RESUMEN
Neutrophilic dermatoses are a group of inflammatory skin conditions characterized by a neutrophilic infiltrate on histopathology with no evidence of infection. These conditions present with a wide range of clinical manifestations, including pustules, bullae, abscesses, papules, nodules, plaques, and ulcers. The classification of neutrophilic dermatoses is based on the localization of neutrophils in the skin. The pathogenic mechanisms of neutrophilic dermatoses involve autoinflammation, neutrophilic dysfunction, clonal somatic mutation and differentiation of the myeloid precursors as encountered in myeloid neoplasm.
Asunto(s)
Dermatitis , Enfermedades de la Piel , Síndrome de Sweet , Humanos , Piel/patología , Enfermedades de la Piel/patología , Biología , Neutrófilos/patología , Síndrome de Sweet/diagnósticoRESUMEN
Tissue immunity and responses to injury depend on the coordinated action and communication among physiological systems. Here, we show that, upon injury, adaptive responses to the microbiota directly promote sensory neuron regeneration. At homeostasis, tissue-resident commensal-specific T cells colocalize with sensory nerve fibers within the dermis, express a transcriptional program associated with neuronal interaction and repair, and promote axon growth and local nerve regeneration following injury. Mechanistically, our data reveal that the cytokine interleukin-17A (IL-17A) released by commensal-specific Th17 cells upon injury directly signals to sensory neurons via IL-17 receptor A, the transcription of which is specifically upregulated in injured neurons. Collectively, our work reveals that in the context of tissue damage, preemptive immunity to the microbiota can rapidly bridge biological systems by directly promoting neuronal repair, while also identifying IL-17A as a major determinant of this fundamental process.
Asunto(s)
Interleucina-17 , Microbiota , Regeneración Nerviosa , Células Th17 , Axones , Regeneración Nerviosa/fisiología , Células Receptoras Sensoriales , Animales , Ratones , Células Th17/citologíaRESUMEN
Immune checkpoint inhibitors (ICIs) are essential components of the cancer therapeutic armamentarium. While ICIs have demonstrated remarkable clinical responses, they can be accompanied by immune-related adverse events (irAEs). These inflammatory side effects are of unclear etiology and impact virtually all organ systems, with the most common being sites colonized by the microbiota such as the skin and gastrointestinal tract. Here, we establish a mouse model of commensal bacteria-driven skin irAEs and demonstrate that immune checkpoint inhibition unleashes commensal-specific inflammatory T cell responses. These aberrant responses were dependent on production of IL-17 by commensal-specific T cells and induced pathology that recapitulated the cutaneous inflammation seen in patients treated with ICIs. Importantly, aberrant T cell responses unleashed by ICIs were sufficient to perpetuate inflammatory memory responses to the microbiota months following the cessation of treatment. Altogether, we have established a mouse model of skin irAEs and reveal that ICIs unleash aberrant immune responses against skin commensals, with long-lasting inflammatory consequences.
Asunto(s)
Dermatitis , Inhibidores de Puntos de Control Inmunológico , Microbiota , Animales , Dermatitis/inmunología , Dermatitis/microbiología , Modelos Animales de Enfermedad , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Inmunidad/efectos de los fármacos , Interleucina-17/metabolismo , Ratones , Microbiota/efectos de los fármacos , Microbiota/inmunología , Staphylococcus epidermidis/efectos de los fármacos , Staphylococcus epidermidis/inmunología , Simbiosis/efectos de los fármacos , Linfocitos T/inmunologíaRESUMEN
OBJECTIVE: To identify the molecular basis of a systemic autoinflammatory disorder (SAID) evocative of TNF receptor-associated periodic syndrome (TRAPS). METHODS: (i) Deep next generation sequencing (NGS) through a SAID gene panel; (ii) variant allele distribution in peripheral blood subpopulations; (iii) in silico analyses of mosaic variants using TNF receptor superfamily 1A (TNFRSF1A) crystal structure; (iv) review of the very rare TNFRSF1A mosaic variants reported previously. RESULTS: In a 36-year-old man suffering from recurrent fever for 12 years, high-depth NGS revealed a TNFRSF1A mosaic variant, c.176G>A p.(Cys59Tyr), which Sanger sequencing failed to detect. This mosaic variant displayed a variant allele fraction of 14% in whole blood; it affects both myeloid and lymphoid lineages. p.(Cys59Tyr), a recurrent germline pathogenic variant, affects a crucial cysteine located in the first cysteine-rich domain (CRD1) and involved in a disulphide bridge. Introduction of a tyrosine at this position is expected to disrupt the CRD1 structure. Review of the three previously reported TNFRSF1A mosaic variants revealed that they are all located in a small region of CRD2 and that germinal cells can be affected. CONCLUSION: This study expands the localization of TNFRSF1A mosaic variants to the CRD1 domain. Noticeably, residues involved in germline TNFRSF1A mutational hot spots can also be involved in post-zygotic mutational events. Including our study, only four patients have been thus far reported with TNFRSF1A mosaicism, highlighting the need for a high-depth NGS-based approach to avoid the misdiagnosis of TRAPS. Genetic counselling has to consider the potential occurrence of TNFRSF1A mosaic variants in germinal cells.
