RESUMO
We describe the unique disease course and cure of SARS-CoV-2 infection in a patient with SCID and graft failure. In absence of a humoral immune response, viral clearance was only achieved after transfusion of convalescent plasma. This observation underscores the necessity of the humoral immune response for SARS-CoV-2 clearance.
Assuntos
COVID-19/terapia , SARS-CoV-2/fisiologia , Imunodeficiência Combinada Severa/complicações , Adulto , Anticorpos Antivirais/sangue , COVID-19/complicações , COVID-19/imunologia , COVID-19/virologia , Feminino , Rejeição de Enxerto/complicações , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/virologia , Humanos , Imunização Passiva , Imunodeficiência Combinada Severa/imunologia , Imunodeficiência Combinada Severa/virologia , Resposta Viral Sustentada , Carga Viral , Replicação Viral , Soroterapia para COVID-19Assuntos
Hepatite E , Imunodeficiência Combinada Severa , Adulto , Anticorpos Antivirais/sangue , Antivirais/uso terapêutico , Doença Crônica , Feminino , Hepatite E/tratamento farmacológico , Hepatite E/genética , Hepatite E/imunologia , Hepatite E/virologia , Vírus da Hepatite E/genética , Vírus da Hepatite E/imunologia , Humanos , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Janus Quinase 3/genética , RNA Viral/sangue , Recidiva , Ribavirina/uso terapêutico , Imunodeficiência Combinada Severa/tratamento farmacológico , Imunodeficiência Combinada Severa/genética , Imunodeficiência Combinada Severa/imunologia , Imunodeficiência Combinada Severa/virologia , Linfócitos T/imunologiaRESUMO
BACKGROUND: Severe Acute Respiratory Syndrome Coronavirus 2 has affected millions of people, and especially in adult patients with underlying diseases lead to death. Meanwhile pediatric patients with inherited defects of T cell should be prone to viral diseases. CASE PRESENTATION: Herein, we report an infant with severe combined immunodeficiencies, who were affected and died because of COVID-19. CONCLUSION: Considering the importance of finding how immune system can affect the viral infection, presentation of COVID-19 in immune deficient patients can be valuable.
Assuntos
COVID-19/patologia , Imunodeficiência Combinada Severa/complicações , Evolução Fatal , Humanos , Recém-Nascido , Masculino , Imunodeficiência Combinada Severa/virologiaRESUMO
BACKGROUND/AIMS: The study aimed to explore the effects of Epstein-Barr virus--encoded BARF1 in human gastric epithelial cells (GES-1). MATERIALS AND METHODS: A eukaryotic expression vector carrying BARF1 gene (pcDNA3.1-BARF1) was constructed. The pcDNA3.1-BARF1 was transfected into GES-1 cells, and they were selected by G418. The GES-1 cells lines that expressed BARF1 (GES-1-BARF1) were obtained. The cycle of GES-1-pcDNA3.1 cells (GES-1 cells transfected with empty vector), GES-1-BARF1 cells (GES-1 cells transfected with BARF1), and TPA-GES-1-BARF1(GES-1-BARF1 cells stimulated by 12-O-tetradecanoylphorbol-13-acetate (TPA) were analyzed by flow cytometry. Colony formation in soft agar and tumorigenicity of the transfected cells in mice with severe combined immunodeficiency (SCID) were also observed. RESULTS: The morphology of GES-1-BARF1 cells were changed from the original shuttle to round, the adhesion between the cells and bottle wall was weakened, and the cells showed overlapping growth. The proliferation rate of GES-1-BARF1 and TPA-GES-1-BARF1 cells were faster than GES-1 and GES-1-pcDNA3.1 cells; the S phase was significantly prolonged for GES-1-BARF1 and TPA-GES-1-BARF1. GES-1-BARF1 and TPA-GES-1-BARF1 cells formed colonies in soft agar, with a cloning rate of 24.2% (58/240) and 40.0% (96/240), respectively; GES-1 and GES-1-pcDNA3.1 cells did not form colonies in soft agar. Tumors were formed in mice with SCID after injecting TPA-GES-1-BARF1 cell groups. Tumor formation did not occur in mice with SCID after injecting GES-1 and GES-1-pcDNA3.1 cell groups, but nodules were formed in the mice with SCID after injecting GES-1-BARF1 cell groups. CONCLUSION: GES-1-BARF1 cells malignant transformation was induced by transfected BARF1 gene and TPA stimulation. This result indicated that tumor formation not only require oncogenes, but also the stimulation of cancer-promoting substance.
