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1.
J Am Acad Dermatol ; 82(3): 575-585.e1, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-29438767

RESUMEN

BACKGROUND: Several European countries recently developed international diagnostic and management guidelines for pemphigus, which have been instrumental in the standardization of pemphigus management. OBJECTIVE: We now present results from a subsequent Delphi consensus to broaden the generalizability of the recommendations. METHODS: A preliminary survey, based on the European Dermatology Forum and the European Academy of Dermatology and Venereology guidelines, was sent to a panel of international experts to determine the level of consensus. The results were discussed at the International Bullous Diseases Consensus Group in March 2016 during the annual American Academy of Dermatology conference. Following the meeting, a second survey was sent to more experts to achieve greater international consensus. RESULTS: The 39 experts participated in the first round of the Delphi survey, and 54 experts from 21 countries completed the second round. The number of statements in the survey was reduced from 175 topics in Delphi I to 24 topics in Delphi II on the basis of Delphi results and meeting discussion. LIMITATIONS: Each recommendation represents the majority opinion and therefore may not reflect all possible treatment options available. CONCLUSIONS: We present here the recommendations resulting from this Delphi process. This international consensus includes intravenous CD20 inhibitors as a first-line therapy option for moderate-to-severe pemphigus.


Asunto(s)
Factores Inmunológicos/administración & dosificación , Pénfigo/diagnóstico , Pénfigo/terapia , Plasmaféresis , Guías de Práctica Clínica como Asunto , Academias e Institutos/normas , Administración Intravenosa , Antígenos CD20/inmunología , Terapia Combinada/métodos , Terapia Combinada/normas , Consenso , Técnica Delphi , Dermatología/métodos , Dermatología/normas , Quimioterapia Combinada/métodos , Quimioterapia Combinada/normas , Europa (Continente) , Glucocorticoides/administración & dosificación , Humanos , Pénfigo/inmunología , Rituximab/administración & dosificación , Índice de Severidad de la Enfermedad
2.
Proc Natl Acad Sci U S A ; 113(7): 1859-64, 2016 Feb 16.
Artículo en Inglés | MEDLINE | ID: mdl-26831096

RESUMEN

Patients with pemphigus vulgaris (PV) harbor antibodies reactive against self-antigens expressed at the surface of keratinocytes, primarily desmoglein (Dsg) 3 and, to a lesser extent, Dsg1. Conventionally, only antibodies targeting these molecules have been thought to contribute to disease pathogenesis. This notion has been challenged by a growing pool of evidence that suggests that antibodies toward additional targets may play a role in disease. The aims of this study were to (i) establish high-throughput protein microarray technology as a method to investigate traditional and putative autoantibodies (autoAbs) in PV and (ii) use multiplexed protein array technology to define the scope and specificity of the autoAb response in PV. Our analysis demonstrated significant IgG reactivity in patients with PV toward the muscarinic acetylcholine receptor subtypes 3, 4, and 5 as well as thyroid peroxidase. Furthermore, we found that healthy first- and second-degree relatives of patients with PV express autoAbs toward desmoglein and non-Dsg targets. Our analysis also identified genetic elements, particularly HLA, as key drivers of autoAb expression. Finally, we show that patients with PV exhibit significantly reduced IgM reactivity toward disease-associated antigens relative to controls. The use of protein microarrays to profile the autoAb response in PV advanced the current understanding of disease and provided insight into the complex relationship between genetics and disease development.


Asunto(s)
Autoantígenos/inmunología , Desmogleínas/inmunología , Antígenos HLA/inmunología , Pénfigo/inmunología , Especificidad de Anticuerpos , Estudios de Casos y Controles , Humanos , Análisis por Matrices de Proteínas
4.
BMC Genomics ; 18(1): 109, 2017 01 28.
Artículo en Inglés | MEDLINE | ID: mdl-28129744

