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1.
J Am Acad Dermatol ; 86(2): 322-330, 2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-34339761

RESUMEN

BACKGROUND: Although hidradenitis suppurativa (HS) shares some transcriptomic and cellular infiltrate features with psoriasis, their skin proteome remains unknown. OBJECTIVE: To define and compare inflammatory protein biomarkers of HS and psoriasis skin. METHODS: We assessed 92 inflammatory biomarkers in HS (n = 13), psoriasis (n = 11), and control skin (n = 11) using Olink high-throughput proteomics. We also correlated HS skin and blood biomarkers using proteomics and RNA sequencing. RESULTS: We identified 57 differentially expressed proteins (DEPs) in lesional psoriasis and 64 DEPs in lesional HS skin, compared to healthy controls. Both HS and psoriasis lesional skin demonstrated a significant upregulation of T helper 1 and T helper 17 proteins. Healthy-appearing perilesional HS skin had 63 DEPs compared to healthy controls. Nonlesional HS and psoriasis skin had 24 and 7 DEPs, respectively, compared to healthy controls. Tumor necrosis factor and 8 other proteins were significantly correlated with clinical severity in perilesional HS skin (2 cm from a nodule). LIMITATIONS: Inclusion of only moderate-to-severe patients and the cohort size. CONCLUSION: HS has a greater inflammatory profile and is more diffusely distributed compared with psoriasis. Proteins correlated with disease severity are potential disease mediators. Perilesional skin is comparably inflamed to lesional skin, suggesting the need to treat beyond skin nodules.


Asunto(s)
Hidradenitis Supurativa , Psoriasis , Biomarcadores/metabolismo , Hidradenitis Supurativa/genética , Humanos , Proteoma/metabolismo , Psoriasis/patología , Piel/patología
2.
J Allergy Clin Immunol ; 149(1): 135-144.e12, 2022 01.
Artículo en Inglés | MEDLINE | ID: mdl-34081946

RESUMEN

BACKGROUND: Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease presenting with diverse manifestations ranging from nodules and abscesses to draining tunnels. Whether the underlying inflammation from lesions extends to relatively healthy-appearing adjacent perilesional and distant nonlesional skin has not been systematically evaluated. OBJECTIVE: We sought to characterize lesional, perilesional, and nonlesional skin in patients with HS. METHODS: Skin biopsy samples were collected under ultrasound guidance from patients with active, untreated moderate-to-severe HS. Site-matched control biopsy samples from healthy volunteers were used for comparison. RESULTS: RNA sequencing demonstrated that HS skin clustered separately from healthy control skin, with perilesional and lesion skin clustering together and away from nonlesional skin. Immunohistochemistry analysis identified psoriasiform hyperplasia with keratin 16 positivity in both perilesional and lesional skin, with comparable levels of CD3+, CD11c+, and neutrophil elastase-positive cellular infiltration. There was a marked upregulation of IL-17 signaling in perilesional and lesional skin. HS samples clustered on the basis of expression of lipocalin-2 (LCN2), with samples characterized by high LCN2 expression in the skin exhibiting a differing transcriptomic profile with significantly higher overall inflammation than that of skin characterized by low LCN2 levels. CONCLUSIONS: Perilesional HS skin has a transcriptomic and molecular profile comparable to that of lesional skin. HS can be grouped into 2 distinct subtypes based on molecular levels of LCN2 in the skin, with the LCN2-high subtype exhibiting an overall higher inflammatory burden and an upregulation of targetable cytokines. To our knowledge, this is the first study to characterize a unique HS subtype (and a potential endotype) that may guide future therapeutic targets.


Asunto(s)
Hidradenitis Supurativa/inmunología , Lipocalina 2/inmunología , Piel/inmunología , Adulto , Anciano , Ensayos Clínicos como Asunto , Femenino , Hidradenitis Supurativa/diagnóstico por imagen , Hidradenitis Supurativa/genética , Hidradenitis Supurativa/patología , Humanos , Inflamación/diagnóstico por imagen , Inflamación/genética , Inflamación/inmunología , Inflamación/patología , Interleucina-17/inmunología , Masculino , Persona de Mediana Edad , Fenotipo , Piel/diagnóstico por imagen , Piel/patología , Transcriptoma , Ultrasonografía Doppler , Adulto Joven
3.
J Allergy Clin Immunol ; 143(2): 604-618, 2019 02.
Artículo en Inglés | MEDLINE | ID: mdl-29803800

