RESUMEN
BACKGROUND: Autoimmune polyendocrine syndrome type 1 (APS-1) is a life-threatening, autosomal recessive syndrome caused by autoimmune regulator (AIRE) deficiency. In APS-1, self-reactive T cells escape thymic negative selection, infiltrate organs, and drive autoimmune injury. The effector mechanisms governing T-cell-mediated damage in APS-1 remain poorly understood. METHODS: We examined whether APS-1 could be classified as a disease mediated by interferon-γ. We first assessed patients with APS-1 who were participating in a prospective natural history study and evaluated mRNA and protein expression in blood and tissues. We then examined the pathogenic role of interferon-γ using Aire-/-Ifng-/- mice and Aire-/- mice treated with the Janus kinase (JAK) inhibitor ruxolitinib. On the basis of our findings, we used ruxolitinib to treat five patients with APS-1 and assessed clinical, immunologic, histologic, transcriptional, and autoantibody responses. RESULTS: Patients with APS-1 had enhanced interferon-γ responses in blood and in all examined autoimmunity-affected tissues. Aire-/- mice had selectively increased interferon-γ production by T cells and enhanced interferon-γ, phosphorylated signal transducer and activator of transcription 1 (pSTAT1), and CXCL9 signals in multiple organs. Ifng ablation or ruxolitinib-induced JAK-STAT blockade in Aire-/- mice normalized interferon-γ responses and averted T-cell infiltration and damage in organs. Ruxolitinib treatment of five patients with APS-1 led to decreased levels of T-cell-derived interferon-γ, normalized interferon-γ and CXCL9 levels, and remission of alopecia, oral candidiasis, nail dystrophy, gastritis, enteritis, arthritis, Sjögren's-like syndrome, urticaria, and thyroiditis. No serious adverse effects from ruxolitinib were identified in these patients. CONCLUSIONS: Our findings indicate that APS-1, which is caused by AIRE deficiency, is characterized by excessive, multiorgan interferon-γ-mediated responses. JAK inhibition with ruxolitinib in five patients showed promising results. (Funded by the National Institute of Allergy and Infectious Diseases and others.).
Asunto(s)
Proteína AIRE , Interferón gamma , Inhibidores de las Cinasas Janus , Poliendocrinopatías Autoinmunes , Adulto , Animales , Femenino , Humanos , Masculino , Ratones , Proteína AIRE/deficiencia , Proteína AIRE/genética , Proteína AIRE/inmunología , Autoanticuerpos/sangre , Autoanticuerpos/inmunología , Quimiocina CXCL9/genética , Interferón gamma/genética , Interferón gamma/inmunología , Inhibidores de las Cinasas Janus/uso terapéutico , Ratones Noqueados , Nitrilos/uso terapéutico , Poliendocrinopatías Autoinmunes/genética , Poliendocrinopatías Autoinmunes/tratamiento farmacológico , Poliendocrinopatías Autoinmunes/inmunología , Pirazoles/uso terapéutico , Pirazoles/farmacología , Pirimidinas/uso terapéutico , Linfocitos T/inmunología , Factores de Transcripción/genética , Factores de Transcripción/inmunología , Proyectos Piloto , Modelos Animales de Enfermedad , Niño , Adolescente , Persona de Mediana EdadRESUMEN
OBJECTIVES: To study the molecular pathogenesis of PAPA (pyogenic arthritis, pyoderma gangrenosum and acne) syndrome, a debilitating hereditary autoinflammatory disease caused by dominant mutation in PSTPIP1. METHODS: Gene knock-out and knock-in mice were generated to develop an animal model. THP1 and retrovirally transduced U937 human myeloid leukaemia cell lines, peripheral blood mononuclear cells, small interfering RNA (siRNA) knock-down, site-directed mutagenesis, cytokine immunoassays, coimmunoprecipitation and immunoblotting were used to study inflammasome activation. Cytokine levels in the skin were evaluated by immunohistochemistry. Responsiveness to Janus kinase (JAK) inhibitors was evaluated ex vivo with peripheral blood mononuclear cells and in vivo in five treatment-refractory PAPA patients. RESULTS: The knock-in mouse model of PAPA did not recapitulate the human disease. In a human myeloid cell line model, PAPA-associated PSTPIP1 mutations activated the pyrin inflammasome, but not the NLRP3, NLRC4 or AIM2 inflammasomes. Pyrin inflammasome activation was independent of the canonical pathway of pyrin serine dephosphorylation and was blocked by the p.W232A PSTPIP1 mutation, which disrupts pyrin-PSTPIP1 interaction. IFN-γ priming of monocytes from PAPA patients led to IL-18 release in a pyrin-dependent manner. IFN-γ was abundant in the inflamed dermis of PAPA patients, but not patients with idiopathic pyoderma gangrenosum. Ex vivo JAK inhibitor treatment attenuated IFN-γ-mediated pyrin induction and IL-18 release. In 5/5 PAPA patients, the addition of JAK inhibitor therapy to IL-1 inhibition was associated with clinical improvement. CONCLUSION: PAPA-associated PSTPIP1 mutations trigger a pyrin-IL-18-IFN-γ positive feedback loop that drives PAPA disease activity and is a target for JAK inhibition.