RESUMEN

BACKGROUND: Significant gaps remain regarding the pathomechanisms underlying the autoimmune response in vitiligo (VL), where the loss of self-tolerance leads to the targeted killing of melanocytes. Specifically, there is incomplete information regarding alterations in the systemic environment that are relevant to the disease state. METHODS: We undertook a genome-wide profiling approach to examine gene expression in the peripheral blood of VL patients and healthy controls in the context of our previously published VL-skin gene expression profile. We used several in silico bioinformatics-based analyses to provide new insights into disease mechanisms and suggest novel targets for future therapy. RESULTS: Unsupervised clustering methods of the VL-blood dataset demonstrate a "disease-state"-specific set of co-expressed genes. Ontology enrichment analysis of 99 differentially expressed genes (DEGs) uncovers a down-regulated immune/inflammatory response, B-Cell antigen receptor (BCR) pathways, apoptosis and catabolic processes in VL-blood. There is evidence for both type I and II interferon (IFN) playing a role in VL pathogenesis. We used interactome analysis to identify several key blood associated transcriptional factors (TFs) from within (STAT1, STAT6 and NF-kB), as well as "hidden" (CREB1, MYC, IRF4, IRF1, and TP53) from the dataset that potentially affect disease pathogenesis. The TFs overlap with our reported lesional-skin transcriptional circuitry, underscoring their potential importance to the disease. We also identify a shared VL-blood and -skin transcriptional "hot spot" that maps to chromosome 6, and includes three VL-blood dysregulated genes (PSMB8, PSMB9 and TAP1) described as potential VL-associated genetic susceptibility loci. Finally, we provide bioinformatics-based support for prioritizing dysregulated genes in VL-blood or skin as potential therapeutic targets. CONCLUSIONS: We examined the VL-blood transcriptome in context with our (previously published) VL-skin transcriptional profile to address a major gap in knowledge regarding the systemic changes underlying skin-specific manifestation of vitiligo. Several transcriptional "hot spots" observed in both environments offer prioritized targets for identifying disease risk genes. Finally, within the transcriptional framework of VL, we identify five novel molecules (STAT1, PRKCD, PTPN6, MYC and FGFR2) that lend themselves to being targeted by drugs for future potential VL-therapy.


Asunto(s)
Perfilación de la Expresión Génica , Transcriptoma , Vitíligo/etiología , Adulto , Anciano , Autoinmunidad/genética , Biomarcadores , Estudios de Casos y Controles , Análisis por Conglomerados , Biología Computacional/métodos , Femenino , Regulación de la Expresión Génica , Ontología de Genes , Redes Reguladoras de Genes , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Persona de Mediana Edad , Anotación de Secuencia Molecular , Terapia Molecular Dirigida , Transducción de Señal , Vitíligo/sangre , Vitíligo/diagnóstico , Vitíligo/tratamiento farmacológico
5.
J Investig Dermatol Symp Proc ; 18(2): S75-S80, 2017 10.
Artículo en Inglés | MEDLINE | ID: mdl-28941499

RESUMEN

Lupus erythematosus is a chronic autoimmune disorder with a protean clinical manifestation affecting virtually every organ including skin, with tremendous variation between patients. This makes it vital to stratify patients on a molecular basis. We used gene microarray technology for large-scale screening combined with bioinformatics to investigate global patterns of gene expression in cutaneous lupus erythematosus to allow further insights into disease heterogeneity. Unbiased clustering exposed a clear separation between cutaneous lupus erythematosus skin and blood samples. Pathway-based analyses of the differentially expressed genes from sample groups within skin and blood showed prominent apoptosis and interferon response signals. Given their well-known role in systemic lupus, the two processes are potentially critical to cutaneous lupus erythematosus as well. We found both coincident and distinct features between systemic lupus and cutaneous lupus erythematosus, as well as several pathways and processes that are specific to the cutaneous disease that offer potential therapeutic choices in the future. Finally, we identified shared cutaneous lupus erythematosus-skin and -blood transcriptional "hot spots" located on the genome that include several differentially expressed genes previously associated with the systemic disease. The differentially expressed genes included in the hot spots with no systemic lupus associations can potentially be targeted in future studies aimed at identifying risk genes related to cutaneous disease.


