RESUMEN
BACKGROUND: Disintegration of the infundibula of terminal hair follicles (HFs) in intertriginous skin areas exhibits the histological hallmark of hidradenitis suppurativa (HS)/acne inversa, featuring a dissecting terminal hair folliculitis. Elevated serum levels of interleukin (IL)-17 and local increase in the ratio of proinflammatory T helper (Th)17 cells and anti-inflammatory regulatory T cells (Tregs) have been reported. Perifollicular Tregs play a key role in HF stem cell homeostasis and infundibular integrity. OBJECTIVES: In this review, we evaluate the Th17/Treg ratio in HS, its aggravating conditions and associated comorbidities. Furthermore, we intended to clarify whether drugs with reported beneficial effects in the treatment of HS readjust the deviated Th17/Treg axis. METHODS: PubMed-listed, peer-reviewed original research articles characterizing Th17/Treg regulation in HS/acne inversa and associated comorbidities were selected for this review. RESULTS: This review presents HS as a disease that exhibits an increased Th17/Treg ratio. Perifollicular deficiencies in Treg numbers or function may disturb HF stem cell homeostasis, initiating infundibular dissection of terminal HFs and perifollicular inflammation. The Th17/Treg imbalance is aggravated by obesity, smoking and decreased Notch signalling. In addition, HS-associated autoimmune diseases exhibit a disturbed Th17/Treg axis resulting in a Th17-dominant state. All drugs that have beneficial effects in the treatment of HS normalize the Th17/Treg ratio. CONCLUSIONS: HS immunopathogenesis is closely related to deviations of the Th17/Treg balance, which may negatively affect Treg-controlled HF stem cell homeostasis and infundibular integrity. Pharmacological intervention should not only attenuate Th17/IL-17 signalling, but should also improve Treg function in order to stabilize HF stem cell homeostasis and infundibular integrity.
Asunto(s)
Enfermedades Autoinmunes/inmunología , Folículo Piloso/patología , Hidradenitis Supurativa/inmunología , Linfocitos T Reguladores/inmunología , Células Th17/inmunología , Enfermedades Autoinmunes/epidemiología , Comorbilidad , Folículo Piloso/citología , Folículo Piloso/inmunología , Hidradenitis Supurativa/sangre , Hidradenitis Supurativa/epidemiología , Hidradenitis Supurativa/patología , Humanos , Interleucina-17/sangre , Recuento de Linfocitos , Obesidad/complicaciones , Obesidad/inmunología , Fumar/efectos adversos , Fumar/inmunología , Células Madre/inmunología , Células Madre/patologíaRESUMEN
In industrialized countries acne presents as an epidemic disease of civilization affecting sebaceous follicles of adolescents and young adults, associated with increased body mass index and insulin resistance. "Western style" diet, characterized by high glycaemic load and increased consumption of insulinotropic milk proteins, plays an important role in acne pathogenesis. On the cellular level, nutrient-derived metabolic signals are sensed by the metabolic transcription factor FoxO1 and integrated by the regulatory kinase mTORC1. mTORC1, the central hub of protein- and lipid biosynthesis, cell growth and proliferation, is activated by insulin, IGF-1 and branched-chain essential amino acids, especially leucine. The understanding of Western diet-mediated nutrient signalling with over-activated mTORC1 offers a reasonable approach for dietary intervention in acne by lowering glycaemic load and consumption of milk and milk products. A suitable diet attenuating increased mTORC1 activity is a Palaeolithic-like diet with reduced intake of sugar, hyperglycaemic grains, milk and milk products but enriched consumption of vegetables and fish.