Asunto(s)
Cisteína , Enfermedades Autoinflamatorias Hereditarias , Masculino , Humanos , Adulto , Cisteína/genética , Receptores Tipo I de Factores de Necrosis Tumoral/genética , Fiebre/genética , Enfermedades Autoinflamatorias Hereditarias/genética , Enfermedades Autoinflamatorias Hereditarias/diagnóstico , MutaciónAsunto(s)
Síndromes Mielodisplásicos , Enfermedades de la Piel , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/metabolismo , Síndromes Mielodisplásicos/patología , Enfermedades de la Piel/genética , Enfermedades de la Piel/metabolismo , Enfermedades de la Piel/patologíaRESUMEN
IMPORTANCE: VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) is a recently described severe adult-onset autoinflammatory disease that is associated with myeloid lineage-restricted ubiquitin-activating enzyme 1 (UBA1) somatic variations that primarily affect the skin (Sweet syndrome), cartilage, and bone marrow. Skin symptoms have been poorly described. OBJECTIVE: To better describe clinical and pathological skin manifestations and their pathophysiology in VEXAS syndrome. DESIGN, SETTING, AND PARTICIPANTS: This multicenter retrospective case series study of clinical and histological features of 8 patients with VEXAS syndrome and skin involvement was conducted in France from December 2007 to March 2021, with molecular data obtained from March to April 2022. Any UBA1 variations were detected by Sanger or next-generation sequencing that was performed on bone marrow and formalin-fixed paraffin-embedded tissue sections of skin lesion biopsies. RESULTS: All 8 patients were men, and the median age at symptom onset was 65.5 years (interquartile range, 54-76 years). All patients had neutrophilic dermatosis skin lesions, including tender red or violaceous papules, sometimes edematous, without fever, arthralgia, recurrence or pathergy, inflammatory edematous papules on the neck and trunk (sometimes umbilicated), and firm erythematous purpuric or pigmented infiltrated plaques and nodules. Three patients had livedo racemosa. The infiltrates were perivascular and consisted of mature neutrophils with leukocytoclasia, which were admixed with myeloperoxidase-positive CD163-positive myeloid cells with indented nuclei and lymphoid cells in all cases. A sequencing analysis of paired bone marrow samples and skin lesion biopsies identified the same loss-of-function UBA1 variation in both samples for all patients. CONCLUSIONS AND RELEVANCE: This case series study describes the different clinical presentations of skin lesions found in VEXAS syndrome, which is characterized histologically by neutrophilic dermatosis. The findings suggested that the dermal infiltrates seen in VEXAS skin lesions are derived from the pathological myeloid clone. This suggests that using therapies that target the pathological clone may be effective in the long-term management of the disease.
Asunto(s)
Síndrome de Sweet , Enzimas Activadoras de Ubiquitina , Adulto , Médula Ósea , Humanos , Masculino , Mutación , Estudios Retrospectivos , Síndrome de Sweet/diagnóstico , Enzimas Activadoras de Ubiquitina/genéticaAsunto(s)
Contractura , Histiocitosis , Adulto , Anticuerpos Monoclonales Humanizados , Humanos , Interleucina-6 , Resultado del TratamientoRESUMEN
BACKGROUND: Some keloids show cystic cavities that give rise to acute inflammatory flares and oozing. These suppurative keloids (SK) have rarely been systematically studied. We conducted a retrospective cohort study to evaluate SK frequency and its risk factors. We also reviewed microbiological analyses as well as the histological features of removed SKs. METHODS: Between July 1, 2015, and September 30, 2016, all adult patients attending a specialized keloid clinic were asked to participate. Clinical information and microbiological results were extracted from each patient's file. Histological features were observed and interpreted. RESULTS: In this study, we observed an SK rate of 26% for a mean keloid history of 17.2 years. Male gender, African ancestry, and a family history of keloids were significantly associated with suppuration. Microbiological examination revealed commensal skin flora 7/9 (77.8%), Staphylococcus aureus 1/9 (11.1%), and Enterococcus faecalis 1/9 (11.1%). CONCLUSION: Suppuration is a common complication of keloids occurring in patients with severe keloid disease and may arise from pilosebaceous occlusion and aseptic inflammation.
