RESUMEN
Dowling Degos disease (DDD) is a rare autosomal dominant genodermatosis characterized by acquired, slowly progressive reticulated pigmented lesions primarily involving flexural skin areas. Mutations in KRT5, POGLUT-1 and POFUT-1 genes have been associated with DDD, and loss-of-function mutations in PSENEN, a subunit of the gamma-secretase complex, were found in patients presenting with DDD or DDD comorbid with hidradenitis suppurativa (HS). A nonsense mutation in NCSTN, another subunit of the gamma-secretase, was already described in a patient suffering from HS and DDD but whether NCSTN could be considered a novel gene for DDD is still debated. Here, we enrolled a four-generation family with HS and DDD. Through Whole Exome Sequencing (WES) we identified a novel nonsense mutation in the NCSTN gene in all the affected family members. To study the impact of this variant, we isolated outer root sheath cells from patients' hair follicles. We showed that this variant leads to a premature stop codon, activates a nonsense-mediated mRNA decay, and causes NCSTN haploinsufficiency in affected individuals. In fact, cells treated with gentamicin, a readthrough agent, had the NCSTN levels corrected. Moreover, we observed that this haploinsufficiency also affects other subunits of the gamma-secretase complex, possibly causing DDD. Our findings clearly support NCSTN as a novel DDD gene and suggest carefully investigating this co-occurrence in HS patients carrying a mutation in the NCSTN gene.
Asunto(s)
Hidradenitis Supurativa , Papulosis Atrófica Maligna , Humanos , Secretasas de la Proteína Precursora del Amiloide/genética , Codón sin Sentido , Hidradenitis Supurativa/complicaciones , Hidradenitis Supurativa/genética , Proteínas de la Membrana/genética , Mutación , Factores de Transcripción/genéticaRESUMEN
BACKGROUND: The genetics of syndromic hidradenitis suppurativa (HS), an immune-mediated condition associated with systemic comorbidities such as inflammatory bowel diseases and arthritis, has not been completely elucidated. OBJECTIVE: To describe clinical features and genetic signature of patients with the main syndromic HS forms, i.e., PASH, PAPASH, and PASH/SAPHO overlapping. METHODS: Whole-exome sequencing (WES) approach was performed in ten patients with syndromic HS. RESULTS: Three clinical settings have been identified based on presence/absence of gut and joint inflammation. Four PASH patients who had also gut inflammation showed three different variants in NOD2 gene, two variants in OTULIN, and a variant in GJB2, respectively. Three PAPASH and three PASH/SAPHO overlapping patients who had also joint inflammation showed two different variants in NCSTN, one in WDR1 and PSTPIP1, and two variants in NLRC4, one of whom was present in a patient with a mixed phenotype characterized by gut and joint inflammation. LIMITATIONS: Limited number of patients that can be counterbalanced by the rarity of syndromic HS. CONCLUSION: Syndromic HS can be considered as a polygenic autoinflammatory condition; currently WES is a diagnostic tool allowing more accurate genotype-phenotype correlation.
Asunto(s)
Artritis , Hidradenitis Supurativa , Piodermia Gangrenosa , Estudios de Asociación Genética , Hidradenitis Supurativa/diagnóstico , Humanos , Inflamación , Piodermia Gangrenosa/diagnóstico , Secuenciación del ExomaRESUMEN
We generated a new humanized mouse model to study HLA-restricted immune responses. For this purpose, we created unique murine hosts by enforcing the expression of human SIRPα by murine phagocytes in murine MHC-deficient HLA-transgenic alymphoid hosts, an approach that allowed the immune reconstitution of nonpermissive mice following injection of human hematopoietic stem cells. We showed that these mouse/human chimeras were able to generate HLA-restricted responses to immunization. These new humanized mice may offer attractive models to study immune responses to human diseases, such as HIV and EBV infections, as well as to assay new vaccine strategies.
