RESUMEN
Susceptibility to tuberculosis is historically ascribed to an inadequate immune response that fails to control infecting mycobacteria. In zebrafish, we find that susceptibility to Mycobacterium marinum can result from either inadequate or excessive acute inflammation. Modulation of the leukotriene A(4) hydrolase (LTA4H) locus, which controls the balance of pro- and anti-inflammatory eicosanoids, reveals two distinct molecular routes to mycobacterial susceptibility converging on dysregulated TNF levels: inadequate inflammation caused by excess lipoxins and hyperinflammation driven by excess leukotriene B(4). We identify therapies that specifically target each of these extremes. In humans, we identify a single nucleotide polymorphism in the LTA4H promoter that regulates its transcriptional activity. In tuberculous meningitis, the polymorphism is associated with inflammatory cell recruitment, patient survival and response to adjunctive anti-inflammatory therapy. Together, our findings suggest that host-directed therapies tailored to patient LTA4H genotypes may counter detrimental effects of either extreme of inflammation.
Asunto(s)
Infecciones por Mycobacterium/tratamiento farmacológico , Infecciones por Mycobacterium/inmunología , Tuberculosis Meníngea/tratamiento farmacológico , Tuberculosis Meníngea/inmunología , Animales , Modelos Animales de Enfermedad , Humanos , Inflamación/inmunología , Leucotrieno A4/genética , Leucotrieno A4/inmunología , Leucotrieno B4/genética , Leucotrieno B4/inmunología , Lipoxinas/inmunología , Mitocondrias/metabolismo , Infecciones por Mycobacterium/genética , Mycobacterium marinum , Polimorfismo Genético , Polimorfismo de Nucleótido Simple , Regiones Promotoras Genéticas , Transducción de Señal , Transcripción Genética , Tuberculosis Meníngea/genética , Factor de Necrosis Tumoral alfa/metabolismo , Pez Cebra/embriología , Pez Cebra/inmunologíaRESUMEN
Exposure to Mycobacterium tuberculosis produces varied early outcomes, ranging from resistance to infection to progressive disease. Here we report results from a forward genetic screen in zebrafish larvae that identify multiple mutant classes with distinct patterns of innate susceptibility to Mycobacterium marinum. A hypersusceptible mutant maps to the lta4h locus encoding leukotriene A(4) hydrolase, which catalyzes the final step in the synthesis of leukotriene B(4) (LTB(4)), a potent chemoattractant and proinflammatory eicosanoid. lta4h mutations confer hypersusceptibility independent of LTB(4) reduction, by redirecting eicosanoid substrates to anti-inflammatory lipoxins. The resultant anti-inflammatory state permits increased mycobacterial proliferation by limiting production of tumor necrosis factor. In humans, we find that protection from both tuberculosis and multibacillary leprosy is associated with heterozygosity for LTA4H polymorphisms that have previously been correlated with differential LTB(4) production. Our results suggest conserved roles for balanced eicosanoid production in vertebrate resistance to mycobacterial infection.