Asunto(s)
Acné Vulgar , Artritis Infecciosa , Modelos Animales de Enfermedad , Inflamasomas , Interferón gamma , Piodermia Gangrenosa , Piodermia Gangrenosa/genética , Humanos , Animales , Ratones , Acné Vulgar/inmunología , Inflamasomas/metabolismo , Inflamasomas/inmunología , Interferón gamma/metabolismo , Inhibidores de las Cinasas Janus/uso terapéutico , Inhibidores de las Cinasas Janus/farmacología , Ratones Noqueados , Proteínas del Citoesqueleto/genética , Proteínas del Citoesqueleto/metabolismo , Retroalimentación Fisiológica , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Pirina/genética , Mutación , Fosfoproteínas/metabolismo , Fosfoproteínas/genética , Técnicas de Sustitución del Gen , Interleucina-18/metabolismo , Células THP-1RESUMEN
BACKGROUND: Adult-onset inflammatory syndromes often manifest with overlapping clinical features. Variants in ubiquitin-related genes, previously implicated in autoinflammatory disease, may define new disorders. METHODS: We analyzed peripheral-blood exome sequence data independent of clinical phenotype and inheritance pattern to identify deleterious mutations in ubiquitin-related genes. Sanger sequencing, immunoblotting, immunohistochemical testing, flow cytometry, and transcriptome and cytokine profiling were performed. CRISPR-Cas9-edited zebrafish were used as an in vivo model to assess gene function. RESULTS: We identified 25 men with somatic mutations affecting methionine-41 (p.Met41) in UBA1, the major E1 enzyme that initiates ubiquitylation. (The gene UBA1 lies on the X chromosome.) In such patients, an often fatal, treatment-refractory inflammatory syndrome develops in late adulthood, with fevers, cytopenias, characteristic vacuoles in myeloid and erythroid precursor cells, dysplastic bone marrow, neutrophilic cutaneous and pulmonary inflammation, chondritis, and vasculitis. Most of these 25 patients met clinical criteria for an inflammatory syndrome (relapsing polychondritis, Sweet's syndrome, polyarteritis nodosa, or giant-cell arteritis) or a hematologic condition (myelodysplastic syndrome or multiple myeloma) or both. Mutations were found in more than half the hematopoietic stem cells, including peripheral-blood myeloid cells but not lymphocytes or fibroblasts. Mutations affecting p.Met41 resulted in loss of the canonical cytoplasmic isoform of UBA1 and in expression of a novel, catalytically impaired isoform initiated at p.Met67. Mutant peripheral-blood cells showed decreased ubiquitylation and activated innate immune pathways. Knockout of the cytoplasmic UBA1 isoform homologue in zebrafish caused systemic inflammation. CONCLUSIONS: Using a genotype-driven approach, we identified a disorder that connects seemingly unrelated adult-onset inflammatory syndromes. We named this disorder the VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome. (Funded by the NIH Intramural Research Programs and the EU Horizon 2020 Research and Innovation Program.).
