RESUMEN
The function and phenotype of γδ T cells in the context of common variable immunodeficiency (CVID) has not been explored. CVID is a primary immunodeficiency disorder characterized by impaired antibody responses resulting in increased susceptibility to infections. γδ T cells are a subset of unconventional T cells that play crucial roles in host defence against infections. In this study, we aim to determine the roles and functions of γδ T cells in CVID. We observe a higher frequency of Vδ1+ γδ T cells compared to healthy controls, particularly in older patients. We also find a higher proportion of effector-memory Vδ1+ γδ T cells and a more clonal T cell receptor (TCR) repertoire in CVID. The most significant driver of the Vδ1+ γδ T cell expansion and phenotype in CVID patients is persistent cytomegalovirus (CMV) viremia. These findings provide valuable insights into γδ T cell biology and their contribution to immune defence in CVID.
Asunto(s)
Inmunodeficiencia Variable Común , Infecciones por Citomegalovirus , Citomegalovirus , Receptores de Antígenos de Linfocitos T gamma-delta , Humanos , Inmunodeficiencia Variable Común/inmunología , Inmunodeficiencia Variable Común/virología , Receptores de Antígenos de Linfocitos T gamma-delta/metabolismo , Receptores de Antígenos de Linfocitos T gamma-delta/inmunología , Masculino , Femenino , Infecciones por Citomegalovirus/inmunología , Infecciones por Citomegalovirus/virología , Adulto , Citomegalovirus/inmunología , Persona de Mediana Edad , Anciano , Adulto Joven , Subgrupos de Linfocitos T/inmunología , Viremia/inmunología , Adolescente , Estudios de Casos y ControlesAsunto(s)
Asma/inmunología , COVID-19/inmunología , Inmunodeficiencia Variable Común/inmunología , Deficiencia de IgG/inmunología , Obesidad Mórbida/inmunología , Infecciones Estafilocócicas/inmunología , Adenosina Monofosfato/análogos & derivados , Adenosina Monofosfato/uso terapéutico , Adulto , Alanina/análogos & derivados , Alanina/uso terapéutico , Antivirales/uso terapéutico , Asma/patología , Asma/terapia , Asma/virología , COVID-19/patología , COVID-19/terapia , COVID-19/virología , Inmunodeficiencia Variable Común/patología , Inmunodeficiencia Variable Común/terapia , Inmunodeficiencia Variable Común/virología , Resultado Fatal , Humanos , Deficiencia de IgG/patología , Deficiencia de IgG/terapia , Deficiencia de IgG/virología , Inmunización Pasiva , Inmunoglobulina G/sangre , Inmunoglobulinas Intravenosas/uso terapéutico , Masculino , Staphylococcus aureus Resistente a Meticilina , Obesidad Mórbida/patología , Obesidad Mórbida/terapia , Obesidad Mórbida/virología , SARS-CoV-2 , Infecciones Estafilocócicas/patología , Infecciones Estafilocócicas/terapia , Infecciones Estafilocócicas/virología , Sueroterapia para COVID-19RESUMEN
Long-term severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) shedding was observed from the upper respiratory tract of a female immunocompromised individual with chronic lymphocytic leukemia and acquired hypogammaglobulinemia. Shedding of infectious SARS-CoV-2 was observed up to 70 days, and of genomic and subgenomic RNA up to 105 days, after initial diagnosis. The infection was not cleared after the first treatment with convalescent plasma, suggesting a limited effect on SARS-CoV-2 in the upper respiratory tract of this individual. Several weeks after a second convalescent plasma transfusion, SARS-CoV-2 RNA was no longer detected. We observed marked within-host genomic evolution of SARS-CoV-2 with continuous turnover of dominant viral variants. However, replication kinetics in Vero E6 cells and primary human alveolar epithelial tissues were not affected. Our data indicate that certain immunocompromised individuals may shed infectious virus longer than previously recognized. Detection of subgenomic RNA is recommended in persistently SARS-CoV-2-positive individuals as a proxy for shedding of infectious virus.