Asunto(s)
Lupus Eritematoso Cutáneo/sangre , Lupus Eritematoso Cutáneo/genética , Lupus Eritematoso Sistémico/genética , Piel , Transcriptoma , Estudios de Casos y Controles , Regulación hacia Abajo , Genómica , Humanos , Análisis de Secuencia por Matrices de Oligonucleótidos , Regulación hacia Arriba
6.
J Drugs Dermatol ; 16(2): 135-139, 2017 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-28300855

RESUMEN

Anti-desmoglein (Dsg) 1 and -Dsg3 antibody titers have an established role in the diagnosis of the autoimmune blistering skin disease pemphigus vulgaris (PV). However, their usefulness for disease monitoring has been controversial. A recent large-scale immunoprofiling study by our group indicated that anti-Dsg1 levels may be a better predictor of disease activity than anti-Dsg3 levels, with declining levels predicting progression from active phase of disease to early remission, irrespective of lesional subtypes. Here, we report an illustrative case of a PV patient with mucocutaneous disease that was followed longitudinally for >2.5 years clinically and by serum serology. Autoantibody levels directed against both Dsg1 and -3 showed a moderate correlation with PDAI scores, supporting a correlation of Dsg1 and 3 levels with disease severity. However, while both anti-Dsg3 and -Dsg1 antibody levels demonstrated a steady parallel decline after initiation of rituximab therapy, only anti-Dsg1 antibodies fell to levels below detectability with the progression to remission, while anti-Dsg3 levels remained elevated. This case illustrates the potential key role and clinical benefit of tracking anti-Dsg1 levels to monitor and conceivably predict disease activity in patients with PV. J Drugs Dermatol. 2017;16(2):135-139..


Asunto(s)
Autoanticuerpos/sangre , Desmogleína 1/inmunología , Desmogleína 3/inmunología , Pénfigo/diagnóstico , Adulto , Diagnóstico Diferencial , Progresión de la Enfermedad , Humanos , Estudios Longitudinales , Masculino , Pénfigo/sangre , Pénfigo/inmunología , Índice de Severidad de la Enfermedad
7.
Exp Dermatol ; 25(11): 839-846, 2016 11.
Artículo en Inglés | MEDLINE | ID: mdl-27305362

RESUMEN

This viewpoint highlights major, partly controversial concepts about the pathogenesis of pemphigus. The monopathogenic theory explains intra-epidermal blistering through the "desmoglein (Dsg) compensation" hypothesis, according to which an antibody-dependent disabling of Dsg 1- and/or Dsg 3-mediated cell-cell attachments of keratinocytes (KCs) is sufficient to disrupt epidermal integrity and cause blistering. The multipathogenic theory explains intra-epidermal blistering through the "multiple hit" hypothesis stating that a simultaneous and synchronized inactivation of the physiological mechanisms regulating and/or mediating intercellular adhesion of KCs is necessary to disrupt epidermal integrity. The major premise for a multipathogenic theory is that a single type of autoantibody induces only reversible changes, so that affected KCs can recover due to a self-repair. The damage, however, becomes irreversible when the salvage pathway and/or other cell functions are altered by a partnering autoantibody and/or other pathogenic factors. Future studies are needed to (i) corroborate these findings, (ii) characterize in detail patient populations with non-Dsg-specific autoantibodies, and (iii) determine the extent of the contribution of non-Dsg antibodies in disease pathophysiology.


Asunto(s)
Pénfigo/etiología , Animales , Desmogleínas/inmunología , Humanos
8.
J Drugs Dermatol ; 15(7): 821-9, 2016 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-27391631

RESUMEN

Rituximab, an anti CD20 monoclonal antibody leading to transitory B cell depletion, is used to treat a wide variety of immune system tumors and immune mediated diseases. While most of data supporting the efficacy and safety of rituximab in treating autoimmune patients is focused on the adult population, the utilization of rituximab (RTX) for a wide range of pediatric conditions is also increasing. While there are a number of published case reports, a comprehensive review of the various uses for rituximab in pediatric dermatology is lacking. To better assess the therapeutic role of rituximab in the management of skin disease in children, here we comprehensively document reported cases of use including details regarding specific treatment regimens, efficacy and safety profile. Evaluation of the data supports consideration for the initiation of rituximab at early time points in the treatment ladder, before certain diseases become refractory to conventional treatment.

J Drugs Dermatol. 2016;15(7):821-829.