Asunto(s)
Antígenos HLA/administración & dosificación , Antígenos HLA/inmunología , Trasplante de Células Madre Hematopoyéticas/métodos , Quimera por Radiación/inmunología , Animales , Animales Recién Nacidos , Antígenos de Diferenciación/administración & dosificación , Antígenos de Diferenciación/sangre , Antígenos de Diferenciación/genética , Supervivencia Celular/genética , Supervivencia Celular/inmunología , Modelos Animales de Enfermedad , Femenino , Antígenos HLA/genética , Humanos , Ratones , Ratones de la Cepa 129 , Ratones Endogámicos C57BL , Ratones Endogámicos NOD , Ratones Noqueados , Ratones SCID , Ratones Transgénicos , Técnicas de Cultivo de Órganos , Quimera por Radiación/genética , Receptores Inmunológicos/administración & dosificación , Receptores Inmunológicos/sangre , Receptores Inmunológicos/genéticaRESUMEN
Host-pathogen interactions are generally initiated by host recognition of microbial components or danger signals triggered by microbial invasion. This recognition involves germline-encoded microbial sensors or pattern-recognition receptors (PRRs). By studying the way in which natural selection has driven the evolution of these microbial sensors in humans, we can identify genes playing an essential role and distinguish them from other, more redundant genes. We characterized the sequence diversity of the NOD-like receptor family, including the NALP and NOD/IPAF subfamilies, in various populations worldwide and compared this diversity with that of other PRR families, such as Toll-like receptors (TLRs) and RIG-I-like receptors (RLRs). We found that most NALPs had evolved under strong selective constraints, suggesting that their functions are essential and possibly much broader than previously thought. Conversely, most NOD/IPAF subfamily members were subject to more relaxed selective constraints, suggesting greater redundancy. Furthermore, some NALP genes, including NLRP1, NLRP14, and CIITA, were found to have evolved adaptively. We identified those variants conferring a selective advantage on some human populations as the most likely targets of positive selection. More generally, the strength of selection differed considerably between the major families of microbial sensors. Endosomal TLRs and most NALPs were found to evolve under stronger purifying selection than most NOD/IPAF subfamily members and cell-surface TLRs and RLRs, suggesting some degree of redundancy in the signaling pathways triggered by these molecules. This study provides novel perspectives and experimentally testable hypotheses concerning the relative biological relevance of the various families of microbial sensors in humans.
Asunto(s)
Evolución Molecular , Inmunidad Innata/genética , Receptores de Reconocimiento de Patrones/genética , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras de Señalización CARD/genética , Proteínas de Unión al Calcio/genética , Citosol/metabolismo , Proteína 58 DEAD Box , ARN Helicasas DEAD-box/genética , Variación Genética , Humanos , Polimorfismo de Nucleótido Simple , Receptores Inmunológicos , Selección Genética , Receptores Toll-Like/genéticaRESUMEN
Lactotransferrin, also known as lactoferrin, is an iron binding glycoprotein that displays antiviral activity against many different infectious agents, including human immunodeficiency virus (HIV)-1. Lactotransferrin is present in the breast milk and in the female genitourinary mucosa and it has been hypothesised as a possible candidate to prevent mother-to-child HIV-1 transmission. To verify if two functional polymorphisms, Thr29Ala and Arg47Lys, in the lactotransferrin encoding gene (LTF) could affect HIV-1 infection and vertical transmission, a preliminary association study was performed in 238 HIV-1 positive and 99 HIV-1 negative children from Brazil, Italy, Africa and India. No statistically significant association for the Thr29Ala and Arg47Lys LTF polymorphisms and HIV-1 susceptibility in the studied populations was found. Additionally LTF polymorphisms frequencies were compared between the four different ethnic groups.