RESUMEN

BACKGROUND: Ichthyoses are a group of rare skin disorders lacking effective treatments. Although genetic mutations are progressively delineated, comprehensive molecular phenotyping of ichthyotic skin could suggest much-needed pathogenesis-based therapy. OBJECTIVE: We sought to profile the molecular fingerprint of the most common orphan ichthyoses. METHODS: Gene, protein, and serum studies were performed on skin and blood samples from 29 patients (congenital ichthyosiform erythroderma, n = 9; lamellar ichthyosis, n = 8; epidermolytic ichthyosis, n = 8; and Netherton syndrome, n = 4), as well as age-matched healthy control subjects (n = 14), patients with psoriasis (n = 30), and patients with atopic dermatitis (AD; n = 16). RESULTS: Using criteria of a fold change of greater than 2 and a false discovery rate of less than 0.05, 132 differentially expressed genes were shared commonly among all ichthyoses, including many IL-17 and TNF-α-coregulated genes, which are considered hallmarks of psoriasis (defensin beta 4A, kynureninase, and vanin 3). Although striking upregulation of TH17 pathway genes (IL17F and IL36B/G) resembling that seen in patients with psoriasis was common to all patients with ichthyoses in a severity-related manner, patients with Netherton syndrome showed the greatest T-cell activation (inducible costimulator [ICOS]) and a broader immune phenotype with TH1/IFN-γ, OASL, and TH2/IL-4 receptor/IL-5 skewing, although less than seen in patients with AD (all P < .05). Ichthyoses lacked the epidermal differentiation and tight junction alterations of patients with AD (loricrin, filaggrin, and claudin 1) but showed characteristic alterations in lipid metabolism genes (ELOVL fatty acid elongase 3 and galanin), with parallel reductions in extracellular lipids and corneocyte compaction in all ichthyoses except epidermolytic ichthyosis, suggesting phenotypic variations. Transepidermal water loss, a functional barrier measure, significantly correlated with IL-17-regulated gene expression (IL17F and IL36A/IL36B/IL36G). CONCLUSION: Similar to patients with AD and psoriasis, in whom cytokine dysregulation and barrier impairment orchestrate disease phenotypes, psoriasis-like immune dysregulation and lipid alterations characterize the ichthyoses. These data support the testing of IL-17/IL-36-targeted therapeutics for patients with ichthyosis similar to those used in patients with psoriasis.


Asunto(s)
Ictiosis/inmunología , Síndrome de Netherton/inmunología , Linfocitos T/inmunología , Células Th17/inmunología , Uniones Estrechas/genética , Adolescente , Adulto , Anciano , Niño , Dermatoglifia del ADN , Femenino , Proteínas Filagrina , Genoma , Humanos , Ictiosis/genética , Interleucina-1/genética , Interleucina-17/genética , Metabolismo de los Lípidos/genética , Activación de Linfocitos , Masculino , Análisis por Micromatrices , Persona de Mediana Edad , Síndrome de Netherton/genética , Transcriptoma , Adulto Joven
4.
J Allergy Clin Immunol ; 143(1): 142-154, 2019 01.
Artículo en Inglés | MEDLINE | ID: mdl-30121291

RESUMEN

BACKGROUND: IL-22 is potentially a pathogenic cytokine in patients with atopic dermatitis (AD), but the molecular effects of IL-22 antagonism have not been defined in human subjects. OBJECTIVE: We sought to evaluate the cellular and molecular effects of IL-22 blockade in tissues from patients with moderate-to-severe AD. METHODS: We assessed lesional and nonlesional skin from 59 patients with moderate-to-severe AD treated with anti-IL-22 (fezakinumab) versus placebo (2:1) using transcriptomic and immunohistochemistry analyses. RESULTS: Greater reversal of the AD genomic profile was seen with fezakinumab versus placebo, namely 25.3% versus 10.5% at 4 weeks (P = 1.7 × 10-5) and 65.5% versus 13.9% at 12 weeks (P = 9.5 × 10-19), respectively. Because IL-22 blockade showed clinical efficacy only in patients with severe AD, we used baseline median IL-22 mRNA expression to stratify for high (n = 30) and low (n = 29) IL-22 expression groups. Much stronger mean transcriptomic improvements were seen with fezakinumab in the IL-22-high drug-treated group (82.8% and 139.4% at 4 and 12 weeks, respectively) than in the respective IL-22-high placebo-treated group (39.6% and 56.3% at 4 and 12 weeks) or the IL-22-low groups. Significant downregulations of multiple immune pathways, including TH1/CXCL9, TH2/CCL18/CCL22, TH17/CCL20/DEFB4A, and TH22/IL22/S100A's, were restricted to the IL-22-high drug group (P < .05). Consistently, tissue predictors of clinical response were mostly genes involved in T-cell and dendritic cell activation and differentiation. CONCLUSIONS: This is the first report showing a profound effect of IL-22 blockade on multiple inflammatory pathways in AD. These data, supported by robust effects in patients with high IL-22 baseline expression, suggest a central role for IL-22 in AD, indicating the need for a precision medicine approach for improving therapeutic outcomes in patients with AD.