Asunto(s)
Enfermedades Autoinmunes/genética , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Inflamación/genética , Mutación Missense , Enzimas Activadoras de Ubiquitina/genética , Edad de Inicio , Anciano , Anciano de 80 o más Años , Citocinas/sangre , Exoma/genética , Genotipo , Arteritis de Células Gigantes/genética , Humanos , Immunoblotting , Masculino , Persona de Mediana Edad , Mieloma Múltiple/genética , Síndromes Mielodisplásicos/genética , Poliarteritis Nudosa/genética , Policondritis Recurrente/genética , Análisis de Secuencia de ADN , Síndrome de Sweet/genética , SíndromeRESUMEN
OBJECTIVES: To test the hypothesis that ROSAH (retinal dystrophy, optic nerve oedema, splenomegaly, anhidrosis and headache) syndrome, caused by dominant mutation in ALPK1, is an autoinflammatory disease. METHODS: This cohort study systematically evaluated 27 patients with ROSAH syndrome for inflammatory features and investigated the effect of ALPK1 mutations on immune signalling. Clinical, immunologic and radiographical examinations were performed, and 10 patients were empirically initiated on anticytokine therapy and monitored. Exome sequencing was used to identify a new pathogenic variant. Cytokine profiling, transcriptomics, immunoblotting and knock-in mice were used to assess the impact of ALPK1 mutations on protein function and immune signalling. RESULTS: The majority of the cohort carried the p.Thr237Met mutation but we also identified a new ROSAH-associated mutation, p.Tyr254Cys.Nearly all patients exhibited at least one feature consistent with inflammation including recurrent fever, headaches with meningeal enhancement and premature basal ganglia/brainstem mineralisation on MRI, deforming arthritis and AA amyloidosis. However, there was significant phenotypic variation, even within families and some adults lacked functional visual deficits. While anti-TNF and anti-IL-1 therapies suppressed systemic inflammation and improved quality of life, anti-IL-6 (tocilizumab) was the only anticytokine therapy that improved intraocular inflammation (two of two patients).Patients' primary samples and in vitro assays with mutated ALPK1 constructs showed immune activation with increased NF-κB signalling, STAT1 phosphorylation and interferon gene expression signature. Knock-in mice with the Alpk1 T237M mutation exhibited subclinical inflammation.Clinical features not conventionally attributed to inflammation were also common in the cohort and included short dental roots, enamel defects and decreased salivary flow. CONCLUSION: ROSAH syndrome is an autoinflammatory disease caused by gain-of-function mutations in ALPK1 and some features of disease are amenable to immunomodulatory therapy.
Asunto(s)
Enfermedades Autoinflamatorias Hereditarias , FN-kappa B , Proteínas Quinasas/genética , Amiloidosis , Animales , Estudios de Cohortes , Mutación con Ganancia de Función , Enfermedades Autoinflamatorias Hereditarias/genética , Humanos , Inflamación/genética , Ratones , Mutación , FN-kappa B/genética , FN-kappa B/metabolismo , Proteínas Quinasas/metabolismo , Calidad de Vida , Proteína Amiloide A Sérica , Síndrome , Inhibidores del Factor de Necrosis TumoralRESUMEN
AIMS: Fibrous cephalic plaques (FCPs) in individuals with tuberous sclerosis complex (TSC) may be excised for cosmetic reasons or biopsied to confirm lesion identification and TSC diagnosis. The aim of this study was to determine the range of histopathological features of FCPs. METHODS AND RESULTS: A retrospective analysis was conducted on 119 adults with TSC. Twenty-one lesions from 16 individuals were evaluated by a dermatopathologist. Additionally, we assessed whether lesion colour or histology varied by anatomical location. Seventy-six lesions were observed in 36 of 119 individuals. Erythematous lesions were more commonly found on the forehead, face or neck than on the scalp (odds ratio = 12.6, P = 0.0001). Thickened and disorganised collagen fibre bundles were present in 95% (20/21) of lesions. Perifollicular fibrosis was observed in 95% (20/21) of lesions, enhanced vascularity was observed in 52% (11/21) of lesions, and features of fibrofolliculoma were observed in 43% (9/21) of lesions. Other abnormalities included features similar to trichofolliculoma, follicular-derived, infundibular-type cysts, and abnormally arranged primitive hair follicles. CONCLUSIONS: FCPs in TSC show thickened bundles of collagen, and hamartomatous changes involving hair follicles. Recognition of these histopathological features may raise the possibility of unsuspected TSC or confirm FCP identification.