Asunto(s)
Síndrome de Inmunodeficiencia Adquirida/transmisión , Predisposición Genética a la Enfermedad/genética , VIH-1/genética , Transmisión Vertical de Enfermedad Infecciosa , Lactoferrina/genética , Polimorfismo de Nucleótido Simple/genética , Síndrome de Inmunodeficiencia Adquirida/etnología , Adolescente , Brasil/etnología , Niño , Estudios de Cohortes , Etnicidad/genética , Femenino , Frecuencia de los Genes/genética , Técnicas de Genotipaje , Humanos , India/etnología , Recién Nacido , Italia/etnología , Masculino , Reacción en Cadena en Tiempo Real de la Polimerasa , Estudios Retrospectivos , Zimbabwe/etnologíaRESUMEN
ß-Defensins are antimicrobial peptides of the innate immune system produced in the skin by various stimuli, including proinflammatory cytokines, bacterial infection, and exposure to UV radiation (UVR). In this study we demonstrate that the UVR-inducible antimicrobial peptide murine ß-defensin-14 (mBD-14) switches CD4(+)CD25(-) T cells into a regulatory phenotype by inducing the expression of specific markers like Foxp3 and CTLA-4. This is functionally relevant because mBD-14-treated T cells inhibit sensitization upon adoptive transfer into naive C57BL/6 mice. Accordingly, injection of mBD-14, comparable to UVR, suppresses the induction of contact hypersensitivity and induces Ag-specific regulatory T cells (Tregs). Further evidence for the ability of mBD-14 to induce Foxp3(+) T cells is provided using DEREG (depletion of Tregs) mice in which Foxp3-expressing cells can be depleted by injecting diphtheria toxin. mBD-14 does not suppress sensitization in IL-10 knockout mice, suggesting involvement of IL-10 in mBD-14-mediated immunosuppression. However, unlike UVR, mBD-14 does not appear to mediate its immunosuppressive effects by affecting dendritic cells. Accordingly, UVR-induced immunosuppression is not abrogated in mBD-14 knockout mice. Together, these data suggest that mBD-14, like UVR, has the capacity to induce Tregs but does not appear to play a major role in UVR-induced immunosuppression. Through this capacity, mBD-14 may protect the host from microbial attacks on the one hand, but tame T cell-driven reactions on the other hand, thereby enabling an antimicrobial defense without collateral damage by the adaptive immune system.
Asunto(s)
Diferenciación Celular/inmunología , Linfocitos T Reguladores/citología , Linfocitos T Reguladores/inmunología , beta-Defensinas/administración & dosificación , beta-Defensinas/fisiología , Traslado Adoptivo , Animales , Antígeno CTLA-4/biosíntesis , Diferenciación Celular/genética , Diferenciación Celular/efectos de la radiación , Dinitrofluorobenceno/administración & dosificación , Femenino , Factores de Transcripción Forkhead/biosíntesis , Inmunofenotipificación , Inyecciones Intravenosas , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neuropilinas/biosíntesis , Linfocitos T Reguladores/efectos de la radiación , Rayos Ultravioleta , beta-Defensinas/deficienciaRESUMEN
Luciferase reporter assays (LRAs) are widely used to assess the activity of specific signal transduction pathways. Although powerful, rapid and convenient, this technique can also generate artifactual results, as revealed for instance in the case of high throughput screens of inhibitory molecules. Here we demonstrate that the previously reported inhibitory effect of the Nod-like receptor (NLR) protein NLRX1 on NF-κB- and type I interferon-dependent pathways in LRAs was a nonspecific consequence of the overexpression of the NLRX1 leucine-rich repeat (LRR) domain. By comparing luciferase activity and luciferase gene expression using quantitative PCR from the same samples, we showed that NLRX1 inhibited LRAs in a post-transcriptional manner. In agreement, NLRX1 also repressed LRAs if luciferase was expressed under the control of a constitutive promoter, although the degree of inhibition by NLRX1 seemed to correlate with the dynamic inducibility of luciferase reporter constructs. Similarly, we observed that overexpression of another NLR protein, NLRC3, also resulted in artifactual inhibition of LRAs; thus suggesting that the capacity to inhibit LRAs at a post-transcriptional level is not unique to NLRX1. Finally, we demonstrate that host type I interferon response to Sendai virus infection was normal in NLRX1-silenced human HEK293T cells. Our results thus highlight the fact that LRAs are not a reliable technique to assess the inhibitory function of NLRs, and possibly other overexpressed proteins, on signal transduction pathways.