Asunto(s)
Anticuerpos Monoclonales/administración & dosificación , Dermatitis Atópica/tratamiento farmacológico , Regulación de la Expresión Génica/efectos de los fármacos , Interleucinas/biosíntesis , Piel/metabolismo , Adulto , Anticuerpos Monoclonales Humanizados , Dermatitis Atópica/inmunología , Dermatitis Atópica/metabolismo , Dermatitis Atópica/patología , Femenino , Regulación de la Expresión Génica/inmunología , Humanos , Interleucinas/inmunología , Masculino , Persona de Mediana Edad , Piel/inmunología , Piel/patología , Células TH1/inmunología , Células TH1/metabolismo , Células TH1/patología , Células Th17/inmunología , Células Th17/metabolismo , Células Th17/patología , Células Th2/inmunología , Células Th2/metabolismo , Células Th2/patología , Interleucina-22
5.
Ann Allergy Asthma Immunol ; 122(1): 99-110.e6, 2019 01.
Artículo en Inglés | MEDLINE | ID: mdl-30223113

RESUMEN

BACKGROUND: African Americans (AA) are disproportionately impacted by atopic dermatitis (AD), with increased prevalence and therapeutic challenges unique to this population. Molecular profiling data informing development of targeted therapeutics for AD are derived primarily from European American (EA) patients. These studies are absent in AA, hindering development of effective treatments for this population. OBJECTIVE: We sought to characterize the global molecular profile of AD in the skin of AA patients as compared with that of EA AD and healthy controls. METHODS: We performed RNA-Seq with reverse transcription polymerase chain reaction validation and immunohistochemistry studies in lesional and nonlesional skin of AA and EA AD patients vs healthy controls. RESULTS: African American AD lesions were characterized by greater infiltration of dendritic cells (DCs) marked by the high-affinity immunoglobulin E (IgE) receptor (FcεR1+) compared with EA AD (P < .05). Both AD cohorts showed similarly robust up-regulation of Th2-related (CCL17/18/26) and Th22-related markers (interleukin [IL]-22, S100A8/9/12), but AA AD featured decreased expression of innate immune (tumor necrosis factor [TNF], IL-1ß), Th1-related (interferon gamma [IFN-γ], MX1, IL-12RB1), and Th17-related markers (IL-23p19, IL-36G, CXCL1) vs EA AD (P < .05). The Th2 (IL-13) and Th22-related products (IL-22, S100A8/9/12) and serum IgE were significantly correlated with clinical severity (Scoring of Atopic Dermatitis [SCORAD]) in AA. Fillagrin (FLG) was exclusively down-regulated in EA AD, whereas loricrin (LOR) was down-regulated in both AD cohorts and negatively correlated with SCORAD in AA. CONCLUSION: The molecular phenotype of AA AD skin is characterized by attenuated Th1 and Th17 but similar Th2/Th22-skewing to EA AD. Our data encourages a personalized medicine approach accounting for phenotype-specific characteristics in future development of targeted therapeutics and clinical trial design for AD.


Asunto(s)
Negro o Afroamericano/estadística & datos numéricos , Citocinas/sangre , Células Dendríticas/inmunología , Dermatitis Atópica/inmunología , Inmunoglobulina E/sangre , Receptores de IgE/inmunología , Adulto , Anciano , Secuencia de Bases , Quimiocina CCL17/sangre , Femenino , Proteínas Filagrina , Humanos , Inmunoglobulina E/inmunología , Interleucinas/inmunología , Masculino , Persona de Mediana Edad , Análisis de Secuencia de ARN , Células TH1/inmunología , Células Th17/inmunología , Células Th2/inmunología , Adulto Joven , Interleucina-22
6.
Ann Allergy Asthma Immunol ; 122(3): 318-330.e3, 2019 03.
Artículo en Inglés | MEDLINE | ID: mdl-30508584

RESUMEN

BACKGROUND: Atopic dermatitis (AD) predominantly affects young children, but our understanding of AD pathogenesis is based on skin and blood samples from long-standing adult AD. Genomic biopsy profiling from early pediatric AD showed significant Th2 and Th17/Th22-skewing, without the characteristic adult Th1 up-regulation. Because obtaining pediatric biopsies is difficult, blood gene expression profiling may provide a surrogate for the pediatric skin signature. OBJECTIVE: To define the blood profile and associated biomarkers of early moderate-to-severe pediatric AD. METHODS: We compared microarrays and reverse transcription polymerase chain reaction (RT-PCR) of blood cells from 28 AD children (<5 years and within 6 months of disease onset) to healthy control blood cells. Differentially expressed genes (DEGs) in blood (fold change [FCH] > 1.2 and false discovery rate [FDR] < 0.05) were then compared with skin DEGs. RESULTS: Eosinophil and Th2 markers (IL5RA, IL1RL1/ST2, HRH4, CCR3, SIGLEC8, PRSS33, CLC from gene arrays; IL13/IL4/CCL22 from RT-PCR) were up-regulated in early pediatric AD blood, whereas IFNG/Th1 was decreased. Th1 markers were negatively correlated with clinical severity (EASI, pruritus, transepidermal water loss [TEWL]), whereas Th2/Th17-induced interleukin (IL)-19 was positively correlated with SCORAD. Although a few RT-PCR-defined immune markers (IL-13/CCL22) were increased in blood, as previously also reported for skin, minimal overlap based on gene array DEGs was seen. CONCLUSION: The whole blood signature of early moderate-to-severe pediatric AD blood cells show predominantly a Th2/eosinophil profile; however, markers largely differ from the skin profile. Given their complementarity, pooling of biomarkers from blood and skin may improve profiling and predictions, providing insight regarding disease course, allergic comorbidity development, and response to systemic medications.