Assuntos
Carcinogênese/genética , Células Epiteliais/metabolismo , Mucosa Gástrica/metabolismo , Herpesvirus Humano 4/genética , Proteínas Virais/metabolismo , Animais , Carcinogênese/induzido quimicamente , Modelos Animais de Doenças , Células Epiteliais/virologia , Mucosa Gástrica/virologia , Humanos , Camundongos , Imunodeficiência Combinada Severa/genética , Imunodeficiência Combinada Severa/virologia , Acetato de Tetradecanoilforbol/análogos & derivados , Acetato de Tetradecanoilforbol/farmacologia , TransfecçãoRESUMO
Human noroviruses (HuNoVs) are a leading cause of acute gastroenteritis worldwide. It is unclear which arm of the immune system regulates resistance to HuNoV infection. Thus, we studied the pathogenesis of human norovirus (HuNoV) in T-B-NK+ Severe Combined Immunodeficiency (SCID) gnotobiotic pigs to investigate the role of innate (especially, natural killer (NK) cells) immunity in HuNoV infection. Forty SCID and non-SCID pigs were randomly grouped: 1) SCID+HuNoV (n = 12); 2) non-SCID+HuNoV (n = 14); 3) SCID mock-inoculated (n = 6); and 4) non-SCID mock-inoculated (n = 8). Pigs (8-14-day-old) were inoculated orally with GII.4 HuNoV strain HS292 (mean 9.1 log10 genomic equivalents/pig) or mock. Daily fecal consistency and fecal viral RNA shedding, and histopathology (at euthanasia) were evaluated. Frequencies of blood and ileal T, B, and NK cells were analyzed by flow cytometry, and a NK cell cytotoxicity assay was performed at post-inoculation day (PID) 8. Unlike the increased infectivity of HuNoV observed previously in T-B-NK- SCID pigs (Lei et al., 2016. Sci. Rep. 6, 25,222), there was no significant difference in frequency of pigs with diarrhea and diarrhea days between T-B-NK+ SCID+HuNoV and non-SCID+HuNoV groups. Cumulative fecal HuNoV RNA shedding at PIDs 1-8, PIDs 9-27, and PIDs 1-27 also did not differ statistically. These observations coincided with the presence of NK cells and NK cell cytotoxicity in the ileum and blood of the SCID pigs. Based on our observations, innate immunity, including NK cell activity, may be critical to mediate or reduce HuNoV infection in T-B-NK+ SCID pigs, and potentially in immunocompetent patients.