Asunto(s)
Dermatología/métodos , Factores Inmunológicos/administración & dosificación , Pediatría/métodos , Rituximab/administración & dosificación , Enfermedades de la Piel/tratamiento farmacológico , Niño , Dermatología/tendencias , Quimioterapia Combinada , Humanos , Inmunoglobulinas Intravenosas/administración & dosificación , Inmunoglobulinas Intravenosas/efectos adversos , Factores Inmunológicos/efectos adversos , Pediatría/tendencias , Rituximab/efectos adversos , Rituximab/uso terapéutico , Sepsis/inducido químicamente , Enfermedades de la Piel/diagnóstico , Neoplasias Cutáneas/diagnóstico , Neoplasias Cutáneas/tratamiento farmacológico
9.
Acta Derm Venereol ; 95(1): 86-90, 2015 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-24691863

RESUMEN

Pemphigus vulgaris (PV) is a rare, potentially life threatening, autoimmune blistering skin disease. The International Pemphigus and Pemphigoid Foundation (IPPF) has recently developed a disease registry with the aim to enhance our understanding of autoimmune bullous diseases with the long-term goal of acquiring information to improve patient care. Patients were recruited to the IPPF disease registry through direct mail, e-mail, advertisements, and articles in the IPPF-quarterly, -website, -Facebook webpage, and IPPF Peer Health Coaches to complete a 38-question survey. We present here the initial analysis of detailed clinical information collected on 393 PV patients. We report previously unrecognized gender differences in terms of lesion location, autoimmune comorbidity, and delay in diagnosis. The IPPF disease registry serves as a useful resource and guide for future clinical investigation.


Asunto(s)
Autoinmunidad , Pénfigo , Sistema de Registros , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Comorbilidad , Diagnóstico Tardío , Progresión de la Enfermedad , Femenino , Encuestas Epidemiológicas , Humanos , Masculino , Persona de Mediana Edad , Pénfigo/diagnóstico , Pénfigo/epidemiología , Pénfigo/inmunología , Pénfigo/terapia , Valor Predictivo de las Pruebas , Desarrollo de Programa , Recurrencia , Inducción de Remisión , Factores de Riesgo , Factores Sexuales , Encuestas y Cuestionarios , Factores de Tiempo , Resultado del Tratamiento , Estados Unidos/epidemiología , Adulto Joven
10.
J Drugs Dermatol ; 14(10): 1103-6, 2015 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-26461820

RESUMEN

IMPORTANCE: Paraneoplastic pemphigus (PNP) is routinely diagnosed by the presence of autoantibodies for desmoplakin by indirect immunofluorescence (IIF) on rat bladder epithelium (RBE). IIF on RBE has recently been found to be positive in select cases of other blistering disorders. A new ELISA that detects envoplakin autoantibodies has recently been developed for the diagnosis of PNP. In this study, we measure the specificity of IIF on RBE and compare it to the new ELISA. OBSERVATIONS: We measured the specificity of IIF on RBE to be 86% which is on the lower end of the previously reported specificity of 83% to 98.9%. The ELISA for envoplakin autoantibodies has a technical sensitivity of 100%, diagnostic sensitivity of 83%, and specificity of 91%. CONCLUSIONS AND RELEVANCE: This ELISA for envoplakin autoantibodies is now commercially available and technically easier to perform then the immunoblot. We recommend that this new ELISA serves as a confirmatory test in cases of a positive IIF on RBE given its higher specificity.


Asunto(s)
Ensayo de Inmunoadsorción Enzimática/métodos , Proteínas de la Membrana/inmunología , Síndromes Paraneoplásicos/diagnóstico , Pénfigo/diagnóstico , Precursores de Proteínas/inmunología , Animales , Autoanticuerpos/inmunología , Desmoplaquinas/inmunología , Técnica del Anticuerpo Fluorescente Indirecta/métodos , Humanos , Síndromes Paraneoplásicos/inmunología , Pénfigo/inmunología , Ratas , Estudios Retrospectivos , Sensibilidad y Especificidad
11.
J Drugs Dermatol ; 14(8): 794-800, 2015 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-26267723