Asunto(s)
COVID-19/inmunología , Inmunodeficiencia Variable Común/inmunología , Leucemia Linfocítica Crónica de Células B/inmunología , SARS-CoV-2/aislamiento & purificación , Anciano , Anticuerpos Antivirales/sangre , Anticuerpos Antivirales/inmunología , COVID-19/complicaciones , COVID-19/virología , Inmunodeficiencia Variable Común/sangre , Inmunodeficiencia Variable Común/complicaciones , Inmunodeficiencia Variable Común/virología , Femenino , Humanos , Leucemia Linfocítica Crónica de Células B/sangre , Leucemia Linfocítica Crónica de Células B/complicaciones , Leucemia Linfocítica Crónica de Células B/virología , Infecciones del Sistema Respiratorio/sangre , Infecciones del Sistema Respiratorio/complicaciones , Infecciones del Sistema Respiratorio/inmunología , Infecciones del Sistema Respiratorio/virología , SARS-CoV-2/inmunología , SARS-CoV-2/patogenicidadRESUMEN
Current approaches to influenza control rely on vaccines matched to viruses in circulation. Universal influenza vaccines would offer the advantage of providing broad protection against diverse strains of influenza virus. Candidate universal vaccines are developed using model systems, often testing in naïve animals. Yet the human population is not naïve, having varied immune histories that include exposure to viruses. We studied a candidate universal influenza vaccine (replication deficient adenoviruses expressing the conserved influenza A antigens NP and M2 [A/NP+M2-rAd]) given intranasally, the route previously shown to be most effective. To model recipients exposed to viruses, we used mice given rhinovirus (RV1B), respiratory syncytial virus (RSV-A2), influenza B virus, or influenza A virus before or after universal influenza vaccine. Vaccine performance was assessed by measuring immune responses to NP and M2, and monitoring weight loss and survival following influenza A challenge. Prior influenza A virus infection enhanced the response to the vaccine by priming to conserved influenza A antigens. RSV-A2 or RV1B had no effect on antibody responses to NP and M2 in serum. None of the viruses inhibited the ability of the vaccine to protect against influenza A virus challenge. The study demonstrates that the usefulness of this universal vaccine is not confined to the immunologically naïve and supports possible use in a human population with a varied history of respiratory infections.
Asunto(s)
Inmunodeficiencia Variable Común/inmunología , Infecciones por Coxsackievirus/inmunología , Enterovirus/inmunología , Inmunogenicidad Vacunal , Virus de la Influenza A/inmunología , Virus de la Influenza B/inmunología , Vacunas contra la Influenza/inmunología , Infecciones por Orthomyxoviridae/prevención & control , Animales , Inmunodeficiencia Variable Común/virología , Infecciones por Coxsackievirus/patología , Femenino , Células HeLa , Humanos , Vacunas contra la Influenza/farmacología , Ratones , Ratones Endogámicos BALB C , Infecciones por Orthomyxoviridae/inmunología , Infecciones por Orthomyxoviridae/patologíaRESUMEN
Common variable immunodeficiency syndrome (CVID) is a heterogeneous disorder characterised by diminished levels of IgG, IgA and/or IgM, and recurrent bacterial infections. Sinopulmonary infections are most commonly reported followed by gastrointestinal (GI) infections. GI tract represents the largest immune organ with abundance of lymphoid cells, its involvement can manifest variably ranging from asymptomatic involvement to florid symptoms and signs. Diffuse nodular lymphoid hyperplasia (DNLH) of the GI tract is characterised by numerous small polypoid nodules of variable size in the small intestine, large intestine or both. It is commonly seen in association to immunodeficiency states such as CVID, IgA deficiency and chronic infections due to Giardia lamblia and Helicobacter pylori and cryptosporidiosis. Repetitive antigenic stimulation leads to lymphoid hyperplasia. We herein describe a case of DNLH of the intestine and another case of duodenal cytomegalovirus (CMV) infection associated with CVID.
Asunto(s)
Inmunodeficiencia Variable Común/virología , Infecciones por Citomegalovirus/complicaciones , Diarrea/virología , Duodeno/patología , Hiperplasia/virología , Intestino Delgado/patología , Trastornos Linfoproliferativos/virología , Adulto , Antivirales/uso terapéutico , Inmunodeficiencia Variable Común/tratamiento farmacológico , Inmunodeficiencia Variable Común/fisiopatología , Infecciones por Citomegalovirus/fisiopatología , Duodeno/virología , Endoscopía del Sistema Digestivo , Ganciclovir/uso terapéutico , Humanos , Hiperplasia/tratamiento farmacológico , Hiperplasia/fisiopatología , Inmunoglobulinas Intravenosas/uso terapéutico , Intestino Delgado/virología , Trastornos Linfoproliferativos/tratamiento farmacológico , Trastornos Linfoproliferativos/fisiopatología , Masculino , Persona de Mediana Edad , Resultado del TratamientoRESUMEN
OBJECTIVE: Predictive factors associated with clinical outcomes of chronic norovirus infection (CNI) in primary immunodeficiency diseases (PIDD) are lacking. METHOD: We sought to characterize CNI using a multi-institutional cohort of patients with PIDD and CNI using the Clinical Immunology Society's CIS-PIDD Listserv e-mail group. RESULTS: Thirty-four subjects (21 males and 13 females) were reported from centers across North America, Europe, and Asia. All subjects were receiving high doses (median IgG dose: 1200â¯mg/kg/month) of supplemental immunoglobulin therapy. Fifty-three percent had a complete absence of B cells (median B-cell count 0; range 0-139 cells/µL). Common Variable Immune Deficiency (CVID) subjects manifested a unique phenotype with B-cell lymphopenia, non O+ blood type, and villous atrophy (logistic regression model, Pâ¯=â¯0.01). Five subjects died, all of whom had no evidence of villous atrophy. CONCLUSION: While Norovirus (NoV) is thought to replicate in B cells, in this PIDD cohort of CNI, B-cell lymphopenia was common, indicating that the presence of B lymphocytes is not essential for CNI.