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Queloide , Adulto , Humanos , Queloide/epidemiología , Queloide/etiología , Queloide/patología , Masculino , Anamnesis , Estudios Retrospectivos , Piel/patología , Supuración/patologíaRESUMEN
OBJECTIVES: TNF receptor-1-associated periodic syndrome (TRAPS) is a rare autosomal dominant autoinflammatory disorder associated with mutations in the TNF receptor super family 1 A (TNFRSF1A) gene. AA amyloidosis (AA) is the most severe complication of TRAPS. To study the occurrence and prognosis of AA in TRAPS, we conducted a retrospective study of all French cases and a systematic literature review. METHODS: This case series includes TRAPS patients followed by our centre from 2000 to 2020 presenting with histologically confirmed AA. We conducted a systematic literature review on the PubMed and EMBASE databases for articles published up to February 2021 following the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines and using the keywords: amyloidoisis, amyloid, TNF receptor-associated periodic syndrome, TNF receptor-associated periodic syndrome, tumor necrosis factor receptor-associated periodic syndrome, TRAPS, TNFRSF1A, familial hibernian fever and hibernian familial fever. RESULTS: A total of 41 TRAPS with AA were studied: three new patients and 38 cases from the literature. AA diagnosis preceded that of TRAPS in 96% of cases, and 17/36 (47%) required renal replacement therapy. Death occurred in 5/36 (14%) with a median follow-up of 23 months. Effect of biologics on AA were available for 21 regimens in 19 patients: 10 improved renal function, seven stabilized and four worsened. Four patients (36% of transplanted patients) relapse AA on kidney graft (only one under etanercept). CONCLUSION: TRAPS is revealed by AA in most cases. Therefore, clinical features of TRAPS should be screened for in AA patients. IL-1 antagonist can help to normalize inflammation and to preserve renal function.
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Amiloidosis/etiología , ADN/genética , Fiebre/complicaciones , Enfermedades Autoinflamatorias Hereditarias/complicaciones , Mutación , Receptores Tipo I de Factores de Necrosis Tumoral/genética , Amiloidosis/genética , Análisis Mutacional de ADN , Fiebre/genética , Fiebre/metabolismo , Enfermedades Autoinflamatorias Hereditarias/genética , Enfermedades Autoinflamatorias Hereditarias/metabolismo , Humanos , Receptores Tipo I de Factores de Necrosis Tumoral/metabolismo , Proteína Amiloide A Sérica/genéticaAsunto(s)
Pustulosis Exantematosa Generalizada Aguda/etiología , Antirreumáticos/efectos adversos , Infecciones por Coronavirus/tratamiento farmacológico , Hidroxicloroquina/efectos adversos , Neumonía Viral/tratamiento farmacológico , Anciano , Antirreumáticos/uso terapéutico , Betacoronavirus , COVID-19 , Femenino , Humanos , Hidroxicloroquina/uso terapéutico , Pandemias , SARS-CoV-2 , Tratamiento Farmacológico de COVID-19Asunto(s)
Prepucio , Paraqueratosis , Prepucio/cirugía , Humanos , Masculino , Paraqueratosis/diagnóstico , PeneRESUMEN
is missing (Short communication).
