisms of innate immunity has enabled pharmaceutical companies to begin to develop novel therapeutics for the purpose of controlling an inflammatory disease. The roles of TLRs in the development of autoimmune diseases have been studied. TLR7 and TLR9 have key roles in production of autoantibodies and/or in development of systemic autoimmune disease. It remains to be determined their role in apoptosis, in the pathogenesis of RNA containing immune complexes, differential expression of TLRs by T regulatory cells.

El papel de la inmunidad innata en la obesidad / The role of innate immunity in obesity

La obesidad en México es un problema de salud preocupante por el incremento en la prevalencia en adultos y niños, y se considera un factor de riesgo para el desarrollo de resistencia a la insulina, así como de otras alteraciones metabólicas. En esta patología se ha observado un incremento en la expresión de los receptores tipo Toll (TLRs) en el adipocito, receptores con participación crucial en la respuesta inmune innata. Se propone que los TLRs están implicados en la inflamación sistémica y en el desarrollo de la resistencia a la insulina. La activación de los TLRs es mediada por ácidos grasos y su expresión está regulada por leptina, adiponectina y PPAR. El conocimiento de la función de los TLRs, tanto en la inflamación como en la diferenciación del adipocito es importante en la búsqueda de nuevos blancos terapéuticos antiinflamatorios que coadyuven en el tratamiento de la obesidad.

Obesity in Mexico is alarmingly increasing in prevalence in adults and children, and it is a risk factor for the development of insulin resistance, as well as, of other metabolic alterations. The discovery of the expression of the Toll-like receptors (TLRs) in adipocytes, suggests an important role in innate immunity. In different models of obesity, there has been observed an increase of TLRs expression in the fat tissue, therefore TLRs could be involved in systemic inflammation in this disease, and in the development of insulin resistance. TLR activation is mediated by fatty acids and their expression is regulated by leptin, adiponectin and PPARs. Knowledge of the role of TLRs in inflammation and adipocyte differentiation and their regulation, then it is important to try to develop new therapeutic anti-inflammatory targets that contribute in the treatment of obesity.

Micoses superficiais e os elementos da resposta imune / Superficial mycosis and the immune response elements

As micoses superficiais são prevalentes em todo o mundo, geralmente ocasionadas por dermatófitos e restritas à camada córnea. A resposta imunológica do hospedeiro às infecções dos fungos dermatófitos depende basicamente das defesas do hospedeiro a metabólitos do fungo, da virulência da cepa ou da espécie infectante e da localização anatômica da infecção. Serão revistos alguns dos fatores da defesa imunológica do hospedeiro que influenciam na eficácia da resposta imune. Em especial, a participação dos receptores de padrão de reconhecimento (PRRs), tais como os receptores toll-like ou os da família lectina (DC-SIGN e dectin-2), que participam da resposta imune inata, conferindo-lhe especificidade e definindo o padrão da resposta imune como um todo. O predomínio celular ou humoral da resposta imune definirá o quadro clínico e o prognóstico da infecção, levando à cura ou cronicidade.

Superficial mycoses are prevalent worldwide. They are often caused by dermatophytes and restricted to the stratum corneum. The host's immune response against infections caused by dermatophytes basically depends on the host's defense against metabolites of the fungi, virulence of the infecting strain or species and anatomical site of the infection. We will review some of the factors of the host's immune defense that influence the efficacy of the immune response. We will particularly review the role of pattern recognition receptors (PRRs), such as toll-like receptors or lectin receptors (DCSIGN and Dectin 2), which participate in the innate immune response, bringing specificity to the immune response and setting its pattern. The predominance of a cellular or humoral immune response determines the clinical manifestations and the prognosis of the infection, leading to healing or chronicity.

Trends in adjuvant development for vaccines: DAMPs and PAMPs as potential new adjuvants

Aluminum salts have been widely used in vaccine formulations and, after their introduction more than 80 years ago, only few vaccine formulations using new adjuvants were developed in the last two decades. Recent advances in the understanding of how innate mechanisms influence the adaptive immunity opened up the possibility for the development of new adjuvants in a more rational design. The purpose of this review is to discuss the recent advances in this field regarding the attempts to determine the molecular basis and the general mechanisms underlying the development of new adjuvants, with particular emphasis on the activation of receptors of innate immune recognition. One can anticipate that the use of these novel adjuvants will also provide a window of opportunities for the development of new vaccines.