Asunto(s)
Epóxido Hidrolasas/genética , Enfermedades de los Peces/genética , Lepra/genética , Tuberculosis/genética , Animales , Modelos Animales de Enfermedad , Enfermedades de los Peces/inmunología , Predisposición Genética a la Enfermedad , Humanos , Lepra/inmunología , Tuberculosis/inmunología , Pez CebraRESUMEN
AIMS: Previously, retinoids have decreased CYP2D6 mRNA expression in vitro and induced CYP3A4 in vitro and in vivo. This study aimed to determine whether isotretinoin administration changes CYP2D6 and CYP3A activities in patients with severe acne. METHODS: Thirty-three patients (22 females and 11 males, 23.5 ± 6.0 years old) expected to receive isotretinoin treatment completed the study. All participants were genotyped for CYP2D6 and CYP3A5. Participants received dextromethorphan (DM) 30 mg orally as a dual-probe substrate of CYP2D6 and CYP3A activity at two study timepoints: pre-isotretinoin treatment and with isotretinoin for at least 1 week. The concentrations of isotretinoin, DM and their metabolites were measured in 2-h postdose plasma samples and in cumulative 0-4-h urine collections using liquid chromatography-mass spectrometry. RESULTS: In CYP2D6 extensive metabolizers, the urinary dextrorphan (DX)/DM metabolic ratio (MR) (CYP2D6 activity marker) was numerically, but not significantly, lower with isotretinoin administration compared to pre-isotretinoin (geometric mean ratio [GMR] [90% confidence interval (CI)] 0.78 [0.55, 1.11]). The urinary 3-hydroxymorphinan (3HM)/DX MR (CYP3A activity marker) was increased (GMR 1.18 [1.03, 1.35]) and the urinary DX-O-glucuronide/DX MR (proposed UGT2B marker) was increased (GMR 1.22 [1.06, 1.39]) with isotretinoin administration compared to pre-isotretinoin. CONCLUSIONS: Administration of isotretinoin did not significantly reduce CYP2D6 activity in extensive metabolizers, suggesting that the predicted downregulation of CYP2D6 based on in vitro data does not translate into humans. We observed a modest increase in CYP3A activity (predominantly CYP3A4) with isotretinoin treatment. The data also suggest that DX glucuronidation is increased following isotretinoin administration.
Asunto(s)
Acné Vulgar , Citocromo P-450 CYP2D6 , Adolescente , Adulto , Femenino , Humanos , Masculino , Adulto Joven , Acné Vulgar/tratamiento farmacológico , Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP2D6/metabolismo , Citocromo P-450 CYP3A/genética , Dextrometorfano , Isotretinoína/efectos adversos , Isotretinoína/farmacología , FenotipoRESUMEN
Scleromyxedema is a rare and frequently disabling disease characterized by generalized waxy papules, skin induration, and cardinal histological features of dermal fibroblastic proliferation, thickened collagen, and mucin deposition. A monoclonal gammopathy is almost always present with rare progression to multiple myeloma. We describe the case of a 54-year-old man who presented with a rash in the setting of a new medication and histological features suggesting a granulomatous drug reaction. Despite discontinuation of the medication, the rash persisted and a second biopsy confirmed an interstitial granulomatous pattern. Serum protein electrophoresis identified the presence of a biclonal gammopathy leading to a diagnosis of granulomatous scleromyxedema. Review of the medical literature reveals only a handful of well-documented similar cases of this rare variant. It is important for pathologists and clinicians to be familiar with this condition to facilitate timely diagnosis and optimal clinical management of these patients.
Asunto(s)
Escleromixedema/diagnóstico , Granuloma/diagnóstico , Humanos , Masculino , Persona de Mediana Edad , Gammopatía Monoclonal de Relevancia Indeterminada/diagnósticoRESUMEN
Tuberculosis, one of the leading causes of death worldwide, stimulates inflammatory responses with beneficial and pathologic consequences. The regulation and nature of an optimal inflammatory response to Mycobacterium tuberculosis remains poorly understood in humans. Insight into mechanisms of negative regulation of the TLR-mediated innate immune response to M. tuberculosis could provide significant breakthroughs in the design of new vaccines and drugs. We hypothesized that TOLLIP and its common variants negatively regulate TLR signaling in human monocytes and are associated with susceptibility to tuberculosis. Using short hairpin RNA knockdown of TOLLIP in peripheral blood human monocytes, we found that TOLLIP suppresses TNF and IL-6 production after stimulation with TLR2 and TLR4 ligands. In contrast, secretion of the anti-inflammatory cytokine IL-10 was induced by TOLLIP. We also discovered two common polymorphisms that are associated with either decreased levels of mRNA expression (rs3750920) or increased IL-6 production (rs5743899) in a sample of 56 healthy volunteers. Furthermore, in a case-population study in Vietnam with 760 cord blood samples and 671 TB case patients, we found that SNPs rs3750920 and rs5743899 were associated with susceptibility to tuberculosis (p = 7.03 × 10(-16) and 6.97 × 10(-7), respectively). These data demonstrate that TOLLIP has an anti-inflammatory effect on TLR signaling in humans and that TOLLIP deficiency is associated with an increased risk of tuberculosis. To our knowledge, these data also show the first associations of TOLLIP polymorphisms with any infectious disease. These data also implicate an unexpected mechanism of negative regulation of TLR signaling in human tuberculosis pathogenesis.