Asunto(s)
Acné Vulgar/dietoterapia , Acné Vulgar/inmunología , Dieta/efectos adversos , Hiperglucemia/dietoterapia , Hiperglucemia/inmunología , Factor I del Crecimiento Similar a la Insulina/inmunología , Complejos Multiproteicos/inmunología , Serina-Treonina Quinasas TOR/inmunología , Conducta Alimentaria , Humanos , Diana Mecanicista del Complejo 1 de la RapamicinaRESUMEN
Acne, one of the most common skin disorders, is also a cardinal component of many systemic diseases or syndromes. Their association illustrates the nature of these diseases and is indicative of the pathogenesis of acne. Congenital adrenal hyperplasia (CAH) and seborrhoea-acne-hirsutism-androgenetic alopecia (SAHA) syndrome highlight the role of androgen steroids, while polycystic ovary (PCO) and hyperandrogenism-insulin resistance-acanthosis nigricans (HAIR-AN) syndromes indicate insulin resistance in acne. Apert syndrome with increased fibroblast growth factor receptor 2 (FGFR2) signalling results in follicular hyperkeratinization and sebaceous gland hypertrophy in acne. Synovitis-acne-pustulosis-hyperostosis-osteitis (SAPHO) and pyogenic arthritis-pyoderma gangrenosum-acne (PAPA) syndromes highlight the attributes of inflammation to acne formation. Advances in the understanding of the manifestation and molecular mechanisms of these syndromes will help to clarify acne pathogenesis and develop novel therapeutic modalities.
Asunto(s)
Acné Vulgar/etiología , Acantosis Nigricans/complicaciones , Acantosis Nigricans/tratamiento farmacológico , Acantosis Nigricans/cirugía , Acné Vulgar/complicaciones , Acné Vulgar/tratamiento farmacológico , Síndrome de Hiperostosis Adquirido/complicaciones , Acrocefalosindactilia/complicaciones , Acrocefalosindactilia/genética , Hiperplasia Suprarrenal Congénita/complicaciones , Hiperplasia Suprarrenal Congénita/tratamiento farmacológico , Alopecia/complicaciones , Artritis Infecciosa/complicaciones , Artritis Infecciosa/tratamiento farmacológico , Dermatitis Seborreica/complicaciones , Femenino , Hirsutismo/complicaciones , Humanos , Hiperandrogenismo/complicaciones , Hiperandrogenismo/tratamiento farmacológico , Hiperandrogenismo/cirugía , Resistencia a la Insulina , Síndrome del Ovario Poliquístico/complicaciones , Síndrome del Ovario Poliquístico/tratamiento farmacológico , Piodermia Gangrenosa/complicaciones , Piodermia Gangrenosa/tratamiento farmacológico , SíndromeRESUMEN
It is the purpose of this review to demonstrate that oral isotretinoin treatment restores all major pathogenetic factors of acne vulgaris by upregulation of the nuclear transcription factor FoxO1, which will be shown to be the major target of retinoid action. Nuclear FoxO1 deficiency is the result of increased growth factor signaling with activated phosphoinositol-3-kinase (PI3K) and Akt kinase during growth hormone signaling of puberty and increased insulin/IGF-1 signaling due to consumption of insulinotropic milk/dairy products as well as hyperglycemic carbohydrates of Western diet. Nuclear FoxO1 deficiency increases androgen receptor transactivation and modifies the activity of important nuclear receptors and key genes involved in pilosebaceous keratinocyte proliferation, sebaceous lipogenesis and expression of perifollicular inflammatory cytokines. Isotretinoin-induced upregulation of nuclear FoxO1 is proposed to be responsible for the mode of action of isotretinoin on all major pathogenetic factors in acne. Acne pathogenesis can be explained at the genomic level of transcriptional regulation. All major events in acne pathogenesis as well as all major effects of isotretinoin treatment appear to be related to modifications of the PI3K/Akt/FoxO1 signaling pathway, the well-known oncogenic pathway. These insights extend our understanding of FoxO1-mediated retinoid action in acne and other hyperproliferative skin diseases, cancer chemoprevention and cutaneous immune regulation. Understanding FoxO´s pivotal regulatory role in acne allows the development of novel treatment strategies and dietary interventions in acne which focus on the restoration of growth factor- and diet-induced imbalances of nuclear FoxO protein levels.