Asunto(s)
Enfermedades de la Piel/patología , Esclerosis Tuberosa/patología , Adulto , Femenino , Fibrosis/etiología , Fibrosis/patología , Cabeza , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Enfermedades de la Piel/etiología , Esclerosis Tuberosa/complicacionesRESUMEN
Patients with autosomal dominant vibratory urticaria have localized hives and systemic manifestations in response to dermal vibration, with coincident degranulation of mast cells and increased histamine levels in serum. We identified a previously unknown missense substitution in ADGRE2 (also known as EMR2), which was predicted to result in the replacement of cysteine with tyrosine at amino acid position 492 (p.C492Y), as the only nonsynonymous variant cosegregating with vibratory urticaria in two large kindreds. The ADGRE2 receptor undergoes autocatalytic cleavage, producing an extracellular subunit that noncovalently binds a transmembrane subunit. We showed that the variant probably destabilizes an autoinhibitory subunit interaction, sensitizing mast cells to IgE-independent vibration-induced degranulation. (Funded by the National Institutes of Health.).
Asunto(s)
Mutación Missense , Receptores Acoplados a Proteínas G/genética , Urticaria/genética , Vibración/efectos adversos , Biopsia , Degranulación de la Célula/genética , Femenino , Histamina/sangre , Humanos , Líbano , Masculino , Mastocitos/fisiología , Persona de Mediana Edad , Linaje , Receptores Acoplados a Proteínas G/metabolismo , Piel/patología , Urticaria/sangre , Urticaria/etiologíaRESUMEN
KEY TEACHING POINTS.
Asunto(s)
Enfermedades de la Piel/diagnóstico , Niño , Enfermedad Crónica , Progresión de la Enfermedad , Femenino , Fiebre/etiología , Humanos , Lipodistrofia/etiología , Neutrófilos , Recurrencia , Enfermedades de la Piel/complicacionesRESUMEN
Ablepharon macrostomia syndrome (AMS) and Barber-Say syndrome (BSS) are rare congenital ectodermal dysplasias characterized by similar clinical features. To establish the genetic basis of AMS and BSS, we performed extensive clinical phenotyping, whole exome and candidate gene sequencing, and functional validations. We identified a recurrent de novo mutation in TWIST2 in seven independent AMS-affected families, as well as another recurrent de novo mutation affecting the same amino acid in ten independent BSS-affected families. Moreover, a genotype-phenotype correlation was observed, because the two syndromes differed based solely upon the nature of the substituting amino acid: a lysine at TWIST2 residue 75 resulted in AMS, whereas a glutamine or alanine yielded BSS. TWIST2 encodes a basic helix-loop-helix transcription factor that regulates the development of mesenchymal tissues. All identified mutations fell in the basic domain of TWIST2 and altered the DNA-binding pattern of Flag-TWIST2 in HeLa cells. Comparison of wild-type and mutant TWIST2 expressed in zebrafish identified abnormal developmental phenotypes and widespread transcriptome changes. Our results suggest that autosomal-dominant TWIST2 mutations cause AMS or BSS by inducing protean effects on the transcription factor's DNA binding.