Asunto(s)
Dermatitis Atópica/genética , Piel/metabolismo , Transcriptoma , Edad de Inicio , Biomarcadores/análisis , Biopsia , Preescolar , Dermatitis Atópica/sangre , Femenino , Perfilación de la Expresión Génica , Humanos , Lactante , Leucocitos Mononucleares/metabolismo , Masculino
8.
Sci Rep ; 8(1): 8439, 2018 May 29.
Artículo en Inglés | MEDLINE | ID: mdl-29844442

RESUMEN

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

9.
J Allergy Clin Immunol ; 141(6): 2094-2106, 2018 06.
Artículo en Inglés | MEDLINE | ID: mdl-29731129

RESUMEN

BACKGROUND: Although atopic dermatitis (AD) often starts in early childhood, detailed tissue profiling of early-onset AD in children is lacking, hindering therapeutic development for this patient population with a particularly high unmet need for better treatments. OBJECTIVE: We sought to globally profile the skin of infants with AD compared with that of adults with AD and healthy control subjects. METHODS: We performed microarray, RT-PCR, and fluorescence microscopy studies in infants and young children (<5 years old) with early-onset AD (<6 months disease duration) compared with age-matched control subjects and adults with longstanding AD. RESULTS: Transcriptomic analyses revealed profound differences between pediatric patients with early-onset versus adult patients with longstanding AD in not only lesional but also nonlesional tissues. Although both patient populations harbored TH2-centered inflammation, pediatric AD also showed significant TH17/TH22 skewing but lacked the TH1 upregulation that characterizes adult AD. Pediatric AD exhibited relatively normal expression of epidermal differentiation and cornification products, which is downregulated in adults with AD. Defects in the lipid barrier (eg, ELOVL fatty acid elongase 3 [ELOVL3] and diacylglycerol o-acyltransferase 2 [DGAT2]) and tight junction regulation (eg, claudins 8 and 23) were evident in both groups. However, some lipid-associated mediators (eg, fatty acyl-CoA reductase 2 and fatty acid 2-hydroxylase) showed preferential downregulation in pediatric AD, and lipid barrier genes (FA2H and DGAT2) showed inverse correlations with transepidermal water loss, a functional measure of the epidermal barrier. CONCLUSIONS: Skin samples from children and adult patients with AD share lipid metabolism and tight junction alterations, but epidermal differentiation complex defects are only present in adult AD, potentially resulting from chronic immune aberration that is not yet present in early-onset disease.


Asunto(s)
Dermatitis Atópica/inmunología , Dermatitis Atópica/metabolismo , Dermatitis Atópica/patología , Edad de Inicio , Preescolar , Femenino , Humanos , Lactante , Inflamación/inmunología , Inflamación/metabolismo , Inflamación/patología , Interleucinas/inmunología , Metabolismo de los Lípidos , Masculino , Persona de Mediana Edad , Subgrupos de Linfocitos T/inmunología , Células Th17/inmunología , Células Th2/inmunología , Interleucina-22
11.
Sci Rep ; 7(1): 8707, 2017 08 18.
Artículo en Inglés | MEDLINE | ID: mdl-28821884

RESUMEN

Beyond classic "allergic"/atopic comorbidities, atopic dermatitis (AD) emerges as systemic disease with increased cardiovascular risk. To better define serum inflammatory and cardiovascular risk proteins, we used an OLINK high-throughput proteomic assay to analyze moderate-to-severe AD (n = 59) compared to psoriasis (n = 22) and healthy controls (n = 18). Compared to controls, 10 proteins were increased in serum of both diseases, including Th1 (IFN-γ, CXCL9, TNF-ß) and Th17 (CCL20) markers. 48 proteins each were uniquely upregulated in AD and psoriasis. Consistent with skin expression, AD serum showed up-regulation of Th2 (IL-13, CCL17, eotaxin-1/CCL11, CCL13, CCL4, IL-10), Th1 (CXCL10, CXCL11) and Th1/Th17/Th22 (IL-12/IL-23p40) responses. Surprisingly, some markers of atherosclerosis (fractalkine/CX3CL1, CCL8, M-CSF, HGF), T-cell development/activation (CD40L, IL-7, CCL25, IL-2RB, IL-15RA, CD6) and angiogenesis (VEGF-A) were significantly increased only in AD. Multiple inflammatory pathways showed stronger enrichment in AD than psoriasis. Several atherosclerosis mediators in serum (e.g. E-selectin, PI3/elafin, CCL7, IL-16) correlated with SCORAD, but not BMI. Also, AD inflammatory mediators (e.g. MMP12, IL-12/IL-23p40, CXCL9, CCL22, PI3/Elafin) correlated between blood and lesional as well as non-lesional skin. Overall, the AD blood signature was largely different compared to psoriasis, with dysregulation of inflammatory and cardiovascular risk markers, strongly supporting its systemic nature beyond atopic/allergic association.