Assuntos
Infecções por Caliciviridae/imunologia , Imunidade Inata , Células Matadoras Naturais/imunologia , Norovirus/imunologia , Imunodeficiência Combinada Severa/virologia , Animais , Infecções por Caliciviridae/virologia , Diarreia/virologia , Fezes/virologia , Vida Livre de Germes , Humanos , Norovirus/patogenicidade , Suínos , Eliminação de Partículas ViraisRESUMO
Severe combined immunodeficiency (SCID) represents one of the most severe forms of primary immunodeficiency (PID) disorders characterized by impaired cellular and humoral immune responses. Here, we report the clinical, immunological, and molecular findings in 57 patients diagnosed with SCID from India. Majority of our patients (89%) presented within 6 months of age. The most common clinical manifestations observed were recurrent pneumonia (66%), failure to thrive (60%), chronic diarrhea (35%), gastrointestinal infection (21%), and oral candidiasis (21%). Hematopoietic Stem Cell Transplantation (HSCT) is the only curative therapy available for treating these patients. Four patients underwent HSCT in our cohort but had a poor survival outcome. Lymphopenia (absolute lymphocyte counts/µL <2,500) was noted in 63% of the patients. Based on immunophenotypic pattern, majority of the cases were T-B- SCID (39%) followed by T-B+ SCID (28%). MHC class II deficiency accounted for 10.5% of our patient group. A total of 49 patients were molecularly characterized in this study and 32 novel variants were identified in our cohort. The spectrum of genetic defects in our cohort revealed a wide genetic heterogeneity with the major genetic cause being RAG1/2 gene defect (n = 12) followed by IL2RG (n = 9) and JAK3 defects (n = 9). Rare forms of SCID like Purine nucleoside phosphorylase (PNP) deficiency, reticular dysgenesis, DNA-Protein Kinase (DNA-PKcs) deficiency, six cases of MHC class II deficiency and two ZAP70 deficiency were also identified in our cohort. Fourteen percent of the defects still remained uncharacterized despite the application of next generation sequencing. With the exception of MHC class II deficiency and ZAP70 deficiency, all SCID patients had extremely low T cell receptor excision (TRECs) (<18 copies/µL).
Assuntos
Imunodeficiência Combinada Severa/genética , Imunodeficiência Combinada Severa/imunologia , Infecções Oportunistas Relacionadas com a AIDS/diagnóstico , Idade de Início , Biomarcadores , Relação CD4-CD8 , Pré-Escolar , Terapia Combinada , Suscetibilidade a Doenças , Feminino , Perfilação da Expressão Gênica , Variação Genética , Humanos , Índia , Lactente , Recém-Nascido , Contagem de Linfócitos , Masculino , Imunodeficiência Combinada Severa/diagnóstico , Imunodeficiência Combinada Severa/virologia , Avaliação de SintomasRESUMO
BACKGROUND: Cytomegalovirus (CMV) infection is a major risk factor for mortality in infants with severe combined immunodeficiency (SCID) and other profound immune defects. Specific antiviral therapy must be initiated early and aggressively because of the potential for antiviral resistance, rapid dissemination and poor transplant outcomes. Combination antiviral therapy is routinely administered for some viral infections, but the value of this approach for the treatment of CMV is unclear. Here we explore a strategy of initial combination therapy for high-risk infants with CMV infection. METHODS: We reviewed medical records of infants ≤6 months of age hospitalized between 2007-2015 who received ganciclovir (GCV) or foscarnet (FOS) monotherapy or initial combination GCV + FOS for CMV disease. The combination therapy group consisted of severely immunocompromised infants being considered for haematopoietic cell transplantation (HCT). RESULTS: Four patients received initial combination antiviral therapy and 26 patients received initial monotherapy during the study period. Combination antiviral recipients demonstrated initial improvement in viraemia and two of three who continued with this therapy survived the infection. Clinically significant resistance mutations did not emerge. Toxicity was common; neutropenia, thrombocytopenia and electrolyte abnormalities were the most frequent adverse events in both groups. Creatinine elevation was uncommon in both groups. CONCLUSIONS: Combination GCV + FOS therapy may be a safe alternative to monotherapy in high-risk infants, especially those who are pre-transplant with primary immune deficiency syndromes and high viral loads.
Assuntos
Antivirais/uso terapêutico , Infecções por Citomegalovirus/tratamento farmacológico , Foscarnet/uso terapêutico , Ganciclovir/uso terapêutico , Hospedeiro Imunocomprometido , Imunodeficiência Combinada Severa/imunologia , Viremia/tratamento farmacológico , Citomegalovirus/efeitos dos fármacos , Citomegalovirus/imunologia , Citomegalovirus/patogenicidade , Infecções por Citomegalovirus/imunologia , Infecções por Citomegalovirus/mortalidade , Infecções por Citomegalovirus/virologia , Quimioterapia Combinada , Feminino , Transplante de Células-Tronco Hematopoéticas , Humanos , Lactente , Recém-Nascido , Masculino , Estudos Retrospectivos , Fatores de Risco , Imunodeficiência Combinada Severa/mortalidade , Imunodeficiência Combinada Severa/terapia , Imunodeficiência Combinada Severa/virologia , Análise de Sobrevida , Carga Viral/efeitos dos fármacos , Viremia/imunologia , Viremia/mortalidade , Viremia/virologiaRESUMO
We describe a case of an infant diagnosed with severe combined immune deficiency (Adenosine Deaminase (ADA), SCID) with severe retinopathy and associated low vision in both eyes at first examination. An extensive infectious work up revealed an enterovirus infection, which suggested an early infectious and severe retinopathy. Genetic causes of congenital retinitis pigmentosa/ Leber's congenital amaurosis could be excluded by whole exome sequencing.