RESUMEN

BACKGROUND: Psoriasis is a common but complex chronic inflammatory skin Disease. Array-based studies can help identify therapeutic targets. OBJECTIVE: To reproducibly assess single-gene transcriptional changes in psoriatic skin. METHODS: We evaluated 210 top candidate genes from a first psoriasis study group (population 1), and then confirmed differential expression in a second independent psoriasis study group (population 2). RESULTS: One hundred and thirty-eight differentially expressed genes were replicated in the 2 studies, of which 57 have not previously been reported as associated with psoriasis. This is significantly greater than the 10 expected false positives. Lesional skin vs uninvolved areas showed inflammatory and cell regulation changes. CONCLUSION: Previously undescribed psoriasis-associated genes revealed in this study may provide potential future targets for development and assessment of novel therapeutic agents for psoriasis.


Asunto(s)
Psoriasis/genética , Piel/metabolismo , Transcripción Genética , Perfilación de la Expresión Génica , Humanos , Inflamación/genética , Análisis de Secuencia por Matrices de Oligonucleótidos , Psoriasis/patología , Reproducibilidad de los Resultados , Piel/patología , Regulación hacia Arriba
12.
Nanomedicine ; 11(1): 137-45, 2015 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-25200612

RESUMEN

We present the nanosurgery on the cytoskeleton of live cells using AFM based nanorobotics to achieve adhesiolysis and mimic the effect of pathophysiological modulation of intercellular adhesion. Nanosurgery successfully severs the intermediate filament bundles and disrupts cell-cell adhesion similar to the desmosomal protein disassembly in autoimmune disease, or the cationic modulation of desmosome formation. Our nanomechanical analysis revealed that adhesion loss results in a decrease in cellular stiffness in both cases of biochemical modulation of the desmosome junctions and mechanical disruption of intercellular adhesion, supporting the notion that intercellular adhesion through intermediate filaments anchors the cell structure as focal adhesion does and that intermediate filaments are integral components in cell mechanical integrity. The surgical process could potentially help reveal the mechanism of autoimmune pathology-induced cell-cell adhesion loss as well as its related pathways that lead to cell apoptosis.


Asunto(s)
Filamentos Intermedios/química , Queratinocitos/citología , Nanomedicina/métodos , Robótica , Cirugía Asistida por Computador/métodos , Apoptosis , Enfermedades Autoinmunes/metabolismo , Cationes , Adhesión Celular , Línea Celular , Citoesqueleto/metabolismo , Desmosomas/metabolismo , Humanos , Microscopía de Fuerza Atómica , Nanoestructuras , Estrés Mecánico
13.
Prev Med ; 69: 8-12, 2014 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-25150382

RESUMEN

OBJECTIVE: Evidence for the effect of non-steroidal anti-inflammatory drugs (NSAIDs) on non-melanoma skin cancer (NMSC) risk is inconsistent. We prospectively examined whether regular, inconsistent, or no/low-use of NSAIDs is associated with lower NMSC risk among 54,728 postmenopausal Caucasian women in the Women's Health Initiative Observational Study enrolled between 1993 and 1998. METHODS: Logistic regression models were used to assess odds of NMSC after adjusting for skin type, sun exposure history and indication for NSAID use. RESULTS: There were 7652 incident cases of NMSC (median follow-up: 6.9years). There was no association between regular NSAID-use and NMSC risk relative to no/low-users. However, in a subgroup analysis of 5325 women with a history of skin cancer (incident NMSC: 1897), odds of NMSC were lower among regular NSAID users whether <5years (OR 0.82, 95% CI: 0.70-0.95) or ≥5years (OR 0.82, 95% CI: 0.69-0.98) of use compared to no/low-users. Inconsistent NSAID use and acetaminophen use were not associated with NMSC risk. CONCLUSION: Overall, NSAID use was not associated with NMSC risk. However, in women with a history of skin cancer, regular NSAID use was associated with 18% lower odds of NMSC. Future studies on potential chemopreventative effects of NSAIDs should focus on subjects with prior history of NMSC.