Asunto(s)
Acné Vulgar/etiología , Fármacos Dermatológicos/farmacología , Factores de Transcripción Forkhead/efectos de los fármacos , Factores de Transcripción Forkhead/fisiología , Isotretinoína/farmacología , Proteína Forkhead Box O1 , Humanos , Transducción de SeñalAsunto(s)
Hidradenitis Supurativa/genética , Receptores Notch/genética , Transducción de Señal/genética , Secretasas de la Proteína Precursora del Amiloide/genética , Citocinas/metabolismo , Humanos , Glicoproteínas de Membrana/genética , Proteínas de la Membrana/genética , Presenilina-1/genética , Factores de Riesgo , Receptores Toll-Like/genéticaAsunto(s)
Acné Vulgar , Fármacos Dermatológicos/uso terapéutico , Factores de Transcripción Forkhead/deficiencia , Isotretinoína/uso terapéutico , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Acné Vulgar/tratamiento farmacológico , Acné Vulgar/metabolismo , Núcleo Celular/metabolismo , Factores de Transcripción Forkhead/metabolismo , Humanos , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Transducción de Señal/efectos de los fármacos , Regulación hacia ArribaRESUMEN
Inverse alterations in plasma levels of low-density lipoprotein cholesterol and high-density lipoprotein cholesterol are recognized side effects of systemic treatment with the synthetic retinoids isotretinoin and etretinate. The mass quotients of total plasma cholesterol and high-density lipoprotein cholesterol as well as low-density lipoprotein cholesterol and high-density lipoprotein cholesterol are well-established predictive risk factors of cardiovascular disease. We evaluated and compared these lipoprotein cholesterol ratios of 80 patients treated systemically with isotretinoin (13-cis-retinoic acid) and 81 patients treated with etretinate (aromatic retinoid). Lipoprotein cholesterol data were derived from 5 lipid studies on isotretinoin, including our own results, and 4 published lipid studies on etretinate. For all isotretinoin and etretinate lipid studies, significant increases in the mean plasma levels of total cholesterol and low-density lipoprotein cholesterol and significant decreases in the mean concentration of high-density lipoprotein cholesterol were demonstrated. In comparison with etretinate, oral isotretinoin gave rise to a nearly twofold percent increase of both lipoprotein cholesterol ratios from pretreatment levels. Furthermore, for isotretinoin, an approximately linear dose-related increase of the ratio of low-density lipoprotein cholesterol and high-density lipoprotein cholesterol could be observed. If sustained over long periods, the mean differential rise of the ratio of low-density lipoprotein cholesterol and high-density lipoprotein cholesterol of 0.92 +/- 0.51 for isotretinoin and 0.56 +/- 0.10 for etretinate indicates an increased risk of cardiovascular disease for both retinoids. Etretinate could be identified as the less harmful retinoid for prolonged oral therapy.
Asunto(s)
Arteriosclerosis/inducido químicamente , Etretinato/farmacología , Tretinoina/farmacología , Colesterol/sangre , HDL-Colesterol/sangre , LDL-Colesterol/sangre , Humanos , Isotretinoína , Retinoides/uso terapéutico , RiesgoRESUMEN
For rapid and sensitive screening of lipid biochemical abnormalities of scaling skin disorders a sequential, one-dimensional high-performance thin-layer chromatographic method (HPTLC) has been developed. All major human stratum corneum lipid classes, i.e., cholesterol sulfate, glucosylceramides, six major ceramide fractions, free sterols, free fatty acids, triglycerides, sterol esters, squalene, and n-alkanes, are separated and quantitated after a stepwise development of a single silica gel 60 HPTLC-plate using three consecutive solvent systems. Reproducible results have been obtained by degradative charring as well as fluorescence detection. By fluorescence detection the method is particularly suitable for the determination of minor amounts of cholesterol sulfate and other sterols.
Asunto(s)
Cromatografía Líquida de Alta Presión/métodos , Lípidos/análisis , Piel/metabolismo , Humanos , Valores de Referencia , Sensibilidad y EspecificidadRESUMEN
Irradiation with suberythemal doses of either UV-A or UV-B yielded an increase in the amount of stratum corneum lipids extracted from the lumbar skin area of 20 volunteers. These lipids were quantified after separation by high-performance thin-layer chromatography. Ten subfractions in the ceramide region were separated; two of them (fractions 7a and 7b) were only detectable after UV-A or UV-B irradiation. Improvement of barrier function after UV irradiation of human skin with suberythemal doses may be related to an increase in the stratum corneum ceramides.