Assuntos
Infecções por Enterovirus/diagnóstico , Infecções Oculares Virais/diagnóstico , Doenças Retinianas/diagnóstico , Imunodeficiência Combinada Severa/diagnóstico , DNA Viral/genética , Enterovirus/genética , Enterovirus/isolamento & purificação , Infecções por Enterovirus/virologia , Infecções Oculares Virais/virologia , Fezes/virologia , Feminino , Seguimentos , Humanos , Lactente , Reação em Cadeia da Polimerase , Doenças Retinianas/virologia , Imunodeficiência Combinada Severa/terapia , Imunodeficiência Combinada Severa/virologia , Transplante de Células-Tronco , Baixa Visão/diagnóstico , Sequenciamento do ExomaRESUMO
Human herpesvirus 6 (HHV-6), a member of the betaherpesvirus family, has two distinct species: HHV-6A and HHV-6B. HHV-6B real-time reverse transcription polymerase chain reaction (RT-PCR) has been used to distinguish between active and latent viral infection. In this study, we developed a real-time RT-PCR assay to detect HHV-6A-specific transcripts and evaluated its reliability for analysis of clinical samples. To develop HHV-6A-specific real-time RT-PCR assays, three different classes of gene transcripts (immediate early: U90; early: U12; and late: U100) were selected as targets. Serial d ilutions of plasmid DNAs containing target sequences and RNAs extracted from HHV-6A-infected cells were used to determine assay specificity and sensitivity. Peripheral blood mononuclear cells (PBMCs) collected from patients with either primary or reactivated HHV-6B infection, and one patient with X-linked severe combined immunodeficiency (X-SCID) with HHV-6A reactivation, were used to evaluate assay reliability. The HHV-6A-specific real-time RT-PCR assays amplified plasmids containing the target sequences at concentrations between 10 and 1 × 106 copies per reaction. The intra-assay coefficients of variation were less than 5%. The three classes of HHV-6A gene transcripts were not detected in any HHV-6B sample isolated from the patients. In the X-SCID patient, high copy numbers of HHV-6A U12 and U100 transcripts were detected in PBMC samples during viremia. Thus, we successfully established highly sensitive and reproducible real-time RT-PCR methods targeting three classes of HHV-6A gene transcripts. This method should be useful for discriminating active HHV-6A infection from either latent infection or chromosomally integrated HHV-6A (ciHHV-6A).