Asunto(s)
Enfermedades Cardiovasculares/sangre , Dermatitis Atópica/sangre , Inflamación/sangre , Proteínas/metabolismo , Adulto , Biomarcadores/metabolismo , Femenino , Humanos , Mediadores de Inflamación/metabolismo , Masculino , Persona de Mediana Edad , Proteómica , Psoriasis/sangre , Factores de Riesgo , Índice de Severidad de la Enfermedad , Transducción de Señal , Piel/patología
12.
Exp Dermatol ; 26(1): 28-35, 2017 01.
Artículo en Inglés | MEDLINE | ID: mdl-27304428

RESUMEN

Atopic dermatitis (AD) is the most common inflammatory skin disease, but treatment options for moderate-to-severe disease are limited. Ustekinumab is an IL-12/IL-23p40 antagonist that suppresses Th1, Th17 and Th22 activation, commonly used for psoriasis patients. We sought to assess efficacy and safety of ustekinumab in patients with moderate-to-severe AD. In this phase II, double-blind, placebo-controlled study, 33 patients with moderate-to-severe AD were randomly assigned to either ustekinumab (n=16) or placebo (n=17), with subsequent crossover at 16 weeks, and last dose at 32 weeks. Background therapy with mild topical steroids was allowed to promote retention. Study endpoints included clinical (SCORAD50) and biopsy-based measures of tissue structure and inflammation, using protein and gene expression studies. The ustekinumab group achieved higher SCORAD50 responses at 12, 16 (the primary endpoint) and 20 weeks compared to placebo, but the difference between groups was not significant. The AD molecular profile/transcriptome showed early robust gene modulation, with sustained further improvements until 32 weeks in the initial ustekinumab group. Distinct and more robust modulation of Th1, Th17 and Th22 but also Th2-related AD genes was seen after 4 weeks of ustekinumab treatment (i.e. MMP12, IL-22, IL-13, IFN-γ, elafin/PI3, CXCL1 and CCL17; P<.05). Epidermal responses (K16, terminal differentiation) showed faster (4 weeks) and long-term regulation (32 weeks) from baseline in the ustekinumab group. No severe adverse events were observed. Ustekinumab had clear clinical and molecular effects, but clinical outcomes might have been obscured by a profound "placebo" effect, most likely due to background topical glucocorticosteroids and possibly insufficient dosing for AD.


Asunto(s)
Dermatitis Atópica/tratamiento farmacológico , Dermatitis Atópica/genética , Fármacos Dermatológicos/uso terapéutico , Ustekinumab/uso terapéutico , Adulto , Quimiocina CCL17/genética , Quimiocina CXCL1/genética , Estudios Cruzados , Dermatitis Atópica/patología , Fármacos Dermatológicos/efectos adversos , Método Doble Ciego , Elafina/genética , Femenino , Perfilación de la Expresión Génica , Humanos , Interferón gamma/genética , Interleucina-13/genética , Interleucinas/genética , Masculino , Metaloproteinasa 12 de la Matriz/genética , Índice de Severidad de la Enfermedad , Transcriptoma/efectos de los fármacos , Ustekinumab/efectos adversos , Interleucina-22
13.
J Allergy Clin Immunol ; 140(1): 134-144.e9, 2017 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-27965110