Asunto(s)
Genes Reporteros , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Luciferasas/biosíntesis , Proteínas Mitocondriales/metabolismo , Células HEK293 , Humanos , Péptidos y Proteínas de Señalización Intercelular/genética , Luciferasas/genética , Proteínas Mitocondriales/genética , FN-kappa B/genética , FN-kappa B/metabolismo , Estructura Terciaria de Proteína , Proteínas Recombinantes/biosíntesis , Proteínas Recombinantes/genética , Transducción de Señal/genéticaRESUMEN
Low monocyte (m)HLA-DR expression is associated with mortality in sepsis. G-286A∗rs3087456 polymorphism in promoter III of HLA class II transactivator (CIITA), the master regulator of HLA, has been associated with autoimmune diseases but its role in sepsis has never been demonstrated. In 203 patients in septic shock, GG genotype was associated with 28-day mortality and mHLA-DR remained low whereas it increased in patients with AA or AG genotype. In ex vivo cells, mHLA-DR failed to augment in GG in comparison with AG or AA genotype on exposure to IFN-γ. Promoter III transcript levels were similar in control monocytes regardless of genotype and exposure to IFN-γ. Promoter III activity was decreased in GG genotype in monocyte cell line but restored after stimulation with IFN-γ. Hereby, we demonstrated that G-286A∗rs3087456 significantly impact mHLA-DR expression in patients with septic shock in part through CIITA promoter III activity, that can be rescued using IFN-γ.
RESUMEN
Hidradenitis suppurativa (HS) is a recurrent inflammatory skin disease with a complex etiopathogenesis whose treatment poses a challenge in the clinical practice. Here, we present a novel integrated pipeline produced by the European consortium BATMAN (Biomolecular Analysis for Tailored Medicine in Acne iNversa) aimed at investigating the molecular pathways involved in HS by developing new diagnosis algorithms and building cellular models to pave the way for personalized treatments. The objectives of our european Consortium are the following: (1) identify genetic variants and alterations in biological pathways associated with HS susceptibility, severity and response to treatment; (2) design in vitro two-dimensional epithelial cell and tri-dimensional skin models to unravel the HS molecular mechanisms; and (3) produce holistic health records HHR to complement medical observations by developing a smartphone application to monitor patients remotely. Dermatologists, geneticists, immunologists, molecular cell biologists, and computer science experts constitute the BATMAN consortium. Using a highly integrated approach, the BATMAN international team will identify novel biomarkers for HS diagnosis and generate new biological and technological tools to be used by the clinical community to assess HS severity, choose the most suitable therapy and follow the outcome.
Asunto(s)
Dermatitis , Hidradenitis Supurativa , Biomarcadores , Dermatitis/complicaciones , Hidradenitis Supurativa/diagnóstico , Hidradenitis Supurativa/genética , Hidradenitis Supurativa/terapia , Salud Holística , Humanos , PielRESUMEN
Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease with a multifactorial aetiology that involves a strict interplay between genetic factors, immune dysregulation and lifestyle. Familial forms represent around 40% of total HS cases and show an autosomal dominant mode of inheritance of the disease. In this study, we conducted a whole-exome sequence analysis on an Italian family of 4 members encompassing a vertical transmission of HS. Focusing on rare damaging variants, we identified a rare insertion of one nucleotide (c.225dupA:p.A76Sfs*21) in the DCD gene encoding for the antimicrobial peptide dermcidin (DCD) that was shared by the proband, his affected father and his 11-years old daughter. Since several transcriptome studies have shown a significantly decreased expression of DCD in HS skin, we hypothesised that the identified frameshift insertion was a loss-of-function mutation that might be associated with HS susceptibility in this family. We thus confirmed by mass spectrometry that DCD levels were diminished in the affected members and showed that the antimicrobial activity of a synthetic DCD peptide resulting from the frameshift mutation was impaired. In order to define the consequences related to a decrease in DCD activity, skin microbiome analyses of different body sites were performed by comparing DCD mutant and wild type samples, and results highlighted significant differences between the groins of mutated and wild type groups. Starting from genetic analysis conducted on an HS family, our findings showed, confirming previous transcriptome results, the potential role of the antimicrobial DCD peptide as an actor playing a crucial part in the etio-pathogenesis of HS and in the maintenance of the skin's physiological microbiome composition; so, we can hypothesise that DCD could be used as a novel target for personalised therapeutic approach.