Asunto(s)
Antiinflamatorios no Esteroideos/uso terapéutico , Neoplasias Cutáneas/prevención & control , Acetaminofén/efectos adversos , Anciano , Antiinflamatorios no Esteroideos/efectos adversos , Aspirina/efectos adversos , Aspirina/uso terapéutico , Femenino , Humanos , Modelos Logísticos , Persona de Mediana Edad , Estudios Prospectivos , Factores de Riesgo , Neoplasias Cutáneas/inducido químicamente , Encuestas y Cuestionarios , Población Blanca , Salud de la Mujer
14.
J Drugs Dermatol ; 13(10): 1225-30, 2014 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-25607557

RESUMEN

Pemphigus vulgaris is a chronic autoimmune blistering disorder of the skin. As with many autoimmune diseases, a female predominance in pemphigus vulgaris is well established. The genetic and physiological basis for this gender bias is not well understood. Moreover, it is unclear whether the affect of gender extends beyond disease susceptibility to influence disease presentation. To address this issue, we performed a comprehensive analysis of 72 male and 125 female pemphigus vulgaris patients across a set of defined demographic (HLA type, ethnicity) and clinical (age at disease onset, anti-desmoglein antibody levels, site of lesions, and history of autoimmune disease) factors. We find that male patients are more likely to present with disease onset before age 40 than females. Additionally, we find that males have increased cutaneous involvement and display greater co-expression of anti-Dsg1 and anti-Dsg3 antibodies, while females tend to have mucosal predominance and stronger personal and family histories of autoimmunity. We do not find any differences in the distribution of HLA type or ethnicity between male and female pemphigus vulgaris patients. Our findings establish that gender does influence disease presentation in pemphigus vulgaris, supporting a role for genetic and hormonal factors in immune dysregulation and perpetuation of the autoimmune phenotype.


Asunto(s)
Antígenos HLA/inmunología , Pénfigo/patología , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pénfigo/inmunología , Estudios Retrospectivos , Factores Sexuales
15.
J Drugs Dermatol ; 13(4): 409-13, 2014 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-24719059

RESUMEN

Alopecia areata (AA) is a common, non-scarring, autoimmune hair-loss disorder with a complex genetic and environmental etiology. A higher incidence rate of AA in the female population is well described. It is unclear why females are more likely to be diagnosed with AA and what, if any, differences in disease phenotype exist between males and females. The identification of gender specific characteristics of disease may help clinical management and patient education in cases of AA. Accordingly, we recruited 481 North-American Caucasian AA patients (336 female, 145 male) to assess age of onset, autoimmune and atopic co-morbidity, nail involvement, family history of AA and autoimmune disease, and disease subtype. There was a female predominance (female to male ratio 2.3:1) in this AA study population. We found that male AA patients are more likely to be diagnosed in childhood (age <10 years, P= 0.067) and have a family history of AA (P= 0.004). On the other hand, female AA patients are more likely to be diagnosed in adolescence (age 10-20 years, P= 0.083), have co-morbid nail involvement (P= 0.0257), and have concomitant autoimmune disease (P= 0.014), particularly thyroid disease (P= 0.058). The clinical implications of disease heterogeneity between males and females remains to be determined.


Asunto(s)
Alopecia Areata/epidemiología , Alopecia Areata/genética , Enfermedades Autoinmunes/epidemiología , Enfermedades de la Uña/epidemiología , Adolescente , Adulto , Edad de Inicio , Anciano , Anciano de 80 o más Años , Alopecia Areata/clasificación , Enfermedades Autoinmunes/genética , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Persona de Mediana Edad , América del Norte/epidemiología , Factores Sexuales , Tiroiditis Autoinmune/epidemiología , Población Blanca , Adulto Joven
16.
bioRxiv ; 2024 Oct 13.
Artículo en Inglés | MEDLINE | ID: mdl-39416220