RESUMEN

BACKGROUND: B cells undergo maturation and class-switching in response to antigen exposure and T-cell help. Early B-cell differentiation has not been defined in patients with early-onset atopic dermatitis (AD). OBJECTIVE: We sought to define the frequency of B-cell subsets associated with progressive B-cell maturation and IgE class-switching. METHODS: We studied 27 children and 34 adults with moderate-to-severe AD (mean SCORAD score, 55 and 65, respectively) and age-matched control subjects (15 children and 27 adults). IgD/CD27 and CD24/CD38 core gating systems and an 11-color flow cytometric panel were used to determine the frequencies of circulating B-cell subsets. Serum total and allergen-specific IgE (sIgE) levels were measured by using ImmunoCAP. RESULTS: Compared with adults, children showed T-cell predominance in the skin. Circulating CD19+CD20+ B-cell counts were lower in patients with pediatric AD than in control subjects (24% vs 33%, P = .04), whereas CD3+ T-cell counts were higher (62% vs 52%, P = .05). A decreased B-cell/T-cell lymphocyte ratio with age was observed only in pediatric control subjects (r = -0.48, P = .07). In pediatric patients with AD, a positive correlation was observed between B-cell/T-cell ratio and nonswitched memory B-cell counts (r = 0.42, P = .03). Higher frequencies of positive sIgE levels were seen in pediatric patients with AD (P < .0001). Diverse sIgE levels correlated with SCORAD scores and age of pediatric patients with AD (P < .01). Positive correlations were observed between activated B-cell and memory T-cell counts (P < .02). In patients with AD, IgE sensitization to most allergens clustered with age, TH1, TH2, total IgE levels, and B-cell memory subsets. CONCLUSIONS: Peripheral B and T cells are altered in pediatric patients with early AD, but T cells predominate in skin lesions.


Asunto(s)
Subgrupos de Linfocitos B/inmunología , Dermatitis Atópica/inmunología , Adulto , Envejecimiento/inmunología , Alérgenos/inmunología , Preescolar , Dermatitis Atópica/sangre , Femenino , Humanos , Inmunoglobulina E/sangre , Inmunoglobulina E/inmunología , Lactante , Masculino , Persona de Mediana Edad , Piel/citología , Piel/inmunología , Linfocitos T/inmunología
14.
J Allergy Clin Immunol ; 139(1): 152-165, 2017 01.
Artículo en Inglés | MEDLINE | ID: mdl-27554821

RESUMEN

BACKGROUND: The ichthyoses are rare genetic disorders associated with generalized scaling, erythema, and epidermal barrier impairment. Pathogenesis-based therapy is largely lacking because the underlying molecular basis is poorly understood. OBJECTIVE: We sought to characterize molecularly cutaneous inflammation and its correlation with clinical and barrier characteristics. METHODS: We analyzed biopsy specimens from 21 genotyped patients with ichthyosis (congenital ichthyosiform erythroderma, n = 6; lamellar ichthyosis, n = 7; epidermolytic ichthyosis, n = 5; and Netherton syndrome, n = 3) using immunohistochemistry and RT-PCR and compared them with specimens from healthy control subjects, patients with atopic dermatitis (AD), and patients with psoriasis. Clinical measures included the Ichthyosis Area Severity Index (IASI), which integrates erythema (IASI-E) and scaling (IASI-S); transepidermal water loss; and pruritus. RESULTS: Ichthyosis samples showed increased epidermal hyperplasia (increased thickness and keratin 16 expression) and T-cell and dendritic cell infiltrates. Increases of general inflammatory (IL-2), innate (IL-1ß), and some TH1/interferon (IFN-γ) markers in patients with ichthyosis were comparable with those in patients with psoriasis or AD. TNF-α levels in patients with ichthyosis were increased only in those with Netherton syndrome but were much lower than in patients with psoriasis and those with AD. Expression of TH2 cytokines (IL-13 and IL-31) was similar to that seen in control subjects. The striking induction of IL-17-related genes or markers synergistically induced by IL-17 and TNF-α (IL-17A/C, IL-19, CXCL1, PI3, CCL20, and IL36G; P < .05) in patients with ichthyosis was similar to that seen in patients with psoriasis. IASI and IASI-E scores strongly correlated with IL-17A (r = 0.74, P < .001) and IL-17/TNF-synergistic/additive gene expression. These markers also significantly correlated with transepidermal water loss, suggesting a link between the barrier defect and inflammation in patients with ichthyosis. CONCLUSION: Our data associate a shared TH17/IL-23 immune fingerprint with the major orphan forms of ichthyosis and raise the possibility of IL-17-targeting strategies.


Asunto(s)
Ictiosis/inmunología , Interleucina-17/inmunología , Interleucina-23/inmunología , Adolescente , Adulto , Anciano , Niño , Dermatitis Atópica/genética , Dermatitis Atópica/inmunología , Femenino , Expresión Génica , Humanos , Ictiosis/genética , Interleucina-17/genética , Interleucina-23/genética , Masculino , Persona de Mediana Edad , Psoriasis/genética , Psoriasis/inmunología , ARN Mensajero/metabolismo , Índice de Severidad de la Enfermedad , Piel/inmunología , Adulto Joven
16.
J Allergy Clin Immunol ; 138(6): 1639-1651, 2016 12.
Artículo en Inglés | MEDLINE | ID: mdl-27671162