Assuntos
DNA Viral/genética , Herpesvirus Humano 6/genética , Reação em Cadeia da Polimerase em Tempo Real/métodos , Infecções por Roseolovirus/diagnóstico , Feminino , Herpesvirus Humano 6/classificação , Herpesvirus Humano 6/isolamento & purificação , Humanos , Leucócitos Mononucleares/virologia , Masculino , Reprodutibilidade dos Testes , Infecções por Roseolovirus/virologia , Sensibilidade e Especificidade , Imunodeficiência Combinada Severa/virologia , Carga Viral , Latência ViralAssuntos
Anemia Hemolítica Autoimune/imunologia , Autoimunidade , Citofagocitose , Eritema Infeccioso/imunologia , Monócitos/imunologia , Neutrófilos/imunologia , Parvovirus B19 Humano/imunologia , Corticosteroides/uso terapêutico , Adulto , Anemia Hemolítica Autoimune/patologia , Anemia Hemolítica Autoimune/terapia , Anemia Hemolítica Autoimune/virologia , Autoimunidade/efeitos dos fármacos , Terapia Combinada , Ciclofosfamida/uso terapêutico , Citofagocitose/efeitos dos fármacos , Quimioterapia Combinada , Eritema Infeccioso/patologia , Eritema Infeccioso/terapia , Eritema Infeccioso/virologia , Eritrócitos/efeitos dos fármacos , Eritrócitos/imunologia , Eritrócitos/patologia , Eritrócitos/virologia , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Fatores Imunológicos/uso terapêutico , Masculino , Monócitos/efeitos dos fármacos , Monócitos/patologia , Monócitos/virologia , Neutrófilos/efeitos dos fármacos , Neutrófilos/patologia , Neutrófilos/virologia , Parvovirus B19 Humano/efeitos dos fármacos , Rituximab/uso terapêutico , Imunodeficiência Combinada Severa/imunologia , Imunodeficiência Combinada Severa/patologia , Imunodeficiência Combinada Severa/terapia , Imunodeficiência Combinada Severa/virologia , Resultado do TratamentoRESUMO
Application of genetically engineered (GE) large animals carrying multi-allelic modifications has been hampered by low efficiency in production and extended gestation period compared to rodents. Here, we rapidly generated RAG2/IL2RG double knockout pigs using direct injection of CRISPR/Cas9 system into developing embryos. RAG2/IL2RG deficient pigs were immunodeficient, characterized by depletion of lymphocytes and either absence of or structurally abnormal immune organs. Pigs were maintained in gnotobiotic facility and evaluated for human norovirus (HuNoV) infection. HuNoV shedding lasted for 16 days in wild type pigs, compared to 27 days (until the end of trials) in RAG2/IL2RG deficient pigs. Additionally, higher HuNoV titers were detected in intestinal tissues and contents and in blood, indicating increased and prolonged HuNoV infection in RAG2/IL2RG deficient pigs and the importance of lymphocytes in HuNoV clearance. These results suggest that GE immunodeficient gnotobiotic pigs serve as a novel model for biomedical research and will facilitate HuNoV studies.
Assuntos
Infecções por Caliciviridae/virologia , Proteínas de Ligação a DNA/genética , Subunidade gama Comum de Receptores de Interleucina/genética , Norovirus/fisiologia , Imunodeficiência Combinada Severa/genética , Imunodeficiência Combinada Severa/virologia , Animais , Infecções por Caliciviridae/sangue , Modelos Animais de Doenças , Técnicas de Inativação de Genes , Engenharia Genética , Vida Livre de Germes , Humanos , Intestinos/virologia , Imunodeficiência Combinada Severa/sangue , Suínos , Carga Viral , Eliminação de Partículas ViraisRESUMO
Norovirus incidence was compared between severe combined immunodeficiency children with (n = 10) and without (n = 8) B cells. 60% of B+ and 63% of B- patients developed norovirus infections therefore norovirus replication in B lymphocytes is not essential for infection.