Asunto(s)
Anomalías Múltiples/genética , Anomalías del Ojo/genética , Enfermedades de los Párpados/genética , Hirsutismo/genética , Hipertelorismo/genética , Hipertricosis/genética , Macrostomía/genética , Modelos Moleculares , Fenotipo , Proteínas Represoras/genética , Anomalías Cutáneas/genética , Proteína 1 Relacionada con Twist/genética , Anomalías Múltiples/patología , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Inmunoprecipitación de Cromatina , Exoma/genética , Anomalías del Ojo/patología , Enfermedades de los Párpados/patología , Células HeLa , Hirsutismo/patología , Humanos , Hipertelorismo/patología , Hipertricosis/patología , Macrostomía/patología , Microscopía Electrónica , Datos de Secuencia Molecular , Mutación Missense/genética , Conformación Proteica , Proteínas Represoras/química , Análisis de Secuencia de ADN , Anomalías Cutáneas/patología , Proteína 1 Relacionada con Twist/química , Pez CebraAsunto(s)
Exantema , Poliendocrinopatías Autoinmunes , Humanos , Exantema/diagnóstico , Exantema/etiologíaRESUMEN
BACKGROUND: Fibrous cephalic plaques (FCPs) stereotypically develop on the forehead of patients with tuberous sclerosis complex (TSC). They constitute a major feature for TSC diagnosis and may present before other TSC-related cutaneous hamartomas. OBJECTIVE: To describe the clinical characteristics of FCPs in TSC. METHODS: A total of 113 patients with TSC were enrolled in an observational cohort study. Retrospective analysis of medical records and skin photography was performed. FCPs were categorized by anatomic location and size. RESULTS: FCPs were observed in 36% of patients (41 of 113). Of 62 total lesions, 58% were 1 to less than 5 cm, 13% were 5 cm or larger, and 29% were of unknown size mostly because of prior excision. The distribution of lesions was 39% on the forehead, 27% on the face (nonforehead), 3% on the neck, and 31% on the scalp. Fourteen patients had similar lesions less than 1 cm in diameter. Histopathologically, FCPs displayed dermal collagenosis, decreased elastic fibers, and features of angiofibromas or fibrofolliculomas. LIMITATIONS: Men were under-represented because the cohort was enriched for patients with TSC with lymphangioleiomyomatosis, which occurs in adult women. CONCLUSION: Two-fifths of FCPs presented on the forehead, with most of the remainder in other locations on the face and scalp. Better recognition of these lesions may lead to earlier diagnosis of TSC.
Asunto(s)
Dermatosis Facial/etiología , Dermatosis del Cuero Cabelludo/etiología , Neoplasias Cutáneas/complicaciones , Esclerosis Tuberosa/complicaciones , Adolescente , Niño , Preescolar , Dermatosis Facial/patología , Femenino , Humanos , Lactante , Masculino , Estudios Retrospectivos , Dermatosis del Cuero Cabelludo/patologíaRESUMEN
KEY TEACHING POINTS.
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Infecciones por Virus de Epstein-Barr/diagnóstico , Hidroa Vacciniforme/diagnóstico , Vesícula/etiología , Enfermedades Óseas Metabólicas/etiología , Enfermedad Crónica , Cicatriz/etiología , Infecciones por Virus de Epstein-Barr/complicaciones , Humanos , Hidroa Vacciniforme/complicaciones , Hidroa Vacciniforme/prevención & control , Masculino , Recurrencia , Luz Solar/efectos adversos , Deficiencia de Vitamina D/complicaciones , Adulto JovenRESUMEN
Background: The most common clinical manifestation of early Lyme disease is the erythema migrans (EM) skin lesion that develops at the tick bite site typically between 7 and 14 days after infection with Borreliella burgdorferi. The host-pathogen interactions that occur in the skin may have a critical role in determining outcome of infection. Methods: Gene arrays were used to characterize the global transcriptional alterations in skin biopsy samples of EM lesions from untreated adult patients with Lyme disease in comparison to controls. Results: The transcriptional pattern in EM biopsies consisted of 254 differentially regulated genes (180 induced and 74 repressed) characterized by the induction of chemokines, cytokines, Toll-like receptors, antimicrobial peptides, monocytoid cell activation markers, and numerous genes annotated as interferon (IFN)-inducible. The IFN-inducible genes included 3 transcripts involved in tryptophan catabolism (IDO1, KMO, KYNU) that play a pivotal role in immune evasion by certain other microbial pathogens by driving the differentiation of regulatory T cells. Conclusions: This is the first study to globally assess the human skin transcriptional response during early Lyme disease. Borreliella burgdorferi elicits a predominant IFN signature in the EM lesion, suggesting a potential mechanism for spirochetal dissemination via IDO1-mediated localized immunosuppression.