RESUMEN

BACKGROUND: Atopic dermatitis (AD) affects 15% to 25% of children and 4% to 7% of adults. Paradigm-shifting discoveries about AD have been based on adult biomarkers, reflecting decades of disease activity, although 85% of cases begin by 5 years. Blood phenotyping shows only TH2 skewing in patients with early-onset pediatric AD, but alterations in early pediatric skin lesions are unknown, limiting advancement of targeted therapies. OBJECTIVE: We sought to characterize the early pediatric AD skin phenotype and its differences from pediatric control subjects and adults with AD. METHODS: Using immunohistochemistry and quantitative real-time PCR, we assessed biopsy specimens from 19 children with AD younger than 5 years within 6 months of disease onset in comparison with adults with AD or psoriasis and pediatric and adult control subjects. RESULTS: In lesional skin children showed comparable or greater epidermal hyperplasia (thickness and keratin 16) and cellular infiltration (CD3+, CD11c+, and FcεRI+) than adults with AD. Similar to adults, strong activation of the TH2 (IL-13, IL-31, and CCL17) and TH22 (IL-22 and S100As) axes and some TH1 skewing (IFN-γ and CXCL10) were present. Children showed significantly higher induction of TH17-related cytokines and antimicrobials (IL-17A, IL-19, CCL20, LL37, and peptidase inhibitor 3/elafin), TH9/IL-9, IL-33, and innate markers (IL-8) than adults (P < .02). Despite the characteristic downregulation in adult patients with AD, filaggrin expression was similar in children with AD and healthy children. Nonlesional skin in pediatric patients with AD showed higher levels of inflammation (particularly IL-17A and the related molecules IL-19 and LL37) and epidermal proliferation (keratin 16 and S100As) markers (P < .001). CONCLUSION: The skin phenotype of new-onset pediatric AD is substantially different from that of adult AD. Although excess TH2 activation characterizes both, TH9 and TH17 are highly activated at disease initiation. Increases in IL-19 levels might link TH2 and TH17 activation.


Asunto(s)
Dermatitis Atópica/patología , Eccema/patología , Hispánicos o Latinos , Psoriasis/patología , Piel/patología , Células Th17/inmunología , Células Th2/inmunología , Adulto , Factores de Edad , Anciano , Preescolar , Citocinas/metabolismo , Dermatitis Atópica/inmunología , Eccema/inmunología , Femenino , Proteínas Filagrina , Humanos , Lactante , Masculino , Persona de Mediana Edad , Psoriasis/inmunología , Estados Unidos
17.
J Allergy Clin Immunol ; 138(1): 169-178, 2016 07.
Artículo en Inglés | MEDLINE | ID: mdl-26948076

RESUMEN

BACKGROUND: Topical glucocorticosteroids are considered an efficient treatment option for atopic dermatitis (AD), but a global assessment of glucocorticosteroid responses on key disease circuits upon weeks to months of treatment is currently lacking. OBJECTIVE: We sought to assess short (4 weeks) and long-term (16 weeks) application of topical glucocorticosteroids on AD skin and define response biomarkers. METHODS: The effects of triamcinolone acetonide cream 0.025% were assessed based on gene expression and immunohistochemistry studies at baseline, 4 weeks, and 16 weeks in biopsy specimens from 15 patients with moderate-to-severe AD. RESULTS: At 16 weeks, only 3 patients were clinical responders (by using SCORAD50 criteria), but 6 patients qualified as responders based on histologic criteria. Baseline characteristics indicated more severe disease in nonresponders. While 3 of 15 patients experienced only transient benefit after 4 weeks, others showed progressive improvements toward 16 weeks. Topical glucocorticosteroid use in patients with AD resulted in improvements of the AD genomic signature of 25.6% at 4 weeks and 71.8% at 16 weeks, respectively, and even 123.9% in the histologic responder group. Cytokines (IL-12p40, IL-13, IL-22, CCL17, CCL18, peptidase inhibitor 3 [PI3]/elafin, and S100As) showed consistent decreases from baseline toward 16 weeks with corresponding improvements in epidermal disease hallmarks (keratin 16 and loricrin) in lesional skin from responders (P < .05). Nonresponders largely showed lesser/nonsignificant reductions in key inflammatory and barrier markers (keratin 16, IL-13, IL-22, CCL17, CCL18, PI3/elafin, S100As, and loricrin). The combination of IL-21 and IFN-γ baseline expression closely predicted individual clinical glucocorticosteroid responses at 16 weeks of treatment. CONCLUSION: Our study indicates that even low-potency glucocorticosteroids can broadly affect immune and barrier responses in patients with moderate-to-severe AD, associating higher baseline severity with increased steroid resistance in patients with AD.