RESUMEN

Pemphigus vulgaris (PV) is a blistering autoimmune disease that affects the skin and mucous membranes. The precise mechanisms by which PV antibodies induce a complete loss of cohesion of keratinocytes are not fully understood. But it is accepted that the process starts with antibody binding to desmosomal targets which leads to its disassembly and subsequent structural changes to cell-cell adhesions. In vitro immunofluorescence imaging of desmosome molecules has been used to characterize this initial phase, often qualitatively. However, there remains an untapped potential of image analysis in providing us more in-depth knowledge regarding ultrastructural changes after antibody binding. Currently, there is no such effort to establish a quantitative framework from immunofluorescence images in PV pathology. We take on this effort here in a comprehensive study to examine the effects of antibodies on key adhesion molecules and the cytoskeletal network, aiming to establish a correlation of ultrastructural changes in cell-cell adhesion with antibody pathogenicity. Specifically, we introduced a data-driven approach to quantitatively evaluate perturbations in adhesion molecules, including desmoglein 3, E-cadherin, as well as the cytoskeleton, following antibody treatment. We identify distinct immunofluorescence imaging signatures that mark the impact of antibody binding on the remodeling of the adhesion molecules and introduce a pathogenicity score to compare the relative effects of different antibodies. From this analysis, we showed that the biophysical response of keratinocytes to distinct PV associated antibodies is highly specific, allowing for accurate prediction of their pathogenicity. For instance, the high pathogenicity scores of the PVIgG and AK23 antibodies show strong agreement with their reported PV pathology. Our data-driven approach offers a more detailed framework for the action of autoantibodies in pemphigus and has the potential to pave the way for the development of effective novel diagnostic methods and therapeutic strategies.

17.
bioRxiv ; 2024 May 06.
Artículo en Inglés | MEDLINE | ID: mdl-38766211

RESUMEN

Binding of autoantibodies to keratinocyte surface antigens, primarily desmoglein 3 (Dsg3) of the desmosomal complex, leads to the dissociation of cell-cell adhesion in the blistering disorder pemphigus vulgaris (PV). After the initial disassembly of desmosomes, cell-cell adhesions actively remodel in association with the cytoskeleton and focal adhesions. Growing evidence highlights the role of adhesion mechanics and mechanotransduction at cell-cell adhesions in this remodeling process, as their active participation may direct autoimmune pathogenicity. However, a large part of the biophysical transformations after antibody binding remains underexplored. Specifically, it is unclear how tension in desmosomes and cell-cell adhesions changes in response to antibodies, and how the altered tensional states translate to cellular responses. Here, we showed a tension loss at Dsg3 using fluorescence resonance energy transfer (FRET)-based tension sensors, a tension loss at the entire cell-cell adhesion, and a potentially compensatory increase in junctional traction force at cell-extracellular matrix adhesions after PV antibody binding. Further, our data indicate that this tension loss is mediated by the inhibition of RhoA at cell-cell contacts, and the extent of RhoA inhibition may be crucial in determining the severity of pathogenicity among different PV antibodies. More importantly, this tension loss can be partially restored by altering actomyosin based cell contractility. Collectively, these findings provide previously unattainable details in our understanding of the mechanisms that govern cell-cell interactions under physiological and autoimmune conditions, which may open the window to entirely new therapeutics aimed at restoring physiological balance to tension dynamics that regulates the maintenance of cell-cell adhesion.

18.
Cancer ; 119(8): 1562-9, 2013 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-23483536

RESUMEN

BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) have been associated with decreased risk of gastric, colorectal, and breast cancer. However, the impact of NSAIDs on the risk of melanoma has been inconsistent. The authors evaluated the association between NSAID use and cutaneous melanoma risk in the Women's Health Initiative (WHI) Observational Study (OS). METHODS: At study entry, use of aspirin (acetylsalicylic acid [ASA]) and nonaspirin NSAIDs was assessed among 59,806 postmenopausal Caucasian women ages 50 to 79 years. Cox proportional hazards models were constructed after adjusting for participant skin type, sun exposure history, and medical indications for NSAID use among other confounders. RESULTS: During a median follow-up of 12 years, 548 incident melanomas were confirmed by medical review. Women who used ASA had a 21% lower risk of melanoma (hazard ratio, 0.79; 95% confidence interval, 0.63-0.98) relative to nonusers. Increased duration of ASA use (<1 year, 1-4 years, and ≥ 5 years) was associated with an 11% lower risk of melanoma for each categorical increase (Ptrend = .01), and women with ≥ 5 years of use had a 30% lower melanoma risk (hazard ratio, 0.70; 95% confidence interval, 0.55-0.94). In contrast, use of non-ASA NSAIDs and acetaminophen were not associated with melanoma risk. CONCLUSIONS: Postmenopausal women who used ASA had a significantly lower risk of melanoma, and longer duration of ASA use was associated with greater protection. Although this study was limited by the observational design and self-report of NSAID use, the findings suggest that ASA may have a chemopreventive effect against the development of melanoma and warrant further clinical investigation.


