RESUMEN
Patients with autoimmune polyendocrinopathy syndrome type 1 (APS-1) caused by autosomal recessive AIRE deficiency produce autoantibodies that neutralize type I interferons (IFNs)1,2, conferring a predisposition to life-threatening COVID-19 pneumonia3. Here we report that patients with autosomal recessive NIK or RELB deficiency, or a specific type of autosomal-dominant NF-κB2 deficiency, also have neutralizing autoantibodies against type I IFNs and are at higher risk of getting life-threatening COVID-19 pneumonia. In patients with autosomal-dominant NF-κB2 deficiency, these autoantibodies are found only in individuals who are heterozygous for variants associated with both transcription (p52 activity) loss of function (LOF) due to impaired p100 processing to generate p52, and regulatory (IκBδ activity) gain of function (GOF) due to the accumulation of unprocessed p100, therefore increasing the inhibitory activity of IκBδ (hereafter, p52LOF/IκBδGOF). By contrast, neutralizing autoantibodies against type I IFNs are not found in individuals who are heterozygous for NFKB2 variants causing haploinsufficiency of p100 and p52 (hereafter, p52LOF/IκBδLOF) or gain-of-function of p52 (hereafter, p52GOF/IκBδLOF). In contrast to patients with APS-1, patients with disorders of NIK, RELB or NF-κB2 have very few tissue-specific autoantibodies. However, their thymuses have an abnormal structure, with few AIRE-expressing medullary thymic epithelial cells. Human inborn errors of the alternative NF-κB pathway impair the development of AIRE-expressing medullary thymic epithelial cells, thereby underlying the production of autoantibodies against type I IFNs and predisposition to viral diseases.
Asunto(s)
Autoanticuerpos , Predisposición Genética a la Enfermedad , Interferón Tipo I , FN-kappa B , Humanos , Autoanticuerpos/inmunología , COVID-19/genética , COVID-19/inmunología , Mutación con Ganancia de Función , Heterocigoto , Proteínas I-kappa B/deficiencia , Proteínas I-kappa B/genética , Interferón Tipo I/antagonistas & inhibidores , Interferón Tipo I/inmunología , Mutación con Pérdida de Función , FN-kappa B/deficiencia , FN-kappa B/genética , Subunidad p52 de NF-kappa B/deficiencia , Subunidad p52 de NF-kappa B/genética , Neumonía Viral/genética , Neumonía Viral/inmunología , Timo/anomalías , Timo/inmunología , Timo/patología , Células Epiteliales Tiroideas/metabolismo , Células Epiteliales Tiroideas/patología , Proteína AIRE , Quinasa de Factor Nuclear kappa BRESUMEN
Unusual viral skin infections might be the first clinical manifestation in children with an inborn error of immunity (IEI). We performed a prospective study from 1 October 2017 to 30 September 2021, at the Department of Pediatric Infectious Diseases and Clinical Immunity of Ibn Rochd University Hospital-Casablanca. During this period, on 591 patients newly diagnosed with a probable IEI, eight of them (1.3%), from six independent families, had isolated or syndromic unusual viral skin infections, which were either profuse, chronic or recurrent infections, and resistant to any treatment. The median age of disease onset was nine years old and all patients were born from a first-degree consanguineous marriage. By combining clinical, immunological and genetic investigations, we identified GATA2 deficiency in one patient with recalcitrant profuse verrucous lesions and monocytopenia (1/8) and STK4 deficiency in two families with HPV lesions, either flat or common warts, and lymphopenia (2/8), as previously reported. We also identified COPA deficiency in twin sisters with chronic profuse Molluscum contagiosum lesions, pulmonary diseases and microcytic hypochromic anemia (2/8). Finally, we also found one patient with chronic profuse MC lesions and hyper IgE syndrome, (1/8) and two patients with either recalcitrant profuse verrucous lesions or recurrent post-herpetic erythema multiforme and a combined immunodeficiency (2/8) with no genetic defect identified yet. Raising clinicians awareness that infectious skin diseases might be the consequence of an inborn error of immunity would allow for optimized diagnosis, prevention and treatment of patients and their families.
RESUMEN
BACKGROUND: Circumcision in hemophiliacs is a delicate surgery because of bleeding risks that could be avoided by adequate substitution of coagulation factor. This practice is very challenging in countries where anti hemophilic treatment is inaccessible. The study aimed to evaluate a circumcision protocol in hemophilia A using low quantities of factor concentrates. METHODS: This prospective study included 26 hemophiliacs A who underwent circumcision in 2014. Medical treatment protocol using low quantity of factor concentrates was drafted by physicians of the Hemophilia Treatment Center and the surgical protocol by experienced surgeons. Assessment criteria were: number of hospitalization days, number of exposure days to factor concentrates, delay to healing and occurrence of bleeding events. RESULTS: Mean age was 9.6 years (1-30). Hemophiliacs patients were classified as severe (n = 8), moderate (n = 9) and mild form (n = 9). Mean number of exposure days to factor VIII concentrates was 6.9 days (5-12) in children and 10.75 days (7-16) in adults (p = 0.0049); mean number of hospitalization days was 3.68 days (2-10) in children and 13.5 days (13-15) in adults (p = 0.0000); delay to healing was 26.47 days (20-35) in children and 25.25 days (22-30) in adults (p = 0.697); five haemophiliacs (19.2%) presented bleeding events after the circumcision. The mean amount of FIII concentrates used per patient was 1743 IU (810-2340). CONCLUSION: The study shows treatment protocol using low quantity of factor concentrates is efficient in hemophilia patients who underwent circumcision.