Asunto(s)
Perfilación de la Expresión Génica , Interacciones Huésped-Patógeno , Interferones/metabolismo , Enfermedad de Lyme/patología , Transducción de Señal , Piel/patología , Adulto , Anciano , Biopsia , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Systemic candidiasis is a leading cause of nosocomial bloodstream infection with a high mortality rate despite treatment. Immune-based strategies are needed to improve outcomes. We previously reported that genetic deficiency in the chemokine receptor CCR1 improves survival and ameliorates tissue damage in Candida-infected mice. Here, we found that treatment of immunocompetent Candida-infected mice with the CCR1-selective antagonist BL5923 improves survival, decreases the kidney fungal burden, and protects from renal tissue injury.
Asunto(s)
Lesión Renal Aguda/prevención & control , Candida albicans/efectos de los fármacos , Candidiasis Invasiva/tratamiento farmacológico , Hemorragia/prevención & control , Piperazinas/farmacología , Receptores CCR1/antagonistas & inhibidores , Lesión Renal Aguda/inmunología , Lesión Renal Aguda/microbiología , Lesión Renal Aguda/mortalidad , Animales , Candida albicans/crecimiento & desarrollo , Candida albicans/patogenicidad , Candidiasis Invasiva/inmunología , Candidiasis Invasiva/microbiología , Candidiasis Invasiva/mortalidad , Esquema de Medicación , Femenino , Expresión Génica , Hemorragia/inmunología , Hemorragia/microbiología , Hemorragia/mortalidad , Interacciones Huésped-Patógeno , Ratones , Ratones Endogámicos C57BL , Receptores CCR1/genética , Receptores CCR1/inmunología , Análisis de SupervivenciaRESUMEN
BACKGROUND: We observed a syndrome of intermittent fevers, early-onset lacunar strokes and other neurovascular manifestations, livedoid rash, hepatosplenomegaly, and systemic vasculopathy in three unrelated patients. We suspected a genetic cause because the disorder presented in early childhood. METHODS: We performed whole-exome sequencing in the initial three patients and their unaffected parents and candidate-gene sequencing in three patients with a similar phenotype, as well as two young siblings with polyarteritis nodosa and one patient with small-vessel vasculitis. Enzyme assays, immunoblotting, immunohistochemical testing, flow cytometry, and cytokine profiling were performed on samples from the patients. To study protein function, we used morpholino-mediated knockdowns in zebrafish and short hairpin RNA knockdowns in U937 cells cultured with human dermal endothelial cells. RESULTS: All nine patients carried recessively inherited mutations in CECR1 (cat eye syndrome chromosome region, candidate 1), encoding adenosine deaminase 2 (ADA2), that were predicted to be deleterious; these mutations were rare or absent in healthy controls. Six patients were compound heterozygous for eight CECR1 mutations, whereas the three patients with polyarteritis nodosa or small-vessel vasculitis were homozygous for the p.Gly47Arg mutation. Patients had a marked reduction in the levels of ADA2 and ADA2-specific enzyme activity in the blood. Skin, liver, and brain biopsies revealed vasculopathic changes characterized by compromised endothelial integrity, endothelial cellular activation, and inflammation. Knockdown of a zebrafish ADA2 homologue caused intracranial hemorrhages and neutropenia - phenotypes that were prevented by coinjection with nonmutated (but not with mutated) human CECR1. Monocytes from patients induced damage in cocultured endothelial-cell layers. CONCLUSIONS: Loss-of-function mutations in CECR1 were associated with a spectrum of vascular and inflammatory phenotypes, ranging from early-onset recurrent stroke to systemic vasculopathy or vasculitis. (Funded by the National Institutes of Health Intramural Research Programs and others.).