Asunto(s)
Epidermis/efectos de la radiación , Lípidos/efectos de la radiación , Rayos Ultravioleta , Adulto , Ceramidas/efectos de la radiación , Cromatografía en Capa Delgada , Epidermis/metabolismo , Femenino , Humanos , Metabolismo de los Lípidos , Masculino , Persona de Mediana EdadRESUMEN
Impaired suppressor T lymphocyte maturation and function in atopic individuals are explained by an insufficient transmission of prostaglandin E (PGE) signals during thymic lymphocyte differentiation as well as an impaired ability of the atopic immune system to activate suppressor T-cells by PGE-mediated feed back mechanisms. We demonstrate that spontaneous in vitro immunoglobulin E synthesis of atopic peripheral blood mononuclear cells could be suppressed by the addition of 10(-6) M to 10(-5) M PGE1 or PGE2. Decreased plasma and breast milk levels of PGE-precursor fatty acids and reduced numbers of PGE2-receptors on atopic lymphocytes have been observed in atopic individuals. These insights might offer a novel approach for the prevention of atopic disease by substitution of the atopic pregnant and nursing woman and her newborn infant with long chain omega-6-fatty acids.
Asunto(s)
Dermatitis Atópica/inmunología , Ácidos Grasos Esenciales/inmunología , Prostaglandinas E/inmunología , Adulto , Alprostadil/farmacología , Dermatitis Atópica/metabolismo , Dinoprostona/farmacología , Ácidos Grasos Esenciales/deficiencia , Ácidos Grasos Esenciales/metabolismo , Femenino , Humanos , Inmunoglobulina E/biosíntesis , Técnicas In Vitro , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/inmunología , Leucocitos Mononucleares/metabolismo , Leche Humana/inmunología , Leche Humana/metabolismo , Embarazo , Prostaglandinas E/metabolismo , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/inmunologíaAsunto(s)
Acné Vulgar/genética , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/genética , Receptores de Interleucina-1/metabolismo , Neoplasias Cutáneas/genética , Acné Vulgar/patología , Adolescente , Proliferación Celular , Células Epiteliales , Humanos , Masculino , Nevo/genética , Nevo/patología , Neoplasias Cutáneas/patologíaRESUMEN
The proposed concept links the alterations in cell-mediated and humoral immunity in atopy to impaired prostaglandin E (PGE)-mediated thymic maturation of T-suppressor lymphocytes and diminished activation of T-suppressor lymphocytes of the peripheral atopic immune system. The decreased sensitivity of atopic T lymphocytes to PGE, recently explained by a reduction of PGE2-receptors on atopic lymphocytes, is regarded as the common underlying defect in atopy. A second defect, the delta-6-desaturase deficiency, affects the regular supply of the PGE-precursors dihomo-gamma-linolenic acid and arachidonic acid and predisposes for atopic dermatitis. Furthermore, the composition of omega-6-fatty acids in breast milk of atopic mothers represents a delta-6-desaturase deficiency. Substitution of the delta-6-desaturase product gamma-linolenic acid to the atopic pregnant and nursing woman and her newborn infant at increased risk for atopy offers a chance for the prevention of atopic diseases.
Asunto(s)
Dermatitis Atópica/prevención & control , Grasas Insaturadas en la Dieta , Ácido Graso Desaturasas/deficiencia , Ácidos Linolénicos/administración & dosificación , Receptores de Prostaglandina/deficiencia , Lactancia Materna , Femenino , Humanos , Inmunoglobulina E/biosíntesis , Recién Nacido , Linoleoil-CoA Desaturasa , Embarazo , Prostaglandinas E/fisiología , Receptores de Prostaglandina E , Linfocitos T/inmunología , Ácido gammalinolénicoRESUMEN
Our hypothesis on the origin of atopy links alterations in omega-6-fatty acid metabolism in atopic persons (i.e., reduced formation of delta-6-desaturase products) to deficient T cell differentiation and function. We suggest that a relative deficiency in dihomo-gamma-linolenic acid-derived prostaglandin E1 is the major etiologic factor for diminished T cell maturation postpartum. Its precursors, gamma-linolenic acid and dihomo-gamma-linolenic acid, are physiologically provided in colostrum and mature breast milk of healthy mothers. Depressed cell-mediated immunity and uncontrolled B-cell response with increased IgE synthesis are explained as prostaglandin E1-dependent defects of T cell differentiation caused by insufficient supply of prostaglandin E1 precursors during early infancy. Thus, in our opinion atopy is a metabolic disorder and the associated immunologic disturbances are epiphenomena.