Asunto(s)
Infecciones por Virus de Epstein-Barr , Linfoma de Células B Grandes Difuso , Linfoma Cutáneo de Células T , Micosis Fungoide , Neoplasias Cutáneas , Humanos , Linfoma de Células B Grandes Difuso/inducido químicamente , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma Cutáneo de Células T/inducido químicamente , Linfoma Cutáneo de Células T/diagnóstico , Linfoma Cutáneo de Células T/tratamiento farmacológico , Metotrexato/efectos adversos , Neoplasias Cutáneas/tratamiento farmacológicoRESUMEN
BACKGROUND: Castleman disease (CD) is a rare non-malignant lymphoproliferation of undetermined origin. Two major disease phenotypes can be distinguished: unicentric CD (UCD) and multicentric CD (MCD). Diagnosis confirmation is based on histopathological findings in a lymph node. We attempted to survey all cases of paediatric CD identified to date in France to set up a national registry aiming to improve CD early recognition, treatment and follow-up, within the context of a new national reference center (http://www.castleman.fr). METHODS: In 2016, we e-mailed a questionnaire to members of the French paediatric immunohaematology society, the paediatric rheumatology society and the Reference Centre for Castleman Disease to retrospectively collect cases of paediatric CD (first symptoms before age 18 years). Anatomopathological confirmation was mandatory. RESULTS: We identified 23 patients (12 girls) with a diagnosis of UCD (n = 17) and MCD (n = 6) between 1994 and 2018. The mean age at first symptoms was 11.47 ± 4.23 years for UCD and 8.3 ± 3.4 years for MCD. The mean diagnosis delay was 8.16 ± 10.32 months for UCD and 5.16 ± 5.81 years for MCD. In UCD, the initial symptoms were isolated lymph nodes (n = 10) or lymph node associated with other symptoms (n = 7); fever was present in 3 patients. Five patients with MCD presented fever. No patients had HIV or human herpesvirus 8 infection. Autoinflammatory gene mutations were investigated in five patients. One patient with MCD carried a K695R heterozygous mutation in MEFV, another patient with MCD and Duchenne myopathy carried two variants in TNFRSF1A and one patient with UCD and fever episodes carried two heterozygous mutations, in IL10RA and IL36RN, respectively. Treatment of UCD was mainly surgical resection, steroids, and radiotherapy. Treatment of MCD included tocilizumab, rituximab, anakinra, steroids, chemotherapy, and splenectomy. Overall survival after a mean of 6.1 ± 6.4 years of follow-up, was 100% for both forms. CONCLUSION: Paediatric CD still seems underdiagnosed, with a significant diagnosis delay, especially for MCD, but new international criteria will help in the future. Unlike adult CD, which is strongly associated with HIV and human herpesvirus 8 infection, paediatric CD could be favored by primary activation of innate immunity and may affect life expectancy less.
Asunto(s)
Enfermedad de Castleman , Adolescente , Adulto , Enfermedad de Castleman/diagnóstico , Niño , Femenino , Francia/epidemiología , Humanos , Interleucinas , Ganglios Linfáticos , Pirina , Estudios Retrospectivos , RituximabAsunto(s)
Exantema , Hiperpigmentación , Cetosis , Prurigo , Humanos , Internet , Prurigo/diagnóstico , Prurigo/tratamiento farmacológicoRESUMEN
Glucocorticoids (GCs) are amongst the most widely used and effective treatments to control inflammatory and autoimmune diseases. In obese subjects, drug dosing adjusted by body weight is problematic, all the more so as patients are at higher risk of GC metabolic side effects. We propose here to describe the determinants of drug pharmacokinetics (PK) in obese subjects and GC pharmacology, and to identify the existing PK studies that may help discussing the best size descriptor for GC dosing in obese subjects. A clinician and a pharmacist screened PubMed using the MeSH Terms: "glucocorticoids" OR "steroidal agents" AND "pharmacokinetics" AND "obesity" OR "overweight". The search was limited to the publications written in English language and to those performed in humans. A systematic search using the MeSH terms was performed until August 31st, 2017. Only three such PK studies have been published so far that compare dexamethasone, prednisolone and methylprednisolone in obese and normal weight subjects. The studies concur that GC partially distribute in the excess of body weight and that adjustment by total body weight (TBW) or by body weight (BW) excess would increase the initial plasma GC concentration after a loading dose and would thus be inappropriate. Contradictory results are observed regarding GC exposure or clearance according to the GC studied. Behind this overwhelming lack of conclusive evidence for adjusting GC by body weight, further PK studies are clearly needed for guiding their dosing. Furthermore, studies demonstrated an increased sensibility to GC, even when GC exposure was reduced, suggesting that adjustment by body weight may not only be unnecessary but also dangerous.