Asunto(s)
Predisposición Genética a la Enfermedad/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Polimorfismo de Nucleótido Simple , Receptor Toll-Like 2/inmunología , Receptor Toll-Like 4/inmunología , Tuberculosis/genética , Ensayo de Inmunoadsorción Enzimática , Técnicas de Silenciamiento del Gen , Genotipo , Humanos , Péptidos y Proteínas de Señalización Intracelular/inmunología , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Monocitos/inmunología , Monocitos/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Transducción de Señal/genética , Transducción de Señal/inmunología , Receptor Toll-Like 2/metabolismo , Receptor Toll-Like 4/metabolismo , Tuberculosis/inmunologíaRESUMEN
Dermatologic concerns are discussed in about a third of all primary care visits. This review discusses treatments for common dermatologic diagnoses addressed in primary care settings, with an emphasis on new and emerging treatments. Topical, oral, and injectable treatment of common forms of alopecia, facial rashes, atopic dermatitis, psoriasis, seborrheic dermatitis, and stasis dermatitis will be discussed to help increase comfort in prescribing and alert providers to common side effects or complications of more intensive treatments used by dermatologists.
Asunto(s)
Enfermedades de la Piel , Humanos , Enfermedades de la Piel/terapia , Enfermedades de la Piel/diagnóstico , Fármacos Dermatológicos/uso terapéutico , Atención Primaria de Salud , Dermatitis Atópica/tratamiento farmacológico , Dermatitis Atópica/terapia , Dermatitis Seborreica/terapia , Dermatitis Seborreica/tratamiento farmacológico , Dermatitis Seborreica/diagnóstico , Psoriasis/terapia , Psoriasis/tratamiento farmacológico , Alopecia/terapia , Alopecia/diagnóstico , Alopecia/tratamiento farmacológicoRESUMEN
Cutaneous mycobacterial infections cause substantial morbidity and are challenging to diagnose and treat. An improved understanding of the dermal immune response to mycobacteria may inspire new therapeutic approaches. We conducted a controlled human infection study with 10 participants who received 2 × 106 CFUs of Mycobacterium bovis bacillus Calmette-Guérin (Tice strain) intradermally and were randomized to receive isoniazid or no treatment. Peripheral blood was collected at multiple time points for flow cytometry, bulk RNA sequencing (RNA-seq), and serum Ab assessments. Systemic immune responses were detected as early as 8 d postchallenge in this M. bovis bacillus Calmette-Guérin-naive population. Injection-site skin biopsies were performed at days 3 and 15 postchallenge and underwent immune profiling using mass cytometry and single-cell RNA-seq, as well as quantitative assessments of bacterial viability and burden. Molecular viability testing and standard culture results correlated well, although no differences were observed between treatment arms. Single-cell RNA-seq revealed various immune and nonimmune cell types in the skin, and communication between them was inferred by ligand-receptor gene expression. Day 3 communication was predominantly directed toward monocytes from keratinocyte, muscle, epithelial, and endothelial cells, largely via the migration inhibitory factor pathway and HLA-E-KLRK1 interaction. At day 15, communication was more balanced between cell types. These data reveal the potential role of nonimmune cells in the dermal immune response to mycobacteria and the utility of human challenge studies to augment our understanding of mycobacterial infections.