Asunto(s)
Alprostadil/metabolismo , Dermatitis Atópica/etiología , Ácidos Linolénicos/metabolismo , Adyuvantes Inmunológicos/fisiología , Alprostadil/fisiología , Lactancia Materna , Diferenciación Celular , Dermatitis Atópica/metabolismo , Ácido Graso Desaturasas/deficiencia , Humanos , Ácidos Linolénicos/fisiología , Linoleoil-CoA Desaturasa , Linfocitos T/citología , Ácido gammalinolénicoRESUMEN
A method for the analytical isoelectric focusing of Nonidet-P40-delipidated apolipoprotein B of human plasma low-density lipoproteins has been developed. Isoelectric focusing was performed in the presence of the zwitterionic nondenaturing detergent Chaps, 3-[(3-cholamidopropyl)-dimethylammonio]-1-propane sulfonate, and the nonionic surfactant Nonidet-P40, polyoxyethyleneglycol p-t-octylphenol with a mean of 9.0 ethylene oxide units per molecule. Low-density lipoprotein (LDL) apolipoprotein B (apo-B) entered 3.75% polyacrylamide gels without precipitation at the sites of sample application, permitting apoprotein recoveries of greater than 90% in the migrating bands. LDL apo-B exhibited 10 distinguishable bands with apparent isoelectric points of 7.34 (band 1), 7.27 (band 2), 7.16 (band 3), 7.02 (band 4), 6.88 (band 5), 6.70 (band 6), 6.61 (band 7), 6.48 (band 8), 6.40 (band 9), and 6.24 (band 10), respectively. Bands 3 and 4, 6 and 7, as well as 8 and 9 could be identified as major double bands. When the focused apo-B was run in a second dimension by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, the same relative molecular weight of B-100 was obtained for all focused bands. After electrotransfer to nitrocellulose paper, all bands reacted with polyclonal anti-human LDL antibody. Furthermore, the detergent-solubilized apo-B retained the immunological properties of native low-density lipoproteins when tested by double immunodiffusion against polyvalent anti-human LDL sera.
Asunto(s)
Apolipoproteínas B/sangre , Ácidos Cólicos/farmacología , Lipoproteínas LDL/sangre , Polietilenglicoles/farmacología , Electroforesis en Gel de Poliacrilamida , Humanos , Focalización Isoeléctrica , OctoxinolRESUMEN
Dry skin is seen in many patients with atopic dermatitis and correlates with a disturbed epidermal barrier function demonstrated by such features as increased transepidermal water loss and diminished stratum corneum hydration. With regard to the importance of stratum corneum lipids for the permeability barrier, we have analysed plantar (n = 8) and lumbar (n = 20) stratum corneum and nail lipids (n = 15) of atopic subjects by high-performance thin-layer chromatography (HPTLC). Compared with controls our investigations show a decrease in the ceramide fraction as a percentage of total lipid and a diminished ratio of ceramides and free sterols in atopic subjects. This implies that impaired ceramide synthesis may be a factor in the pathogenesis of atopic xerosis.
Asunto(s)
Dermatitis Atópica/fisiopatología , Ictiosis/fisiopatología , Metabolismo de los Lípidos , Uñas/metabolismo , Piel/metabolismo , Humanos , Factores de RiesgoRESUMEN
A four-year-old boy presented with hepatomegaly, vacuolized granulocytes (Jordans' anomaly) and slightly progressive myopathy as signs of multisystem triglyceride storage disease. The nine-year-old sister of the patient also showed Jordans' anomaly and early fatigability, but no overt weakness. Biochemical analysis revealed normal values for carnitines, carnitine palmityl transferase in serum and striated muscle, and beta-oxidation enzymes in striated muscles. Distribution of non-membrane-bound lipids in granulocytes, fibroblasts, smooth muscle cells and striated muscle was compatible with Chanarin-Dorfman syndrome. In contrast to Chanarin-Dorfman syndrome, our patients lacked congenital ichthyosis.