Assuntos
Linfócitos B/virologia , Infecções por Caliciviridae/patologia , Norovirus/imunologia , Imunodeficiência Combinada Severa/virologia , Adolescente , Linfócitos B/patologia , Infecções por Caliciviridae/imunologia , Criança , Pré-Escolar , Humanos , Lactente , Estudos RetrospectivosAssuntos
Disbiose/microbiologia , Trato Gastrointestinal/microbiologia , Doença Enxerto-Hospedeiro/microbiologia , Transplante de Células-Tronco Hematopoéticas , Microbiota/imunologia , Imunodeficiência Combinada Severa/microbiologia , Antibacterianos/uso terapêutico , Antifúngicos/uso terapêutico , Antivirais/uso terapêutico , Infecções Bacterianas/tratamento farmacológico , Infecções Bacterianas/imunologia , Infecções Bacterianas/microbiologia , Disbiose/imunologia , Fezes/microbiologia , Feminino , Trato Gastrointestinal/imunologia , Trato Gastrointestinal/virologia , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/prevenção & controle , Doença Enxerto-Hospedeiro/virologia , Humanos , Lactente , Recém-Nascido , Estudos Longitudinais , Masculino , Micoses/tratamento farmacológico , Micoses/imunologia , Micoses/microbiologia , Agonistas Mieloablativos/uso terapêutico , Projetos Piloto , Imunodeficiência Combinada Severa/imunologia , Imunodeficiência Combinada Severa/terapia , Imunodeficiência Combinada Severa/virologia , Condicionamento Pré-Transplante , Viroses/tratamento farmacológico , Viroses/imunologia , Viroses/virologiaRESUMO
We report for the first time Rotarix vaccine-acquired rotavirus infections with viremia in 2 infants vaccinated before being diagnosed with severe combined immune deficiency. Monitoring the first infant revealed that persistent rotavirus infection resolved after complete immune reconstitution was achieved by gene therapy.
Assuntos
Vacinas contra Rotavirus/efeitos adversos , Rotavirus/fisiologia , Imunodeficiência Combinada Severa/imunologia , Imunodeficiência Combinada Severa/virologia , Viremia , Eliminação de Partículas Virais , Feminino , Terapia Genética , Humanos , Lactente , Contagem de Linfócitos , Masculino , Imunodeficiência Combinada Severa/diagnóstico , Imunodeficiência Combinada Severa/terapia , Carga ViralRESUMO
We develop a mathematical model for the interaction between two competing equine infectious anemia virus strains and neutralizing antibodies. We predict that elimination of one or both virus strains depends on the initial antibody levels, the strength of antibody mediated neutralization, and the persistence of antibody over time. We further show that the ability of a subdominant, neutralization resistant virus to dominate the infection transiently or permanently is dependent on the antibody-mediated neutralization effect. Finally, we determine conditions for persistence of both virus strains. We fit our models to virus titers from horses (foals) with severe combined immunodeficiency to estimate virus-host parameters and to validate analytical results.
Assuntos
Anemia Infecciosa Equina/virologia , Cavalos/virologia , Interações Hospedeiro-Patógeno , Vírus da Anemia Infecciosa Equina/fisiologia , Imunodeficiência Combinada Severa/veterinária , Imunodeficiência Combinada Severa/virologia , Animais , Simulação por Computador , Modelos Biológicos , Mutação/genética , Análise Numérica Assistida por Computador , RNA Viral/metabolismoRESUMO
The tropism of herpes simplex virus (HSV-1) for human sensory neurons infected in vivo was examined using dorsal root ganglion (DRG) xenografts maintained in mice with severe combined immunodeficiency (SCID). In contrast to the HSV-1 lytic infectious cycle in vitro, replication of the HSV-1 F strain was restricted in human DRG neurons despite the absence of adaptive immune responses in SCID mice, allowing the establishment of neuronal latency. At 12 days after DRG inoculation, 26.2% of human neurons expressed HSV-1 protein and 13.1% expressed latency-associated transcripts (LAT). Some infected neurons showed cytopathic changes, but HSV-1, unlike varicella-zoster virus (VZV), only rarely infected satellite cells and did not induce fusion of neuronal and satellite cell plasma membranes. Cell-free enveloped HSV-1 virions were observed, indicating productive infection. A recombinant HSV-1-expressing luciferase exhibited less virulence than HSV-1 F in the SCID mouse host, enabling analysis of infection in human DRG xenografts for a 61-day interval. At 12 days after inoculation, 4.2% of neurons expressed HSV-1 proteins; frequencies increased to 32.1% at 33 days but declined to 20.8% by 61 days. Frequencies of LAT-positive neurons were 1.2% at 12 days and increased to 40.2% at 33 days. LAT expression remained at 37% at 61 days, in contrast to the decline in neurons expressing viral proteins. These observations show that the progression of HSV-1 infection is highly restricted in human DRG, and HSV-1 genome silencing occurs in human neurons infected in vivo as a consequence of virus-host cell interactions and does not require adaptive immune control.
