RESUMEN
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
RESUMEN
Immune responses need to be controlled tightly to prevent autoimmune diseases, yet underlying molecular mechanisms remain partially understood. Here, we identify biallelic mutations in three patients from two unrelated families in differentially expressed in FDCP6 homolog (DEF6) as the molecular cause of an inborn error of immunity with systemic autoimmunity. Patient T cells exhibit impaired regulation of CTLA-4 surface trafficking associated with reduced functional CTLA-4 availability, which is replicated in DEF6-knockout Jurkat cells. Mechanistically, we identify the small GTPase RAB11 as an interactor of the guanine nucleotide exchange factor DEF6, and find disrupted binding of mutant DEF6 to RAB11 as well as reduced RAB11+CTLA-4+ vesicles in DEF6-mutated cells. One of the patients has been treated with CTLA-4-Ig and achieved sustained remission. Collectively, we uncover DEF6 as player in immune homeostasis ensuring availability of the checkpoint protein CTLA-4 at T-cell surface, identifying a potential target for autoimmune and/or cancer therapy.
Asunto(s)
Antígeno CTLA-4/metabolismo , Proteínas de Unión al ADN/deficiencia , Factores de Intercambio de Guanina Nucleótido/deficiencia , Enfermedades de Inmunodeficiencia Primaria/genética , Antígeno B7-1/metabolismo , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/inmunología , Técnicas de Inactivación de Genes , Factores de Intercambio de Guanina Nucleótido/genética , Factores de Intercambio de Guanina Nucleótido/inmunología , Homeostasis , Humanos , Células Jurkat , Linfocitos T/metabolismo , Linfocitos T/fisiología , Proteínas de Unión al GTP rab/genética , Proteínas de Unión al GTP rab/metabolismoRESUMEN
PURPOSE: Autosomal recessive mutations in LRBA, encoding for LPS-responsive beige-like anchor protein, were described in patients with a common variable immunodeficiency (CVID)-like disease characterized by hypogammaglobulinemia, autoimmune cytopenias, and enteropathy. Here, we detail the clinical, immunological, and genetic features of a patient with severe autoimmune manifestations. METHODS: Whole exome sequencing was performed to establish a molecular diagnosis. Evaluation of lymphocyte subsets was performed for immunological characterization. Medical files were reviewed to collect clinical and immunological data. RESULTS: A 7-year-old boy, born to consanguineous parents, presented with autoimmune hemolytic anemia, hepatosplenomegaly, autoimmune thyroiditis, and severe autoimmune gastrointestinal manifestations. Immunological investigations revealed low immunoglobulin levels and low numbers of B and NK cells. Treatment included immunoglobulin replacement and immunosuppressive therapy. Seven years after disease onset, the patient developed severe neurological symptoms resembling acute disseminated encephalomyelitis, prompting allogeneic hematopoietic stem cell transplantation (HSCT) with the HLA-identical mother as donor. Whole exome sequencing of the patient uncovered a homozygous 1 bp deletion in LRBA (c.7162delA:p.T2388Pfs*7). Importantly, during 2 years of follow-up post-HSCT, marked clinical improvement and recovery of immune function was observed. CONCLUSIONS: Our data suggest a beneficial effect of HSCT in patients with LRBA deficiency.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/genética , Anemia Hemolítica Autoinmune/terapia , Linfocitos B/inmunología , Inmunodeficiencia Variable Común/terapia , Trasplante de Células Madre Hematopoyéticas , Células Asesinas Naturales/inmunología , Eliminación de Secuencia/genética , Anemia Hemolítica Autoinmune/diagnóstico , Anemia Hemolítica Autoinmune/genética , Autoinmunidad , Niño , Inmunodeficiencia Variable Común/diagnóstico , Inmunodeficiencia Variable Común/genética , Consanguinidad , Análisis Mutacional de ADN , Antígenos HLA/inmunología , Histocompatibilidad , Humanos , Inmunoglobulinas/sangre , Masculino , Resultado del TratamientoRESUMEN
There have been no previous reports on the use of interferon-free combinations in pediatric patients with chronic hepatitis C infection. An infected adolescent with severe sickle cell disease underwent stem cell transplantation and subsequent treatment with sofosbuvir and simeprevir during ongoing immunosuppression. Despite the emergence of peripheral edema as a side effect, treatment was continued with sustained antiviral response.