Asunto(s)
Antiinfecciosos , Dermcidinas , Hidradenitis Supurativa , Niño , Humanos , Antiinfecciosos/metabolismo , Hidradenitis Supurativa/genética , Hidradenitis Supurativa/metabolismo , Mutación , Péptidos/genética , Péptidos/metabolismo , Piel/metabolismo , Masculino , FemeninoRESUMEN
Toll-like receptors (TLRs) are considered an essential component of the innate immune system, initiating inflammatory responses following infection of the host. Humans have 10 functional TLRs, differing in their subcellular distributions and the microbial agonists they sense. The phylogenetically conserved TLR1-2-6 family is unique in that TLR1 and TLR6 form heterodimers with TLR2 to mediate signalling in response to agonists. Epidemiological genetic studies have identified several TLR variants that appear to influence susceptibility to infectious diseases, but the functional consequences of which remain largely unknown. Here, we assessed the functional impact of the TLR1-2-6 variants with altered amino acid sequences segregating naturally in the human population. We used an NF-κB reporter assay in TLR-transfected human embryonic kidney 293T cells stimulated with the corresponding TLR agonists. We found that among the 41 naturally occurring variants with amino acid alterations identified in the TLR1-2-6 family, 14 of them (five TLR1, four TLR2, and five TLR6 variants) displayed marked impairment of NF-κB activation. Most of these variants are present at very low population frequencies and are population-specific. These observations suggest that rare, nonsynonymous TLR mutations are likely to have deleterious effects on immune responses and may therefore contribute to complex susceptibility to infection at the population level.
Asunto(s)
Variación Genética , Receptor Toll-Like 1/genética , Receptor Toll-Like 2/genética , Receptor Toll-Like 6/genética , Evolución Molecular , Células HEK293 , Humanos , Mutación/genética , Población/genética , Receptor Toll-Like 1/inmunología , Receptor Toll-Like 2/inmunología , Receptor Toll-Like 6/inmunologíaRESUMEN
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive and resistant cancer with no available effective therapy. We have previously demonstrated that nucleolin targeting by N6L impairs tumor growth and normalizes tumor vessels in PDAC mouse models. Here, we investigated new pathways that are regulated by nucleolin in PDAC. We found that N6L and nucleolin interact with ß-catenin. We found that the Wnt/ß-catenin pathway is activated in PDAC and is necessary for tumor-derived 3D growth. N6L and nucleolin loss of function induced by siRNA inhibited Wnt pathway activation by preventing ß-catenin stabilization in PDAC cells. N6L also inhibited the growth and the activation of the Wnt/ß-catenin pathway in vivo in mice and in 3D cultures derived from MIA PaCa2 tumors. On the other hand, nucleolin overexpression increased ß-catenin stabilization. In conclusion, in this study, we identified ß-catenin as a new nucleolin interactor and suggest that the Wnt/ß-catenin pathway could be a new target of the nucleolin antagonist N6L in PDAC.
RESUMEN
Hidradenitis Suppurativa (HS) is a severe inflammatory pathology of the skin characterized by chronic recurrent inflamed lesions, nodules, sinus tracts and abscesses usually manifests after puberty, which involves scalp, neck, axillae, perineum and infra-mammary areas. Nowadays treatment options range from short or long courses of antibiotics, anti-inflammatory and biologic drugs, to surgery. Other suggested treatments consider the employment of laser devices, mainly microsurgical lasers (such as CO2 and intense pulsed lasers) and photodynamic therapy. This review explores the potential use of photobiomodulation (PBM), already used for the treatment of other skin conditions, such as acne, hypertrophic scars, wrinkles, and burns, as potential novel therapy for HS. PBM has been reported to have beneficial effects on promoting wound healing, angiogenesis, vasodilation, and relieving from pain and inflammation, as recently demonstrated in an in-vitro model mimicking HS disease. In addition, PBM, specifically set at the blue wavelength, has been recently reported as exerting an anti-bacterial activity. Therefore, considering all these PBM features especially its ability to decrease pain and inflammation and to lead to faster wound healing, thus improving patients' quality of life, we hypothesize its employment as adjuvant third line treatment for the management of HS both in young and adult patients.