Assuntos
Gânglios Espinais/virologia , Herpes Simples/virologia , Herpesvirus Humano 1/fisiologia , Imunodeficiência Combinada Severa/virologia , Tropismo Viral , Aciclovir/administração & dosagem , Aciclovir/análogos & derivados , Aciclovir/farmacologia , Animais , Gânglios Espinais/patologia , Expressão Gênica , Herpes Simples/tratamento farmacológico , Herpes Simples/metabolismo , Herpesvirus Humano 1/efeitos dos fármacos , Herpesvirus Humano 1/metabolismo , Herpesvirus Humano 3 , Humanos , Luciferases/biossíntese , Camundongos , Camundongos SCID , Células Satélites Perineuronais/virologia , Transplante Heterólogo , Valaciclovir , Valina/administração & dosagem , Valina/análogos & derivados , Valina/farmacologia , Proteínas Virais/metabolismo , Latência Viral , Replicação ViralRESUMO
Generalized verrucosis has been described in the past as synonymous with epidermodysplasia verruciformis. It has been shown, however, that epidermodysplasia verruciformis and other genetic or immunodeficiency diseases are just a subset of diffuse infections with human papillomavirus termed "generalized verrucosis." This article defines generalized verrucosis and distinct diseases associated with generalized warts. The indications for histopathologic testing, human papillomavirus typing, and other laboratory analyses and potential treatment options are discussed.
Assuntos
Infecções por Papillomavirus/complicações , Verrugas/complicações , Imunodeficiência de Variável Comum/complicações , Imunodeficiência de Variável Comum/terapia , Imunodeficiência de Variável Comum/virologia , Infecções por HIV/complicações , Humanos , Síndrome de Imunodeficiência com Hiper-IgM/complicações , Síndrome de Imunodeficiência com Hiper-IgM/terapia , Síndrome de Imunodeficiência com Hiper-IgM/virologia , Síndromes de Imunodeficiência/complicações , Síndromes de Imunodeficiência/terapia , Terapia de Imunossupressão/efeitos adversos , Papillomaviridae/genética , Infecções por Papillomavirus/terapia , Infecções por Papillomavirus/virologia , Doenças da Imunodeficiência Primária , Imunodeficiência Combinada Severa/complicações , Imunodeficiência Combinada Severa/terapia , Imunodeficiência Combinada Severa/virologia , T-Linfocitopenia Idiopática CD4-Positiva/complicações , T-Linfocitopenia Idiopática CD4-Positiva/terapia , Verrugas/terapia , Verrugas/virologiaRESUMO
BACKGROUND: CD27 is a lymphocyte costimulatory molecule that regulates T-cell, natural killer (NK) cell, B-cell, and plasma cell function, survival, and differentiation. On the basis of its function and expression pattern, we considered CD27 a candidate gene in patients with hypogammaglobulinemia. OBJECTIVE: We sought to describe the clinical and immunologic phenotypes of patients with genetic CD27 deficiency. METHODS: A molecular and extended immunologic analysis was performed on 2 patients lacking CD27 expression. RESULTS: We identified 2 brothers with a homozygous mutation in CD27 leading to absence of CD27 expression. Both patients had persistent symptomatic EBV viremia. The index patient was hypogammaglobulinemic, and immunoglobulin replacement therapy was initiated. His brother had aplastic anemia in the course of his EBV infection and died from fulminant gram-positive bacterial sepsis. Immunologically, lack of CD27 expression was associated with impaired T cell-dependent B-cell responses and T-cell dysfunction. CONCLUSION: Our findings identify a role for CD27 in human subjects and suggest that this deficiency can explain particular cases of persistent symptomatic EBV viremia with hypogammaglobulinemia and impaired T cell-dependent antibody generation.