Asunto(s)
Anemia de Células Falciformes/complicaciones , Antivirales/administración & dosificación , Hepatitis C Crónica/tratamiento farmacológico , Simeprevir/administración & dosificación , Sofosbuvir/administración & dosificación , Trasplante de Células Madre , Receptores de Trasplantes , Adolescente , Antivirales/efectos adversos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Edema/inducido químicamente , Humanos , Masculino , Inhibidores de Proteasas/administración & dosificación , Inhibidores de Proteasas/efectos adversos , Simeprevir/efectos adversos , Sofosbuvir/efectos adversos , Respuesta Virológica SostenidaRESUMEN
The significance of the BK virus (BKV) and possible co-factors for the development of late onset haemorrhagic cystitis (HC) in allogeneic haematopoetic stem cell (HSCT)-transplanted patients is reviewed. BKV-associated HC causes significant morbidity and mortality in HSCT patients, however, BK-viruria cannot distinguish patients at risk of HC, since it is observed in patients with and without HC. Several studies have therefore attempted to identify co-factors for the development of HC. Acute graft versus host disease was in the past, though less so recently, reported to correlate to the incidence of HC. However, patients who had received grafts from unrelated donors (URD) and had had full conditioning prior to HSCT were shown to have an increased risk of HC, compared to patients who had received HSCT from a related donor (RD) or patients who had received reduced intensity conditioning. In conclusion, HSCT patients with BK-viruria, an URD and receiving full conditioning have an increased risk of developing HC.
Asunto(s)
Virus BK/fisiología , Cistitis/etiología , Cistitis/prevención & control , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trasplante de Células Madre Hematopoyéticas/métodos , Acondicionamiento Pretrasplante/métodos , Virus BK/genética , Cistitis/genética , Cistitis/virología , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/virología , Humanos , Infecciones por Polyomavirus/etiología , Infecciones por Polyomavirus/genética , Infecciones por Polyomavirus/prevención & control , Infecciones por Polyomavirus/virología , Donantes de Tejidos , Trasplante Homólogo , Infecciones Tumorales por Virus/etiología , Infecciones Tumorales por Virus/genética , Infecciones Tumorales por Virus/prevención & control , Infecciones Tumorales por Virus/virologíaRESUMEN
An association of a viral infection in utero and development of acute lymphoblastic leukemia (ALL) has been suggested. Cytomegalovirus (CMV) has been reported as a leading agent of intrauterine infections resulting in some cases of congenital infections. The authors investigated the presence of prenatal CMV infection in children who later developed ALL. Guthrie cards were obtained from 48 children with ALL and 46 healthy children and were analyzed for the presence of CMV DNA by a real-time TaqMan PCR. CMV DNA was not detected in Guthrie cards from the children with ALL, from the control healthy children. The results show that prenatal CMV infection does not seem to be associated with later development of childhood ALL.
Asunto(s)
Infecciones por Citomegalovirus/congénito , Citomegalovirus/aislamiento & purificación , ADN Viral/sangre , Tamizaje Neonatal/instrumentación , Leucemia-Linfoma Linfoblástico de Células Precursoras/epidemiología , Viremia/congénito , Adolescente , Adulto , Recolección de Muestras de Sangre/instrumentación , Niño , Preescolar , Citomegalovirus/patogenicidad , Infecciones por Citomegalovirus/embriología , Infecciones por Citomegalovirus/epidemiología , Femenino , Enfermedades Fetales/sangre , Enfermedades Fetales/virología , Humanos , Lactante , Recién Nacido , Masculino , Reacción en Cadena de la Polimerasa , Leucemia-Linfoma Linfoblástico de Células Precursoras/virología , Embarazo , Complicaciones Infecciosas del Embarazo/virología , Efectos Tardíos de la Exposición Prenatal , Estudios Retrospectivos , Factores de Riesgo , Suecia/epidemiología , Viremia/virologíaRESUMEN
The influence of BK-viruria, donor background, and conditioning on the development of hemorrhagic cystitis was examined in 90 allogeneic hematopoetic stem cell transplant patients, of whom 15 developed hemorrhagic cystitis. Thirty-two patients had related and 58 had unrelated donors, while 44 received full, and 46 received reduced intensity conditioning (RIC). BK-viruria was more common in patients with hemorrhagic cystitis than in those without (p<0.01), and hemorrhagic cystitis was less common in patients with related donors than in those with unrelated donors (p=0.02). Finally, hemorrhagic cystitis and BK-viruria were less common in patients receiving RIC, rather than full conditioning (p<0.01 and p<0.01, respectively).