Asunto(s)
Hidradenitis Supurativa/terapia , Terapia por Luz de Baja Intensidad/métodos , Calidad de Vida , Antibacterianos/administración & dosificación , Antiinflamatorios/administración & dosificación , Productos Biológicos/administración & dosificación , Hidradenitis Supurativa/fisiopatología , Humanos , Terapia por Láser/métodos , Fotoquimioterapia/métodos , Cicatrización de HeridasRESUMEN
BACKGROUND: Diagnosis of pyoderma gangrenosum, acne and hidradenitis suppurativa (PASH) and pyogenic arthritis, pyoderma gangrenosum, acne, and hidradenitis suppurativa (PAPASH) patients, in spite of recently identified genetic variations, is just clinical, since most patients do not share the same mutations, and the mutations themselves are not informative of the biological pathways commonly disrupted in these patients. OBJECTIVE: To reveal genetic changes more closely related to PASH and PAPASH etiopathogenesis, identifying novel common pathways involved in these diseases. METHODS: Cohort study on PASH (n = 4) and PAPASH (n = 1) patients conducted using whole exome sequencing (WES) approach and a novel bioinformatic pipeline aimed at discovering potentially candidate genes selected from density mutations and involved in pathways relevant to the disease. RESULTS: WES results showed that patients presented 90 genes carrying mutations with deleterious and/or damage impact: 12 genes were in common among the 5 patients and bared 237 ns ExonVar (54 and 183 in homozygosis and heterozygosis, respectively). In the pathway enrichment analysis, only 10 genes were included, allowing us to retrieve 4 pathways shared by all patients: (1) Vitamin D metabolism, (2) keratinization, (3) formation of the cornified envelope and (4) steroid metabolism. Interestingly, all patients had vitamin D levels lower than normal, with a mean value of 10 ng/mL. CONCLUSION: Our findings, through a novel strategy for analysing the genetic background of syndromic HS patients, suggested that vitamin D metabolism dysfunctions seem to be crucial in PASH and PAPASH pathogenesis. Based on low vitamin D serum levels, its supplementation is envisaged.
Asunto(s)
Acné Vulgar/diagnóstico , Artritis Infecciosa/diagnóstico , Secuenciación del Exoma , Hidradenitis Supurativa/diagnóstico , Piodermia Gangrenosa/diagnóstico , Piel/patología , Vitamina D/metabolismo , Acné Vulgar/genética , Acné Vulgar/metabolismo , Acné Vulgar/patología , Adolescente , Adulto , Artritis Infecciosa/genética , Artritis Infecciosa/metabolismo , Artritis Infecciosa/patología , Biología Computacional , Femenino , Estudios de Seguimiento , Hidradenitis Supurativa/genética , Hidradenitis Supurativa/metabolismo , Hidradenitis Supurativa/patología , Humanos , Queratinocitos/patología , Masculino , Piodermia Gangrenosa/genética , Piodermia Gangrenosa/metabolismo , Piodermia Gangrenosa/patología , Piel/citología , Síndrome , Adulto JovenRESUMEN
Hidradenitis suppurativa (HS) is a chronic, relapsing, inflammatory skin disease. HS appears to be a primary abnormality in the pilosebaceous-apocrine unit. In this work, we characterized hair follicle stem cells (HFSCs) isolated from HS patients and more precisely the outer root sheath cells (ORSCs). We showed that hair follicle cells from HS patients had an increased number of proliferating progenitor cells and lost quiescent stem cells. Remarkably, we also showed that the progression of replication forks was altered in ORSCs from hair follicles of HS patients, leading to activation of the ATR/CHK1 pathway. These alterations were associated with an increased number of micronuclei and with the presence of cytoplasmic ssDNA, leading to the activation of the IFI16/STING pathway and the production of type I IFNs. This mechanistic analysis of the etiology of HS in the HFSC compartment establishes a formal link between genetic predisposition and skin inflammation observed in HS.
