RESUMEN
Patients with primary immunodeficiencies are especially vulnerable to developing severe coronavirus disease 2019 (COVID-19) after infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Cytotoxic T lymphocyte antigen-4 (CTLA-4) is an important regulator of immune responses, and patients who suffer from CTLA4 haploinsufficiency have hyperactivation of effector T cells and infiltration of various organs. Overexpression of CTLA4 has been associated with a more severe disease course in patients with COVID-19, but there have only been a few reports on the disease course of COVID-19 in patients with CTLA4 haploinsufficiency. We report on a 33-year-old female with a history of immune thrombocytopenia, autoimmune haemolytic anaemia, granulomatous-lymphocytic interstitial lung disease, and common variable immunodeficiency who developed COVID-19. She was admitted and discharged from the hospital several times in the months thereafter and remained symptomatic and had a positive SARS-CoV-2 PCR for up to 137 days after the first symptoms. No SARS-CoV-2 antibodies were identified in the patients' serum. The disease was finally controlled after repeated infusions of convalescent plasma and treatment of concurrent bacterial and fungal infections. Genetic analysis revealed a likely pathogenic variant in CTLA4, and CTLA4 expression on regulatory T-cells was low. This case illustrates that patients with primary immunodeficiencies who have a protracted disease course of COVID-19 could benefit from convalescent plasma therapy.
Asunto(s)
Enfermedades Pulmonares/genética , Linfopenia/genética , Enfermedades de Inmunodeficiencia Primaria/genética , Proteínas de Unión al GTP rac/genética , Adulto , Linfocitos B/inmunología , Progresión de la Enfermedad , Proteínas Activadoras de GTPasa/metabolismo , Mutación con Ganancia de Función , Enfermedad Injerto contra Huésped/tratamiento farmacológico , Guanosina Trifosfato/metabolismo , Trasplante de Células Madre Hematopoyéticas , Heterocigoto , Humanos , Memoria Inmunológica/inmunología , Inmunosupresores/uso terapéutico , Lactante , Enfermedades Pulmonares/inmunología , Enfermedades Pulmonares/fisiopatología , Enfermedades Pulmonares/cirugía , Trasplante de Pulmón , Linfopenia/inmunología , Masculino , Simulación del Acoplamiento Molecular , Neutrófilos , Enfermedades de Inmunodeficiencia Primaria/inmunología , Enfermedades de Inmunodeficiencia Primaria/terapia , Recurrencia , Infecciones del Sistema Respiratorio/inmunología , Subgrupos de Linfocitos T/inmunología , Linfocitos T/inmunología , Proteínas de Unión al GTP rac/inmunología , Proteínas de Unión al GTP rac/metabolismo , Proteínas de Unión al GTP rac/ultraestructura , Proteína RCA2 de Unión a GTPRESUMEN
Serotonergic signaling is involved in many neurobiological processes and disturbed 5-HT homeostasis is implicated in a variety of psychiatric and addictive disorders. Here, we describe the functional characterization of the serotonin transporter (SERT) knockout rat model, that is generated by N-ethyl-N-nitrosurea (ENU)-driven target-selected mutagenesis. Biochemical characterization revealed that SERT mRNA and functional protein are completely absent in homozygous knockout (SERT-/-) rats, and that there is a gene dose-dependent reduction in the expression and function of the SERT in heterozygous knockout rats. As a result, 5-HT homeostasis was found to be severely affected in SERT-/- rats: 5-HT tissue levels and depolarization-induced 5-HT release were significantly reduced, and basal extracellular 5-HT levels in the hippocampus were ninefold increased. Interestingly, we found no compensatory changes in in vitro activity of tryptophan hydroxylase and monoamine oxidase, the primary enzymes involved in 5-HT synthesis and degradation, respectively. Similarly, no major adaptations in non-serotonergic systems were found, as determined by dopamine and noradrenaline transporter binding, monoamine tissue levels, and depolarization-induced release of dopamine, noradrenaline, glutamate and GABA. In conclusion, neurochemical changes in the SERT knockout rat are primarily limited to the serotonergic system, making this novel rat model potentially very useful for studying the behavioral and neurobiological consequences of disturbed 5-HT homeostasis.
Asunto(s)
Química Encefálica/genética , Proteínas de Transporte de Serotonina en la Membrana Plasmática/deficiencia , Serotonina/metabolismo , Animales , Animales Modificados Genéticamente , Monoaminooxidasa/metabolismo , Mutagénesis/efectos de los fármacos , Mutagénesis/fisiología , Neurotransmisores/metabolismo , Nitrosometiluretano/farmacología , Ratas , Proteínas de Transporte de Serotonina en la Membrana Plasmática/fisiología , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Triptófano Hidroxilasa/metabolismoRESUMEN
The D(3) dopamine receptor has been implicated in several neuropsychiatric disorders, including schizophrenia, Parkinson's disease and addiction. Sequence variation in the D(3) gene can lead to subtle alteration in receptor structure or gene expression and thus to a different phenotype. In this study we examine the sequence variation in the D(3) gene in 96 rat strains and substrains. Interestingly, the analyses revealed 10 polymorphisms in the 5'flanking region and four polymorphisms in intronic regions of the gene. Moreover, two single nucleotide polymorphisms (SNPs) that result in amino acid changes were found in the last exon of the D(3) gene in the RNU/Mol strain. Additionally, bioinformatic analysis of the 5'flanking region and first intron of the gene revealed putative transcription factor binding sites that are conserved between mouse and human and are affected by the SNPs, possibly resulting in altered regulation of the subsequent transcription factor.