Asunto(s)
Virus BK , Cistitis/epidemiología , Cistitis/virología , Trasplante de Células Madre Hematopoyéticas , Hemorragia/epidemiología , Hemorragia/virología , Infecciones por Polyomavirus/epidemiología , Infecciones Tumorales por Virus/epidemiología , Orina/virología , Adolescente , Adulto , Niño , Cistitis/orina , Femenino , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Hemorragia/orina , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Infecciones por Polyomavirus/cirugía , Infecciones por Polyomavirus/orina , Acondicionamiento Pretrasplante/efectos adversos , Trasplante Homólogo , Infecciones Tumorales por Virus/cirugía , Infecciones Tumorales por Virus/orinaRESUMEN
BACKGROUND: There has been much speculation about the cause of childhood acute lymphoblastic leukemia (ALL). It has been suggested, on the basis of findings in epidemiological studies, that ALL may be initiated by an in utero infection of the fetus. The human parvovirus B19 (B19) is etiologically related to human diseases, including erythema infectiosum and aplastic crisis, but it has not yet been considered to be involved in the development of ALL. Therefore, the aim of this study was to investigate, whether prenatal B19 infection could still be indirectly correlated with the development of childhood ALL. PROCEDURES: Fifty-four Guthrie cards, collected at 3-5 days of age, from Swedish children who subsequently developed ALL, as well as from 50 healthy controls, were investigated by nested PCR for the presence of B19 DNA. RESULTS: B19 DNA was not detected in any of the Guthrie cards from ALL patients or from healthy controls, although all tested samples had amplifiable cellular DNA as confirmed by an HLA DQ specific PCR. CONCLUSION: B19 DNA was not found in any of the Guthrie cards from children who later developed ALL or in the healthy controls. These findings suggest that it is less likely that childhood ALL is associated with an in utero in fection with B19.
Asunto(s)
ADN Viral/sangre , Tamizaje Neonatal , Parvovirus B19 Humano/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/virología , Adolescente , Estudios de Casos y Controles , Niño , Preescolar , Humanos , Recién Nacido , Transmisión Vertical de Enfermedad Infecciosa , Leucemia-Linfoma de Células T del Adulto/etiología , Leucemia-Linfoma de Células T del Adulto/virología , Reacción en Cadena de la Polimerasa , Leucemia-Linfoma Linfoblástico de Células Precursoras B/etiología , Leucemia-Linfoma Linfoblástico de Células Precursoras B/virología , Leucemia-Linfoma Linfoblástico de Células Precursoras/etiología , Suecia/epidemiologíaRESUMEN
BACKGROUND: Hemorrhagic cystitis (HC) in allogeneic bone marrow transplanted (BMT) patients is associated with BK virus (BKV) reactivation manifested as BK viruria. However, since 77-90% of all adult BMT patients excrete BKV, viral reactivation alone cannot be responsible for HC. Recently, a significant overrepresentation of C-->G mutations in the Sp1 binding site in the non-coding control region (NCCR) of BKV was shown to be present in HC patients and absent in non-HC patients. OBJECTIVES: We aimed to investigate if this mutation resulted in excessive BKV excretion in HC patients. STUDY DESIGN: A Real-Time PCR was developed and used to quantify BKV in urine samples from 21 patients with HC, with and without the mutations, as well as from patients without HC. RESULTS: Quantification of BKV was successful in 18 of 21 urine patients (six with and six without C-->G mutations) and six patients without HC. A mean of 3.0 x 10(6) BKV copies/microl was detected in urine samples of HC patients with C-->G mutations, compared to a mean of 1.5 x 10(6) BKV copies/microl in HC patients without C-->G mutations and a mean of 1.0 x 10(6) BKV copies/microl in patients without HC. The obtained differences were however not statistically significant, due to one individual non-HC patient with an extremely high BKV copy number. Nevertheless, while 50% of the samples in the HC groups expressed 1 x 10(6) copies/microl or more, only one of the samples in the non-HC group contained a virus quantity higher than 5 x 10(5) copies. CONCLUSIONS: Although we could not confirm that the C-->G mutations in the Sp1 site of BKV were responsible for an increased viral load in patients with HC, our data suggest that levels of BKV above 10(4) copies/microl may indicate a risk for HC.