Asunto(s)
Daño del ADN , Replicación del ADN , Folículo Piloso/metabolismo , Hidradenitis Supurativa/metabolismo , Proteínas de la Membrana/metabolismo , Proteínas Nucleares/metabolismo , Fosfoproteínas/metabolismo , Células Madre/metabolismo , Adolescente , Adulto , Proteínas de la Ataxia Telangiectasia Mutada/metabolismo , Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1)/metabolismo , Femenino , Folículo Piloso/patología , Hidradenitis Supurativa/patología , Humanos , Inflamación/metabolismo , Inflamación/patología , Masculino , Persona de Mediana Edad , Células Madre/patologíaRESUMEN
Hidradenitis suppurativa/acne inversa (HS) is a chronic inflammatory disease involving hair follicles that presents with painful nodules, abscesses, fistulae, and hypertrophic scars, typically occurring in apocrine gland bearing skin. Establishing a diagnosis of HS may take up to 7 years after disease onset. HS severely impairs the quality of life of patients and its high frequency causes significant costs for health care system. HS patients have an increased risk of developing associated diseases, such as inflammatory bowel diseases and spondyloarthropathies, thereby suggesting a common pathophysiological mechanism. Familial cases, which are around 35% of HS patients, have allowed the identification of susceptibility genes. HS is perceived as a complex disease where environmental factors trigger chronic inflammation in the skin of genetically predisposed individuals. Despite the efforts made to understand HS etiopathogenesis, the exact mechanisms at the basis of the disease need to be still unraveled. In this review, we considered all OMICs studies performed on HS and observed that OMICs contribution in the context of HS appeared as not clear enough and/or rich of useful clinical information. Indeed, most studies focused only on one aspect-genome, transcriptome, or proteome-of the disease, enrolling small numbers of patients. This is quite limiting for the genetic studies, from different geographical areas and looking at a few aspects of HS pathogenesis without any integration of the findings obtained or a comparison among different studies. A strong need for an integrated approach using OMICs tools is required to discover novel actors involved in HS etiopathogenesis. Moreover, we suggest the constitution of consortia to enroll a higher number of patients to be analyzed following common and consensus OMICs strategies. Comparison and integration with the findings present in the OMICs repositories are mandatory. In a theoretic pipeline, the Skin-OMICs profile obtained from each HS patient should be compared and integrated with repositories and literature data by using appropriate InterOMICs approach. The final goal is not only to improve the knowledge of HS etiopathogenesis but also to provide novel tools to the clinicians with the eventual aim of offering a tailored treatment for HS patients.
Asunto(s)
Hidradenitis Supurativa/genética , Hidradenitis Supurativa/patología , Animales , Genoma/genética , Humanos , Inflamación/genética , Inflamación/patología , Proteoma/genética , Transcriptoma/genéticaRESUMEN
Mutations in NCSTN gene (encoding for nicastrin protein) are associated with hidradenitis suppurativa (HS), a chronic inflammatory disease involving hair follicles. HS is clinically handled with drugs but the most severe cases are treated with surgery. Photobiomodulation (PBM) therapy, already used in the treatment of skin diseases such as acne, herpes virus lesions, ultraviolet damage, vitiligo, hypertrophic scar, keloid, burn, psoriasis and diabetic chronic wounds, could be beneficial as an adjuvant supportive treatment to promote and foster the healing process after skin excision in HS. The effects of PBM therapy in promoting the wound closure are evaluated in a HaCaT cells NCSTN-/-, assessing cell metabolism, migration rate, proliferation and cell cycle progression. In our experimental model, PBM exerts a potent action on metabolism of mutated keratinocytes, incrementing adenosine triphosphate (ATP) production at 2 hours, while after 24 hours an increase of metabolism with a decrement of intracellular ATP levels were recorded. Moreover, PBM speeds up the wound closure, inducing cells' migration without affecting their proliferation.Based on our findings, we suggest the use of PBM in HS patients, who undergo major surgery with large skin excision.