Asunto(s)
Antiinflamatorios no Esteroideos/administración & dosificación , Aspirina/administración & dosificación , Melanoma/epidemiología , Población Blanca/estadística & datos numéricos , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Femenino , Humanos , Incidencia , Melanoma/etnología , Melanoma/prevención & control , Persona de Mediana Edad , Posmenopausia , Modelos de Riesgos Proporcionales , Factores de Riesgo , Neoplasias Cutáneas/epidemiología , Neoplasias Cutáneas/etnología , Neoplasias Cutáneas/prevención & control , Estados Unidos/epidemiología
19.
Exp Dermatol ; 22(2): 108-12, 2013 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-23362868

RESUMEN

Non-classical human leucocyte antigen-E (HLA-E) mediates natural killer and CD8+ T-cell activity, suggesting a role in the regulation of autoimmunity. HLA-E*0103X/*0103X has been associated with Behcet's disease and HLA-E *0101/*0103X with childhood onset diabetes. We investigated HLA-E allele status in 52 Caucasian and Ashkenazi Jewish Pemphigus vulgaris (PV) patients and 51 healthy controls by restriction fragment length polymorphism-polymerase chain reaction and amplification refractory mutation system. Associations were determined via chi-square test, Fisher's exact test and logistical regression analysis. HLA-E outcomes included presumed homozygous *0101/*0101 or *0103X/*0103X genotype status or *0101/*0103X heterozygous status. PV did not significantly associate with either *0101/*0101 or *0101/*0103X genotypes. HLA-E*0103X/*0103X (presumed homozygote) is significantly increased in patients with PV versus controls (P = 0.0146, OR = 3.730, 95%CI = 1.241-11.213). Our data provide the first evidence that HLA-E*0103X is a marker for genetic risk in PV.


Asunto(s)
Predisposición Genética a la Enfermedad , Antígenos de Histocompatibilidad Clase I/genética , Pénfigo/genética , Polimorfismo Genético , Adulto , Anciano , Alelos , Linfocitos T CD8-positivos/metabolismo , Estudios de Casos y Controles , Codón , Femenino , Frecuencia de los Genes , Genotipo , Heterocigoto , Homocigoto , Humanos , Masculino , Persona de Mediana Edad , Pénfigo/etnología , Reacción en Cadena de la Polimerasa , Polimorfismo de Longitud del Fragmento de Restricción , Antígenos HLA-E
20.
Genomics ; 100(1): 18-26, 2012 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-22584065

RESUMEN

There are major gaps in our knowledge regarding the exact mechanisms and genetic basis of psoriasis. To investigate the pathogenesis of psoriasis, gene expression in 10 skin (5 lesional, 5 nonlesional) and 11 blood (6 psoriatic, 5 nonpsoriatic) samples were examined using Affymetrix HG-U95A microarrays. We detected 535 (425 upregulated, 110 downregulated) DEGs in lesional skin at 1% false discovery rate (FDR). Combining nine microarray studies comparing lesional and nonlesional psoriatic skin, 34.5% of dysregulated genes were overlapped in multiple studies. We further identified 20 skin and 2 blood associated transcriptional "hot spots" at specified genomic locations. At 5% FDR, 11.8% skin and 10.4% blood DEGs in our study mapped to one of the 12 PSORS loci. DEGs that overlap with PSORS loci may offer prioritized targets for downstream genetic fine mapping studies. Novel DEG "hot spots" may provide new targets for defining susceptibility loci in future studies.


Asunto(s)
Perfilación de la Expresión Génica/métodos , Regulación de la Expresión Génica/genética , Psoriasis/sangre , Psoriasis/genética , Piel/metabolismo , Adulto , Anciano , Estudios de Casos y Controles , Femenino , Sitios Genéticos/genética , Humanos , Masculino , Persona de Mediana Edad , Análisis de Secuencia por Matrices de Oligonucleótidos/métodos , Psoriasis/patología , ARN Mensajero/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Piel/química , Piel/patología
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