Asunto(s)
Antiinflamatorios/administración & dosificación , Dermatitis Atópica/tratamiento farmacológico , Esteroides/administración & dosificación , Administración Tópica , Adulto , Anciano , Biopsia , Análisis por Conglomerados , Dermatitis Atópica/diagnóstico , Dermatitis Atópica/genética , Femenino , Perfilación de la Expresión Génica , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Masculino , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Piel/metabolismo , Piel/patología , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Subgrupos de Linfocitos T/patología , Factores de Tiempo , Resultado del Tratamiento , Adulto Joven
18.
J Allergy Clin Immunol ; 137(1): 118-129.e5, 2016 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-26441226

RESUMEN

BACKGROUND: Atopic dermatitis (AD) and psoriasis pathogeneses involve skin barrier impairment and immune dysregulation; however, the contribution of B-cell imbalances to these diseases has not yet been determined. OBJECTIVE: We sought to quantify B-cell populations and antibody-secreting cells in the blood of patients with AD, patients with psoriasis, and control subjects. METHODS: We studied 34 adults with moderate-to-severe AD (mean SCORAD score, 65), 24 patients with psoriasis (mean Psoriasis Area and Severity Index score, 16), and 27 healthy subjects using an 11-color flow cytometric antibody panel. IgD/CD27 and CD24/CD38 core gating systems were used to determine frequencies of plasmablasts and naive, memory, transitional, and activated B cells. RESULTS: We measured increased CD19(+)CD20(+) B-cell counts in the skin and blood of patients with AD (P < .01). Significantly higher frequencies of chronically activated CD27(+) memory and nonswitched memory B cells were observed in patients with AD (P < .05), with lower values of double-negative populations (4% for patients with AD vs. 7% for patients with psoriasis [P = .001] and 6% for control subjects [P = .02]). CD23 expression was highest in patients with AD and correlated with IgE levels (P < .01) and disease severity (r = 0.6, P = .0002). Plasmablast frequencies and IgE expression were highest in all memory subsets of patients with AD (P < .01). Finally, CD19(+)CD24(++)CD38(++) transitional and CD19(+)CD24(-)CD38(-) new memory B-cell counts were higher in patients with AD versus those in patients with psoriasis (2.8% vs. 1.4% [P = .001] and 9.2% vs. 5.7% [P = .02], respectively). CONCLUSIONS: AD is accompanied by systemic expansion of transitional and chronically activated CD27(+) memory, plasmablast, and IgE-expressing memory subsets. These data create a critical basis for the future understanding of this debilitating skin disease.


Asunto(s)
Subgrupos de Linfocitos B/inmunología , Dermatitis Atópica/inmunología , Psoriasis/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Antígenos CD/inmunología , Dermatitis Atópica/sangre , Femenino , Humanos , Inmunoglobulina E/sangre , Activación de Linfocitos , Masculino , Persona de Mediana Edad
19.
J Allergy Clin Immunol ; 137(4): 1091-1102.e7, 2016 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-26431582

RESUMEN

BACKGROUND: Petrolatum is a common moisturizer often used in the prevention of skin infections after ambulatory surgeries and as a maintenance therapy of atopic dermatitis (AD). However, the molecular responses induced by petrolatum in the skin have never been assessed. OBJECTIVE: We sought to define the cutaneous molecular and structural effects induced by petrolatum. METHODS: Thirty-six healthy subjects and 13 patients with moderate AD (mean SCORAD score, 39) were studied by using RT-PCR, gene arrays, immunohistochemistry, and immunofluorescence performed on control skin, petrolatum-occluded skin, and skin occluded with a Finn chamber only. RESULTS: Significant upregulations of antimicrobial peptides (S100A8/fold change [FCH], 13.04; S100A9/FCH, 11.28; CCL20/FCH, 8.36; PI3 [elafin]/FCH, 15.40; lipocalin 2/FCH, 6.94, human ß-defensin 2 [DEFB4A]/FCH, 4.96; P < .001 for all) and innate immune genes (IL6, IL8, and IL1B; P < .01) were observed in petrolatum-occluded skin compared with expression in both control and occluded-only skin. Application of petrolatum also induced expression of key barrier differentiation markers (filaggrin and loricrin), increased stratum corneum thickness, and significantly reduced T-cell infiltrates in the setting of "normal-appearing" or nonlesional AD skin, which is known to harbor barrier and immune defects. CONCLUSIONS: Petrolatum robustly modulates antimicrobials and epidermal differentiation barrier measures. These data shed light on the beneficial molecular responses of petrolatum in barrier-defective states, such as AD and postoperative wound care.


Asunto(s)
Antiinfecciosos/farmacología , Dermatitis Atópica/tratamiento farmacológico , Emolientes/farmacología , Vaselina/farmacología , Piel/efectos de los fármacos , Administración Cutánea , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Antiinfecciosos/uso terapéutico , Biomarcadores/metabolismo , Estudios de Casos y Controles , Dermatitis Atópica/inmunología , Dermatitis Atópica/metabolismo , Emolientes/uso terapéutico , Femenino , Proteínas Filagrina , Humanos , Proteínas de Filamentos Intermediarios/metabolismo , Masculino , Proteínas de la Membrana/metabolismo , Persona de Mediana Edad , Vaselina/uso terapéutico , Piel/inmunología , Piel/metabolismo , Adulto Joven
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