Asunto(s)
Adenosina Desaminasa/deficiencia , Adenosina Desaminasa/genética , Péptidos y Proteínas de Señalización Intercelular/deficiencia , Péptidos y Proteínas de Señalización Intercelular/genética , Mutación , Accidente Cerebrovascular/genética , Enfermedades Vasculares/genética , Edad de Inicio , Animales , Modelos Animales de Enfermedad , Endotelio Vascular/patología , Femenino , Fiebre/genética , Humanos , Masculino , Linaje , Poliarteritis Nudosa/genética , Análisis de Secuencia de ADN , Piel/patología , Vasculitis/genética , Vasculitis/patología , Pez CebraRESUMEN
KEY TEACHING POINTS.
Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Papulosis Atrófica Maligna/diagnóstico , Papulosis Atrófica Maligna/tratamiento farmacológico , Dolor Abdominal/etiología , Antiarrítmicos/uso terapéutico , Fibrilación Atrial/tratamiento farmacológico , Fibrilación Atrial/etiología , Inhibidores del Factor Xa/uso terapéutico , Femenino , Humanos , Papulosis Atrófica Maligna/complicaciones , Metoprolol/uso terapéutico , Persona de Mediana Edad , Parestesia/etiología , Pirazoles/uso terapéutico , Piridonas/uso terapéutico , Insuficiencia de la Válvula Tricúspide/etiologíaRESUMEN
Candida albicans is part of the normal commensal microbiota of mucosal surfaces in a large percentage of the human population. However, perturbations of the host's immune response or bacterial microbiota have been shown to predispose individuals to the development of opportunistic Candida infections. It was recently discovered that a defect in the chemokine receptor CX3CR1 increases susceptibility of mice and humans to systemic candidiasis. However, whether CX3CR1 confers protection against mucosal C. albicans infection has not been investigated. Using two different mouse models, we found that Cx3cr1 is dispensable for the induction of interleukin 17A (IL-17A), IL-22, and IL-23 in the tongue after infection, as well as for the clearance of mucosal candidiasis from the tongue or lower gastrointestinal (GI) tract colonization. Furthermore, the dysfunctional human CX3CR1 allele CX3CR1-M280 was not associated with development of recurrent vulvovaginal candidiasis (RVVC) in women. Taken together, these data indicate that CX3CR1 is not essential for protection of the host against mucosal candidiasis, underscoring the dependence on different mammalian immune factors for control of mucosal versus systemic Candida infections.
Asunto(s)
Candida albicans/inmunología , Candidiasis Vulvovaginal/inmunología , Candidiasis/inmunología , Infecciones Oportunistas/inmunología , Receptores de Quimiocina/inmunología , Alelos , Animales , Receptor 1 de Quimiocinas CX3C , Candidiasis/genética , Candidiasis/microbiología , Candidiasis Vulvovaginal/genética , Candidiasis Vulvovaginal/microbiología , Modelos Animales de Enfermedad , Femenino , Tracto Gastrointestinal/inmunología , Tracto Gastrointestinal/microbiología , Expresión Génica , Interacciones Huésped-Patógeno , Humanos , Interleucina-17/genética , Interleucina-17/inmunología , Interleucina-23/genética , Interleucina-23/inmunología , Interleucinas/genética , Interleucinas/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Infecciones Oportunistas/genética , Infecciones Oportunistas/microbiología , Receptores de Quimiocina/deficiencia , Receptores de Quimiocina/genética , Lengua/inmunología , Lengua/microbiología , Vagina/inmunología , Vagina/microbiología , Interleucina-22RESUMEN
Episodic angioedema with eosinophilia (Gleich syndrome) is a rare disorder characterized by episodes of angioedema and eosinophilia that occur at monthly intervals and resolve spontaneously without therapy. Despite the striking periodicity of this disorder, its similarity to other cyclic hematopoietic disorders with multilineage involvement has not been assessed. To characterize the involvement of cell lineages in the etiology and pathogenesis of episodic angioedema with eosinophilia, four subjects were evaluated by blood counts and other analyses over the course of 1-2 months. Surface marker expression was assessed on T cells by flow