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
Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is an inherited disorder of immunity which leads to increased risk for mucocutaneous candidiasis and multiorgan autoimmune disease. While alopecia areata (AA) has been described in some patients with APECED, the extent and timing of AA is not well established and extent and timing of concomitant vitiligo and hypothyroidism has not been described. We evaluated an APECED cohort followed at the National Institutes of Health for the timing of development of associated diseases. We found AA occurred earlier in those with APECED than in the general population, was rarely the first sign of APECED, and the timing of AA onset did correlate with the timing of onset of vitiligo or hypothyroidism which also occurred at high rates and early age.
Asunto(s)
Alopecia Areata , Hipotiroidismo , Poliendocrinopatías Autoinmunes , Vitíligo , Humanos , Poliendocrinopatías Autoinmunes/complicaciones , Poliendocrinopatías Autoinmunes/epidemiología , Alopecia Areata/complicaciones , Alopecia Areata/epidemiología , Alopecia Areata/diagnóstico , Vitíligo/complicaciones , Vitíligo/epidemiología , Hipotiroidismo/complicaciones , Hipotiroidismo/epidemiologíaRESUMEN
Binding levels and neutralization activity of anti-type 1 interferon autoantibodies peaked during acute coronavirus disease 2019 and markedly decreased thereafter. Most patients maintained some ability to neutralize type 1 interferon into convalescence despite lower levels of binding immunoglobulin G. Identifying these autoantibodies in healthy individuals before the development of critical viral disease may be challenging.
Asunto(s)
COVID-19 , Interferón Tipo I , Autoanticuerpos , Humanos , Inmunoglobulina G , Interferón-alfaRESUMEN
BACKGROUND: SARS-CoV-2 vaccination is recommended in patients with inborn errors of immunity (IEIs); however, little is known about immunogenicity and safety in these patients. OBJECTIVE: We sought to evaluate the impact of genetic diagnosis, age, and treatment on antibody response to COVID-19 vaccine and related adverse events in a cohort of patients with IEIs. METHODS: Plasma was collected from 22 health care worker controls, 81 patients with IEIs, and 2 patients with thymoma; the plasma was collected before immunization, 1 to 6 days before the second dose of mRNA vaccine, and at a median of 30 days after completion of the immunization schedule with either mRNA vaccine or a single dose of Johnson & Johnson's Janssen vaccine. Anti-spike (anti-S) and anti-nucleocapsid antibody titers were measured by using a luciferase immunoprecipitation systems method. Information on T- and B-cell counts and use of immunosuppressive drugs was extracted from medical records, and information on vaccine-associated adverse events was collected after each dose. RESULTS: Anti-S antibodies were detected in 27 of 46 patients (58.7%) after 1 dose of mRNA vaccine and in 63 of 74 fully immunized patients (85.1%). A lower rate of seroconversion (7 of 11 [63.6%]) was observed in patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. Previous use of rituximab and baseline counts of less than 1000 CD3+ T cells/mL and less than 100 CD19+ B cells/mL were associated with lower anti-S IgG levels. No significant adverse events were reported. CONCLUSION: Vaccinating patients with IEIs is safe, but immunogenicity is affected by certain therapies and gene defects. These data may guide the counseling of patients with IEIs regarding prevention of SARS-CoV-2 infection and the need for subsequent boosts.