Rol de los receptores tipo toll en la patogénesis de la rinitis alérgica: [revisión] / Toll like receptors role in the allergic rhinitis: [review]

La rinitis alérgica afecta alrededor de seiscientos millones de personas alrededor del mundo, siendo actualmente la enfermedad recurrente con mayor prevalencia. En su patogénesis participa una compleja red de mediadores humorales y celulares participantes del perfil inmunológico Th2. Junto con el sistema inmune adaptativo, componentes de la inmunidad innata han mostrado jugar un importante rol en enfermedades alérgicas, tales como dermatitis atópica y asma bronquial. En el presente trabajo evaluamos el rol de los receptores tipo Toll en rinitis alérgica, realizando una revisión de avanzada con respecto a la expresión, función y modulación de estos receptores en esta enfermedad.

Allergic rhinitis (AR) affects about six hundred million people worldwide and is now considered the most prevalent recurrent disease. The pathogenesis of AR involves a complex network of cellular and humeral mediators involved in the Th2 immune profile. Together with the adaptive immune system, components of innate immunity have shown to play an important role in allergic diseases such as atopic dermatitis and bronchial asthma. The present review describes the role of Toll-like receptors in allergic rhinitis. We discuss the importance of the receptors expression, function and modulation in this disease.

Novas funções da proteina AIRE: 1) seu papel na resposta mediada por dectina-1 em fagocitos mononucleares humanos: 2) sua associação com a queratina 17, proteina dos filamentos intermediarios / New roles of AIRE protein

A Poliendocrinopatia autoimune associada a candidíase e distrofia ectodérmica (APECED) é um síndrome caracterizado pela presença de pelo menos dois sintomas clínicos, endocrinopatia autoimune, sendo que as mais comuns são hipoparatiroidismo, doença de Addison, além de candidíase mucocutânea crônica. É também comum nos pacientes o desenvolvimento de distrofia ectodérmica, como distrofia nas unhas ou alopécia. O APECED é produzido por mutações no gene AIRE, que codifica uma proteína com propriedades reguladoras na transcrição de proteínas ectópicas no timo, o que estaria envolvido na seleção negativa de células T auto-reativas, e conseqüentemente no desenvolvimento da doença autoimune. No entanto a associação da deficiência da proteína AIRE com a suscetibilidade a candidíase ou a distrofia ectodérmica permanecem obscuras. No presente trabalho, investigamos a possibilidade que esta associação esteja envolvida com a expressão e função da proteína AIRE no ambiente extra-tímico. Usando células de sangue periférico de pacientes com mutações no AIRE...

The autoimmune polyendocrinopathy candidiasis and ectodermal dystrophy (APECED) is characterized by the presence of two from three major clinical symptoms: Addison's disease, and/or hypoparathyroidism, and/or chronic mucocutaneous candidiasis. These patients develop also ectodermal dystrophies like nail dystrophy and alopecia. APECED is caused by mutations in the autoimmune regulator gene (AIRE). This gene encodes a protein with DNA binding capacity that can transcriptionally modulate ectopic peripheral tissue antigen (PTA) expression in the thymus, facilitating T cell negative selection. Defects in AIRE may be related with the development of multipleendocrine failure of autoimmune origin in patients with APECED. In spite of this, the role of AIRE deficiency in the C. albicans susceptibility or ectodermal dystrophy, common features in APECED patients, remains to be elucidated. In the present work we explored the hypothesis that candidiasis and ectodermal dystrophy are associated with the extra-thymic role of AIRE...

The role of MHC haplotypes H2d/H2b in mouse resistance/susceptibility to cyst formation is influenced by the lineage of infective Toxoplasma gondii strain

Toxoplasma gondii strains displaying the Type I/III genotype are associated with acquired ocular toxoplasmosis in humans. Here, we used a mice model to characterize some immunological mechanisms involved in host resistance to infection with such strains. We have chosen the Type I/III strains D8, G2 and P-Br, which cause a chronic infection in mice that resembles human toxoplamosis. Mice deficient of molecules MyD88, IFN-gamma, and IL-12 were susceptible to all three parasite strains. This finding indicates the importance of innate mechanisms in controlling infection. On the other hand, MHC haplotype did not influenced resistance/susceptibility; since mice lineages displaying a same genetic background but different MHC haplotypes (H2b or H2d) developed similar mortality and cyst numbers after infection with those strains. In contrast, the C57BL/6 genetic background, and not MHC haplotype, was critical for development of intestinal inflammation caused by any of the studied strains. Finally, regarding effector mechanisms, weobserved that B and CD8+ T lymphocytes controlled survival,whereas the inducible nitric oxide synthase influenced cyst numbers in brains of mice infected with Type I/III strains. These findings are relevant to further understanding of the immunologic mechanisms involved in host protection and pathogenesis during infection with T. gondii.