cytometry and clonality by polymerase chain reaction. Intracellular cytokine evaluation, bone marrow and skin biopsies were performed during different parts of the cycle. Cycling of multiple cell lineages, including neutrophils, lymphocytes and eosinophils, was observed in the four subjects with the disorder with a periodicity of 25-35 days. An aberrant CD3(-)CD4(+) T-cell population was detected in all four subjects, and T-cell receptor rearrangement studies showed a clonal pattern in three subjects. A peak of type II cytokines was detected in the serum of subjects prior to the onset of symptoms and eosinophil cycling and corresponded to ex-vivo type II cytokines detected intracellularly in CD3(+)CD4(+)CD154(+) T cells. Although the etiology of episodic angioedema with eosinophilia is not yet known, multiple lineages, including lymphocytes, neutrophils and mast cells, are involved and may be related to disease pathogenesis. Whether these cells act directly or promote eosinophilia and eosinophil activation remains to be elucidated. All subjects gave informed consent and were evaluated under an Institutional Review Board-approved protocol (NCT00001406).
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Angioedema/diagnóstico , Linaje de la Célula/inmunología , Eosinofilia/diagnóstico , Adulto , Angioedema/complicaciones , Angioedema/inmunología , Angioedema/patología , Antígenos CD/inmunología , Médula Ósea/inmunología , Médula Ósea/patología , Citocinas/inmunología , Eosinofilia/complicaciones , Eosinofilia/inmunología , Eosinofilia/patología , Eosinófilos/inmunología , Eosinófilos/patología , Femenino , Expresión Génica , Humanos , Inmunofenotipificación , Masculino , Mastocitos/inmunología , Mastocitos/patología , Persona de Mediana Edad , Neutrófilos/inmunología , Neutrófilos/patología , Periodicidad , Piel/inmunología , Piel/patología , Síndrome , Linfocitos T/inmunología , Linfocitos T/patologíaRESUMEN
Key teaching points ⢠Synovitis-acne-pustulosis-hyperostosis-osteitis (SAPHO) syndrome is characterized by distinctive osteoarticular manifestations and a spectrum of neutrophilic dermatoses. ⢠The most common dermatologic manifestations include palmoplantar pustulosis, acne conglobata, and acne fulminans. ⢠SAPHO syndrome should be considered in patients presenting osteoarticular pain, particularly involving the anterior chest wall and/or spine, and neutrophilic skin lesions.
Asunto(s)
Síndrome de Hiperostosis Adquirido/patología , Adulto , Femenino , HumanosRESUMEN
Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome is a newly characterized autoinflammatory disorder, caused by mutations in PSMB8. It is characterized by early-onset fevers, accompanied by a widespread, violaceous, and often annular cutaneous eruption. Although the exact pathogenesis of this syndrome is still obscure, it is postulated that the inflammatory disease manifestations stem from excess secretion of interferons. Based on preliminary blood cytokine and gene expression studies, the signature seems to come mostly from type I interferons, which are proposed to lead to the recruitment of immature myeloid cells into the dermis and subcutis. In this study, we systematically analyzed skin biopsies from 6 patients with CANDLE syndrome by routine histopathology and immunohistochemistry methods. Skin lesions showed the presence of extensive mixed dermal and subcutaneous inflammatory infiltrate, composed of mononuclear cells, atypical myeloid cells, neutrophils, eosinophils, and some mature lymphocytes. Positive LEDER and myeloperoxidase staining supported the presence of myeloid cells. Positive CD68/PMG1 and CD163 staining confirmed the existence of histiocytes and monocytic macrophages in the inflammatory infiltrate. CD123 staining was positive, demonstrating the presence of plasmacytoid dendritic cells. Uncovering the unique histopathological and immunohistochemical features of CANDLE syndrome provides tools for rapid and specific diagnosis of this disorder and further insight into the pathogenesis of this severe life-threatening condition.