Asunto(s)
Factores de Edad , Linfocitos B/inmunología , Vacunas contra la COVID-19/inmunología , COVID-19/inmunología , Poliendocrinopatías Autoinmunes/inmunología , SARS-CoV-2/fisiología , Linfocitos T/inmunología , Adolescente , Adulto , Anciano , Anticuerpos Antivirales/sangre , Formación de Anticuerpos , COVID-19/genética , Estudios de Cohortes , Proteínas de la Nucleocápside de Coronavirus/inmunología , Femenino , Humanos , Inmunización Secundaria , Inmunogenicidad Vacunal , Inmunoglobulina G/sangre , Inmunosupresores/uso terapéutico , Recuento de Linfocitos , Masculino , Persona de Mediana Edad , Fosfoproteínas/inmunología , Poliendocrinopatías Autoinmunes/tratamiento farmacológico , Poliendocrinopatías Autoinmunes/genética , Rituximab/uso terapéutico , Seroconversión , Glicoproteína de la Espiga del Coronavirus/inmunología , Adulto Joven , Tratamiento Farmacológico de COVID-19RESUMEN
CONTEXT: The monogenic disorder autoimmune polyendocrine syndrome type 1 (APS-1) or autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) manifests frequently with hypoparathyroidism, which requires treatment with oral supplementation with calcium and active vitamin D analogs. The majority of APS-1/APECED patients also suffer from intestinal malabsorption, which complicates the management of hypoparathyroidism and may lead to refractory severe hypocalcaemia. In such situations, reliance on intravenous calcium carries a high risk of nephrocalcinosis and renal damage. METHODS: Here, we report our experience of periprocedural subcutaneous administration of recombinant human parathyroid hormone (rhPTH 1-34) in APS-1/APECED patients. Serum calcium was measured up to five times within the 36-hour period starting the evening before the scheduled procedure and ending the morning following the procedure. RESULTS: Twenty-seven APS-1/APECED patients with hypoparathyroidism (aged 4-67 years) underwent 31 invasive gastrointestinal and/or pulmonary procedures. The patients received an average rhPTH1-34 dose of 9.6 ± 1.4 µg by subcutaneous injection. 92% of the adults and 54% of children in our cohort had evidence of nephrocalcinosis. Mean calcium levels remained stable and ranged from 2.06 to 2.17 mmol/L with minimal fluctuation. None of our patients experienced periprocedural adverse events connected with hypocalcaemia. CONCLUSION: rhPTH 1-34 is an alternative to conventional therapy in patients with APS-1/APECED and hypoparathyroidism undergoing invasive procedures. Subcutaneous PTH1-34 given directly before and after procedures resulted in well-controlled serum calcium levels maintained in the low-normal range and avoided the need for intravenous calcium which may contribute to renal calcifications and tubular damage.
Asunto(s)
Hipocalcemia , Hipoparatiroidismo , Hormona Paratiroidea , Poliendocrinopatías Autoinmunes , Adulto , Calcio/sangre , Niño , Humanos , Hipocalcemia/tratamiento farmacológico , Hipoparatiroidismo/tratamiento farmacológico , Hormona Paratiroidea/administración & dosificación , Poliendocrinopatías Autoinmunes/sangre , Poliendocrinopatías Autoinmunes/tratamiento farmacológicoAsunto(s)
Infecciones Neumocócicas/complicaciones , Poliendocrinopatías Autoinmunes/complicaciones , Sepsis/complicaciones , Enfermedades del Bazo/complicaciones , Adulto , Femenino , Humanos , Infecciones Neumocócicas/sangre , Poliendocrinopatías Autoinmunes/sangre , Sepsis/sangre , Enfermedades del Bazo/sangre , Streptococcus pneumoniae/aislamiento & purificaciónAsunto(s)
Proteinuria , Triazoles , Humanos , Proteinuria/inducido químicamente , Triazoles/efectos adversosAsunto(s)
Ingestión de Alimentos , Ayuno/efectos adversos , Peritonitis/etiología , Poliendocrinopatías Autoinmunes/complicaciones , Adulto , Biomarcadores/sangre , Peso Corporal , Proteína C-Reactiva/metabolismo , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Peritonitis/sangre , Peritonitis/diagnóstico , Poliendocrinopatías Autoinmunes/sangre , Poliendocrinopatías Autoinmunes/diagnóstico , Tomografía Computarizada por Rayos X , Adulto JovenRESUMEN
Prototheca wickerhamii is a rare cause of cutaneous and systemic infection that requires long treatment courses with potentially toxic medications. We describe a patient with cutaneous protothecosis refractory to triazole monotherapy who experienced clinical and radiographic improvement with the novel oral lipid nanocrystal formulation of amphotericin B without experiencing toxicity.