Cepas de Toxoplasma gondii que apresentam o genótipo I/III são associadas a toxoplasmose ocular adquirida em humanos. No presente trabalho, nós utilizamos um modelo da doença em camundongos para caracterizar mecanismos imunológicos envolvidos na resistência do hospedeiro à infecção por aquelas cepas. Escolhemos as cepas D8, G2 e P-Br, que causam infecção crônica em camundongos, semelhante à toxoplasmose humana. Camundongos deficientes em MyD88, IFN-G e IL-12 foram susceptíveis a infecções com todas as três linhagens do parasita. Esses dados indicam a importância de mecanismos inatos no controle da infecção. Por outro lado, o haplótipo do MHC não influenciou na resistência/susceptibilidade, na medida em que linhagens de camundongos com um mesmo "background'' genético, mas diferentes haplótipos de MHC (H2b e H2d) apresentam o índice de mortalidade e número de cistos semelhantes após a infecção com aquelas cepas do parasita. Em contraste, o "background'' genético de C57BL/6, mas não o haplótipo de MHC, foi crítico para o desenvolvimento de inflamação intestinal causada pelas cepas estudadas. Finalmente, com relação aos mecanismos efetores, observamos que linfócitos B e T CD8+ controlam a sobrevivência após infecção. Por outro lado, a ativação da enzima óxido nítrico sintase induzida foi um fator importante para controle do número de cistos cerebrais em camundongos infectados com cepas do Tipo I/III. Esses achados são relevantes para o melhor entendimento dos mecanismos imunológicos envolvidos na proteção e patogênese durante infecção com T. gondii.

Papel de las células dendríticas en la infección por HIV y HCV / The role of dendritic cells in the infection by HIV and HCV

Las células dendríticas son las principales células presentadoras de antígenos para el montaje de la respuesta inmune. Por lo tanto es importante estudiar de qué manera intervienen en el equilibrio que el sistema inmune desarrolla frente a infecciones virales persistentes como la infección por el HIV o el HCV. En esta revisión se presentan en primer término generalidades sobre las diferentes clases de células dendríticas, las características fenotípicas y funcionales que las definen y los receptores que pueden estar involucrados en la infección viral. Luego se analiza su participación en los mecanismos de defensa o facilitadores de la infección por estos virus. Es importante tener en cuenta estos conocimientos para poder diseñar adecuadas estrategias de vacunación o protección y para intentar la reconstrucción funcional del sistema inmune impidiendo la subversión de los mecanismos inmunes de defensa causada por la infección con el HIV y el HCV.

Dendritic cells are most important as antigen presenting cells during the induction of an effective immune response. Therefore, it is important to study their role during the generation of persistent or chronic viral infections, such as HIV or HCV infection. In this review we shall describe the phenotypic and functional characteristics of the different classes of dendritic cells and of their membrane receptors. Their participation in defence or facilitation mechanisms involved in the immune response against these viruses will be discussed. It is important to take this knowledge into account when trying to design therapeutic strategies for protection or reconstruction of the immune system that may be altered as a consequence of infection with HIV or HCV.

Toll-like receptor signal transduction

Toll-like receptors (TLRs) are the archetypal pattern recognition receptors in sensing exogenous pathogens. Activation of TLRs is a first line of defense of the immune system, leading to the activation and recruitment of neutrophils and macrophages to sites of infection and enhances antimicrobial activity. The TLR signaling through different intracellular molecules, such as MAP kinases and IkappaB kinases which are conserved signaling elements for many receptors, leads to a distinct set of proinflammatory gene expressions. However, how these pathways differentially and precisely control the transcription of identical genes remains largely unknown. Our review focuses on the details of up-to- date signaling molecules including negative regulators and their role in controlling innate immune response. We also stress the importance of developing systemic approaches for the global understanding of TLR signaling so that appropriate drug therapeutic targets can be identified for regulating inflammatory diseases.

Toll-like Receptors are Key Participants in Innate Immune Responses

During an infection, one of the principal challenges for the host is to detect the pathogen and activate a rapid defensive response. The Toll-like family of receptors (TLRs), among other pattern recognition receptors (PRR), performs this detection process in vertebrate and invertebrate organisms. These type I transmembrane receptors identify microbial conserved structures or pathogen-associated molecular patterns (PAMPs). Recognition of microbial components by TLRs initiates signaling transduction pathways that induce gene expression. These gene products regulate innate immune responses and further develop an antigen-specific acquired immunity. TLR signaling pathways are regulated by intracellular adaptor molecules, such as MyD88, TIRAP/Mal, between others that provide specificity of individual TLR- mediated signaling pathways. TLR-mediated activation of innate immunity is involved not only in host defense against pathogens but also in immune disorders. The involvement of TLR-mediated pathways in auto-immune and inflammatory diseases is described in this review article.