Asunto(s)
Mycobacterium bovis , Piel , Humanos , Mycobacterium bovis/inmunología , Piel/inmunología , Piel/microbiología , Piel/patología , Masculino , Adulto , Isoniazida/uso terapéutico , Isoniazida/farmacología , Femenino , Tuberculosis/inmunología , Tuberculosis/microbiología , Adulto Joven , Antituberculosos/uso terapéuticoAsunto(s)
Inmunodeficiencia Variable Común/complicaciones , Inmunodeficiencia Variable Común/diagnóstico , Granuloma/etiología , Granuloma/patología , Dermatosis de la Mano/patología , Biopsia con Aguja , Femenino , Granuloma/terapia , Dermatosis de la Mano/etiología , Humanos , Inmunoglobulinas Intravenosas/uso terapéutico , Inmunohistoquímica , Enfermedades Raras , Medición de Riesgo , Rondas de Enseñanza , Resultado del Tratamiento , Adulto JovenRESUMEN
The packaging of DNA into chromatin allows eukaryotic cells to organize and compact their genomes but also creates an environment that is generally repressive to nuclear processes that depend upon DNA accessibility. There are several classes of enzymes that modulate the primary structure of chromatin to regulate various DNA-dependent processes. The biochemical activities of the yeast Isw1 ATP-dependent chromatin-remodeling enzyme have been well characterized in vitro, but little is known about how these activities are utilized in vivo. In this work, we sought to discern genetic backgrounds that require Isw1 activity for normal growth. We identified a three-way genetic interaction among Isw1, the NuA4 histone acetyltransferase complex, and the Swr1 histone replacement complex. Transcription microarray analysis revealed parallel functions for these three chromatin-modifying factors in the regulation of TATA-containing genes, including the repression of a large number of stress-induced genes under normal growth conditions. In contrast to a recruitment-based model, we find that the NuA4 and Swr1 complexes act throughout the genome while only a specific subset of the genome shows alterations in transcription.
Asunto(s)
Acetiltransferasas/metabolismo , Adenosina Trifosfatasas/metabolismo , Proteínas de Unión al ADN/metabolismo , Regulación hacia Abajo , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/enzimología , Acetilación , Acetiltransferasas/deficiencia , Adenosina Trifosfatasas/deficiencia , Ensamble y Desensamble de Cromatina/genética , Proteínas de Unión al ADN/deficiencia , Regulación hacia Abajo/efectos de los fármacos , Regulación Fúngica de la Expresión Génica/efectos de los fármacos , Genoma Fúngico/genética , Histona Acetiltransferasas , Histonas/metabolismo , Lisina/metabolismo , Pruebas de Sensibilidad Microbiana , Mutación/genética , Regiones Promotoras Genéticas/genética , Transporte de Proteínas , Saccharomyces cerevisiae/citología , Saccharomyces cerevisiae/efectos de los fármacos , Sirolimus/farmacología , Factores de Transcripción/metabolismo , Transcripción GenéticaRESUMEN
Scleromyxedema is notable for significant morbidity and mortality. A generalized eruption of waxy papules in the absence of thyroid disease with histologic findings of mucin deposition, increased fibroblast proliferation, and fibrosis are the characteristic features of scleromyxedema. We report a case of scleromyxedema that, on histology, was associated with interstitial granuloma annulare-like features. Based on our literature review, this is a rare presentation of this disease. Familiarity with the histologic aspects of scleromyxedema, as described in this report, can help to improve the accuracy of this diagnosis, particularly in atypical presentations.