Asunto(s)
Virus BK/aislamiento & purificación , Trasplante de Médula Ósea , Cistitis/virología , ADN Viral/orina , Infecciones por Polyomavirus/orina , Infecciones Tumorales por Virus/orina , Virus BK/genética , Sitios de Unión/genética , Sistemas de Computación , Cistitis/diagnóstico , Análisis Mutacional de ADN , Hemorragia/virología , Humanos , Huésped Inmunocomprometido , Mutación Puntual , Reacción en Cadena de la Polimerasa , Infecciones por Polyomavirus/diagnóstico , Infecciones por Polyomavirus/virología , Factor de Transcripción Sp1/metabolismo , Trasplante Homólogo , Infecciones Tumorales por Virus/diagnóstico , Infecciones Tumorales por Virus/virología , Orina/virología , Activación ViralRESUMEN
BACKGROUND: Epidemiological evidence has suggested that some childhood acute lymphoblastic leukemia (ALL) may be initiated in utero and may have an infectious etiology. The human polyomavirus JC virus (JCV) has been discussed as a candidate virus, but its presence has not been demonstrated in leukemia cells from children with ALL. The aim of this study was, therefore, to investigate if prenatal human polyomavirus infection could still indirectly be correlated to the development of childhood ALL. PROCEDURE: Fifty-four Guthrie cards (stored, dried blood spots filter papers, routinely collected from newborns for different screening analyses), collected at 3-5 days of age, from Swedish children who subsequently developed ALL, as well as from 37 healthy controls, were investigated by nested PCR for the presence of human polyomaviruses JCV and BK virus (BKV). RESULTS: JCV and BKV DNA were not detected in any of the Guthrie cards from ALL patients or from healthy controls, although all tested samples had amplifiable DNA as confirmed by an HLA DQ PCR. CONCLUSIONS: JCV or BKV were not found in any of the dried blood spots of children who later developed ALL or in the healthy controls. These findings suggest that it is unlikely that childhood ALL is associated with an in utero infection with JCV or BKV, although it is not possible to exclude an association with an in utero infection that has become latent in the kidneys with very low levels of circulating virus at birth.
Asunto(s)
ADN Viral/aislamiento & purificación , Virus JC/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/virología , Adolescente , Estudios de Casos y Controles , Niño , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Virus JC/aislamiento & purificación , Virus JC/patogenicidad , Masculino , Reacción en Cadena de la Polimerasa , Infecciones por Polyomavirus/complicaciones , Leucemia-Linfoma Linfoblástico de Células Precursoras/etiología , Infecciones Tumorales por Virus/complicacionesRESUMEN
UNLABELLED: Simian virus 40 (SV40), a contaminant of polio vaccines used in the United States and Europe between 1955 and 1963, has been detected with high frequency in human malignant mesotheliomas (MM). In Sweden, from 1958, due to production in Javanese macaque kidney cells and SV40 testing from 1961, only polio vaccine claimed to be free of SV40 has been used. Hence, we aimed to screen Swedish MM patients for the presence of SV40. MATERIALS AND METHODS: Forty-one paraffin-embedded pleural MM samples, obtained from patients born from 1893-1958, were examined for amplifiable DNA. Testable samples were thereafter evaluated for the presence of SV40 DNA by two types of polymerase chain reactions (PCR) followed by sequencing. RESULTS: SV40 could be confirmed by sequencing in only 3 of the 30 MM samples containing DNA that could be amplified by PCR. CONCLUSION: The presence of SV40 is not frequent in Swedish MM patients.