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/deficiencia , Secretasas de la Proteína Precursora del Amiloide/genética , Técnicas de Inactivación de Genes , Terapia por Luz de Baja Intensidad , Glicoproteínas de Membrana/deficiencia , Glicoproteínas de Membrana/genética , Cicatrización de Heridas/efectos de la radiación , Ciclo Celular/efectos de la radiación , Línea Celular , Movimiento Celular/efectos de la radiación , Proliferación Celular/efectos de la radiación , Humanos , Queratinocitos/metabolismo , Queratinocitos/efectos de la radiaciónRESUMEN
Poor ambient air quality is associated with increased morbidity and mortality, including respiratory infections. However, its effects on various host-defense mechanisms are poorly understood. This study utilized an in vitro model to study the effect of particulate matter (PM(2.5)) on one antimicrobial mechanism of host defense in the airway, beta-defensin-2 and its bovine homologue, tracheal antimicrobial peptide (TAP) induction in response to lipopolysaccharide (LPS) and IL-1beta. Our model utilized cultured primary bovine tracheal epithelial (BTE) cells and the human alveolar type II epithelial cell line, A549, treated with 0-20 microg/cm(2) residual oil fly ash (ROFA) for 6 h. The cells were then washed and stimulated for 18 h with 100 ng/ml LPS or for 6 h with 100 ng/ml IL-1beta. ROFA inhibited the LPS-induced increase in TAP mRNA and protein without inducing significant cytotoxicity. As little as 2.5 microg/cm(2) of ROFA inhibited LPS-induced TAP gene expression by 30%. The inhibitory activity was associated with the soluble fraction and not the washed particle. The activity in the leachate was attributed to vanadium, but not nickel or iron. SiO(2) and TiO(2) were utilized as controls and did not inhibit LPS induction of TAP gene expression in BTE. ROFA also inhibited the increase of IL-1beta-induced human beta-defensin-2, a homologue of TAP, in A549 cells. The results show that ROFA, V(2)O(5), and VOSO(4) inhibit the ability of airway epithelial cells to respond to inflammatory stimuli at low, physiologically relevant doses and suggest that exposure to these agents could result in an impairment of defense against airborne pathogens.
Asunto(s)
Carbono/toxicidad , Regulación de la Expresión Génica/efectos de los fármacos , Tráquea/efectos de los fármacos , Vanadio/toxicidad , beta-Defensinas/genética , Secuencia de Bases , Línea Celular , Ceniza del Carbón , Cartilla de ADN , Relación Dosis-Respuesta a Droga , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Humanos , Espectrometría de Masas , Material Particulado , Alveolos Pulmonares/citología , Alveolos Pulmonares/efectos de los fármacos , Alveolos Pulmonares/metabolismo , Tráquea/citología , Tráquea/metabolismoRESUMEN
Celiac disease is a multifactorial disorder caused, in genetically susceptible patients, by the ingestion of dietary gluten. Very little is known about the genetic factors, but there is a strong association of two HLA haplotypes (DQ2 or alpha1*05, beta1*02 and DQ8 or alpha1*0301, beta1*0302) with the disease. We investigated the relationship between polymorphisms in the first exon of the MBL2 gene, which encodes for mannose binding lectin (MBL) and celiac disease. Moreover we studied the MBL role by immunohistochemistry and TUNEL. Results were confirmed by clinical findings. We enrolled 149 Italian celiac patients; 116 were characterized by the presence of DQ2 or DQ8. The HLA haplotype was established by allelic specific PCR while the MBL2 genotype was resolved by melting temperature assay. Immunohistochemistry and TUNEL assays were performed on serial sections of biopsy specimens from celiac patients and healthy controls. MBL2 allele and genotype frequencies varied significantly between celiac patients and healthy controls. The frequencies of the 0 allele were 28% in DQ2 or DQ8 celiac patients, 36% in HLA atypical celiac patients, and 22% in healthy controls. Interestingly, the MBL2 0/0 genotype was present in 7 of 33 HLA atypical celiac patients (21%) and in 13 of 116 HLA typical celiac patients (13%) but in only 7 of 147 healthy controls (5%). Furthermore, we found that MBL2 genotype is strongly associated with the occurrence of secondary autoimmune diseases. Immunohistochemistry and TUNEL findings support a role of MBL2 in the clearance of apoptotic cells. In conclusion, MBL2 variants, responsible for lower MBL levels, are associated with celiac disease and higher risk of developing autoimmune diseases. Here we propose a role for MBL in the disease which could be easily applied to other autoimmune disorders.