Assuntos
Anemia Aplástica/imunologia , Infecções por Vírus Epstein-Barr/imunologia , Infecções por Bactérias Gram-Positivas/imunologia , Herpesvirus Humano 4/imunologia , Imunodeficiência Combinada Severa/imunologia , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/genética , Viremia/imunologia , Agamaglobulinemia/etiologia , Anemia Aplástica/complicações , Anemia Aplástica/genética , Anemia Aplástica/fisiopatologia , Anemia Aplástica/virologia , Linfócitos B/imunologia , Linfócitos B/metabolismo , Linfócitos B/patologia , Células Cultivadas , Consanguinidade , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/genética , Infecções por Vírus Epstein-Barr/fisiopatologia , Infecções por Vírus Epstein-Barr/virologia , Evolução Fatal , Infecções por Bactérias Gram-Positivas/complicações , Infecções por Bactérias Gram-Positivas/genética , Infecções por Bactérias Gram-Positivas/fisiopatologia , Infecções por Bactérias Gram-Positivas/virologia , Herpesvirus Humano 4/patogenicidade , Humanos , Imunidade Humoral/genética , Masculino , Mutação/genética , Linhagem , Imunodeficiência Combinada Severa/complicações , Imunodeficiência Combinada Severa/genética , Imunodeficiência Combinada Severa/fisiopatologia , Imunodeficiência Combinada Severa/virologia , Irmãos , Linfócitos T/imunologia , Linfócitos T/metabolismo , Linfócitos T/patologia , Viremia/genética , Viremia/virologia , Adulto JovemRESUMO
Infants with severe primary combined immunodeficiency (SCID) and children post-allogeneic hematopoietic stem cell transplantation (HSCT) are extremely susceptible to unusual infections. The lack of generic tools to detect disease-causing viruses among more than 200 potential human viral pathogens represents a major challenge to clinicians and virologists. We investigated retrospectively the causes of a fatal disseminated viral infection with meningoencephalitis in an infant with gamma C-SCID and of chronic gastroenteritis in 2 other infants admitted for HSCT during the same time period. Analysis was undertaken by combining cell culture, electron microscopy and sequence-independent single primer amplification (SISPA) techniques. Caco-2 cells inoculated with fecal samples developed a cytopathic effect and non-enveloped viral particles in infected cells were detected by electron microscopy. SISPA led to the identification of astrovirus as the pathogen. Both sequencing of the capsid gene and the pattern of infection suggested nosocomial transmission from a chronically excreting index case to 2 other patients leading to fatal infection in 1 and to transient disease in the others. Virus-specific, real-time reverse transcription polymerase chain reaction was then performed on different stored samples to assess the extent of infection. Infection was associated with viremia in 2 cases and contributed to death in 1. At autopsy, viral RNA was detected in the brain and different other organs, while immunochemistry confirmed infection of gastrointestinal tissues. This report illustrates the usefulness of the combined use of classical virology procedures and modern molecular tools for the diagnosis of unexpected infections. It illustrates that astrovirus has the potential to cause severe disseminated lethal infection in highly immunocompromised pediatric patients.
Assuntos
Infecções por Astroviridae/diagnóstico , Infecções por Astroviridae/virologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Imunodeficiência Combinada Severa/virologia , Transplante Homólogo/efeitos adversos , Infecções por Astroviridae/mortalidade , Células CACO-2 , Humanos , Lactente , Masculino , RNA Viral/genética , Reação em Cadeia da Polimerase em Tempo Real , Estudos Retrospectivos , Imunodeficiência Combinada Severa/mortalidade , Imunodeficiência Combinada Severa/terapiaRESUMO
Using the equine infectious anemia virus (EIAV) lentivirus model system, we previously demonstrated protective effects of broadly neutralizing immune plasma in young horses (foals) with severe combined immunodeficiency (SCID). However, in vivo selection of a neutralization-resistant envelope variant occurred. Here, we determined the protective effects of purified immunoglobulin with more potent broadly neutralizing activity. Overall, protection correlated with the breadth and potency of neutralizing activity in vitro. Four of five SCID foals were completely protected against homologous challenge, while partial protection occurred following heterologous challenge. These results support the inclusion of broadly neutralizing antibodies in lentivirus control strategies.