Asunto(s)
Granuloma Anular/diagnóstico , Escleromixedema/diagnóstico , Diagnóstico Diferencial , Granuloma Anular/complicaciones , Granuloma Anular/patología , Humanos , Masculino , Persona de Mediana Edad , Prurito/etiología , Escleromixedema/complicaciones , Escleromixedema/patologíaAsunto(s)
Artritis Reumatoide/tratamiento farmacológico , Carcinoma de Células Escamosas/inducido químicamente , Inmunoconjugados/efectos adversos , Queratosis Actínica/inducido químicamente , Neoplasias Cutáneas/inducido químicamente , Abatacept , Artritis Reumatoide/diagnóstico , Biopsia con Aguja , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/cirugía , Femenino , Estudios de Seguimiento , Humanos , Inmunoconjugados/uso terapéutico , Inmunohistoquímica , Inmunosupresores/efectos adversos , Inmunosupresores/uso terapéutico , Inyecciones Intravenosas , Queratosis Actínica/patología , Queratosis Actínica/cirugía , Persona de Mediana Edad , Medición de Riesgo , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/cirugíaRESUMEN
There are several classes of ATP-dependent chromatin remodeling complexes, which modulate the structure of chromatin to regulate a variety of cellular processes. The budding yeast, Saccharomyces cerevisiae, encodes two ATPases of the ISWI class, Isw1p and Isw2p. Previously Isw1p was shown to copurify with three other proteins. Here we identify these associated proteins and show that Isw1p forms two separable complexes in vivo (designated Isw1a and Isw1b). Biochemical assays revealed that while both have equivalent nucleosome-stimulated ATPase activities, Isw1a and Isw1b differ in their abilities to bind to DNA and nucleosomal substrates, which possibly accounts for differences in specific activities in nucleosomal spacing and sliding. In vivo, the two Isw1 complexes have overlapping functions in transcriptional regulation of some genes yet distinct functions at others. In addition, these complexes show different contributions to cell growth at elevated temperatures.
Asunto(s)
Adenosina Trifosfatasas/metabolismo , Proteínas de Unión al ADN/metabolismo , Nucleosomas/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Adenosina Trifosfatasas/genética , Adenosina Trifosfatasas/aislamiento & purificación , Secuencias de Aminoácidos , Secuencia de Aminoácidos , ADN de Hongos/metabolismo , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/aislamiento & purificación , Regulación Fúngica de la Expresión Génica , Sustancias Macromoleculares , Datos de Secuencia Molecular , Mutación , Análisis de Secuencia por Matrices de Oligonucleótidos , Isoformas de Proteínas , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/aislamiento & purificación , Homología de Secuencia de AminoácidoRESUMEN
This article reviewed some of the more common diseases of the skin appendages that are encountered in medicine: hyperhidrosis, acne, AA, FPHL, AGA, and TE. The pathophysiology behind the conditions and their treatments were discussed so that the clinician can make logical therapeutic choices for their affected patients.
Asunto(s)
Acné Vulgar/tratamiento farmacológico , Alopecia/terapia , Hiperhidrosis/terapia , Inhibidores de la Liberación de Acetilcolina/uso terapéutico , Algoritmos , Alopecia/clasificación , Alopecia/diagnóstico , Antibacterianos/uso terapéutico , Antitranspirantes/uso terapéutico , Peróxido de Benzoílo/uso terapéutico , Toxinas Botulínicas/uso terapéutico , Anticonceptivos Hormonales Orales/uso terapéutico , Fármacos Dermatológicos/uso terapéutico , Finasterida/uso terapéutico , Folículo Piloso/anatomía & histología , Humanos , Hiperhidrosis/diagnóstico , Hiperhidrosis/etiología , Iontoforesis , Ácidos Mandélicos/uso terapéutico , Minoxidil/uso terapéutico , Antagonistas Muscarínicos/uso terapéutico , Uñas/anatomía & histología , Retinoides/uso terapéutico , Espironolactona/uso terapéutico , Glándulas Sudoríparas/anatomía & histología , Glándulas Sudoríparas/cirugía , SimpatectomíaRESUMEN
When assessing a patient with a new dermatologic condition, developing a differential diagnosis is essential to ensure the condition is not elusive as a workup and potential therapy are considered. Subsequent narrowing of that differential based on history and physical examination can allow a more targeted approach to diagnostic testing and triage, and hasten an effective treatment and resolution. The authors hope to have provided useful historical and clinical clues to aid in the rapid differentiation of the more common diagnoses for alopecias and rashes of the face, intertriginous areas, and legs.