Asunto(s)
Infecciones por Caliciviridae/inmunología , Síndromes de Inmunodeficiencia/virología , Norovirus/fisiología , Adolescente , Adulto , Linfocitos B/patología , Infecciones por Caliciviridae/mortalidad , Infecciones por Caliciviridae/patología , Enfermedad Crónica , Inmunodeficiencia Variable Común/inmunología , Inmunodeficiencia Variable Común/patología , Inmunodeficiencia Variable Común/terapia , Inmunodeficiencia Variable Común/virología , Femenino , Gastroenteritis/inmunología , Gastroenteritis/mortalidad , Gastroenteritis/patología , Humanos , Inmunización Pasiva , Síndromes de Inmunodeficiencia/inmunología , Síndromes de Inmunodeficiencia/patología , Síndromes de Inmunodeficiencia/terapia , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Norovirus/genética , Estudios Retrospectivos , Adulto JovenRESUMEN
PURPOSE OF REVIEW: Vaccination against influenza in patients with primary antibody deficiency is recommended. Common variable immunodeficiency (CVID) is the most frequent and clinically relevant antibody deficiency disease and is by definition characterized by an impaired vaccination response. The purpose of this review is to present the current knowledge of humoral and cellular vaccine response to influenza in CVID patients. RECENT FINDINGS: Studies conducted in CVID patients demonstrated an impaired humoral response upon influenza vaccination. Data on cellular immune response are in part conflicting, with two out of three studies showing responses similar to healthy controls. Available data suggest a benefit from influenza vaccination in CVID patients. Therefore, annual influenza vaccination in patients and their close household contacts is recommended.
Asunto(s)
Inmunodeficiencia Variable Común/inmunología , Huésped Inmunocomprometido , Gripe Humana/prevención & control , Vacunación , Animales , Inmunodeficiencia Variable Común/virología , Humanos , Inmunidad Celular , Vacunas contra la Influenza/inmunología , Gripe Humana/inmunología , Linfocitos T/inmunologíaRESUMEN
Enterovirus in the nervous system can present with protean manifestations, including polio-like paralysis, movement disorders, and seizures. This is a report of a single case of a rapidly progressive dementing illness in a young woman with common variable immunodeficiency (CVID). Over the course of several months, she developed profound aphasia, apraxia, and cerebellar signs. She underwent brain biopsy which was suggestive of toxoplasmosis; despite an adequate course of treatment, she continued to decline and ultimately died. Autopsy and PCR testing revealed diffuse coxsackie B3 infiltration in the meninges and brain parenchyma. To our knowledge, this is the first description of enterovirus causing a dementing illness in a young immunosuppressed adult. We highlight the need for a broad differential diagnosis, especially for immunocompromised individuals, who may present in an atypical fashion.
Asunto(s)
Inmunodeficiencia Variable Común/diagnóstico , Demencia/diagnóstico , Enterovirus Humano B/patogenicidad , Infecciones por Enterovirus/diagnóstico , Huésped Inmunocomprometido , Adulto , Encéfalo/inmunología , Encéfalo/patología , Encéfalo/virología , Inmunodeficiencia Variable Común/inmunología , Inmunodeficiencia Variable Común/patología , Inmunodeficiencia Variable Común/virología , Demencia/inmunología , Demencia/patología , Demencia/virología , Diagnóstico Diferencial , Enterovirus Humano B/inmunología , Infecciones por Enterovirus/inmunología , Infecciones por Enterovirus/patología , Infecciones por Enterovirus/virología , Resultado Fatal , Femenino , HumanosRESUMEN
OBJECTIVES: A severe enteropathy of unknown etiology can be associated with common variable immunodeficiency (CVID). METHODS: S tool and archived small intestinal mucosal biopsies from patients with CVID enteropathy were analyzed by PCR for the presence of Norovirus RNA. The PCR products were sequenced to determine the relationship of viral isolates. Stool samples from 10 patients with CVID but no enteropathy served as controls. RESULTS: All eight patients in our CVID cohort with enteropathy showed persistent fecal excretion of Norovirus. Analysis of archived duodenal biopsies revealed a strong association between the presence of Norovirus and villous atrophy over a period of up to 8 years. Analysis of the viral isolates from each patient revealed distinct strains of genogroup II.4. Sequence analysis from consecutive biopsy specimens of one patient demonstrated persistence of the same viral strain over a 6-year period. CVID patients without enteropathy showed no evidence of Norovirus carriage. Viral clearance occurred spontaneously in one patient and followed oral Ribavirin therapy in two further patients, and resulted in complete symptomatic and histological recovery. However, Ribavirin treatment in two further patients was unsuccessful. CONCLUSIONS: Norovirus is an important pathogen for patients with CVID and a cause of CVID enteropathy, as viral clearance, symptom resolution, and histological recovery coincide. Ribavirin requires further evaluation as a potential therapy.
Asunto(s)
Infecciones por Caliciviridae/virología , Inmunodeficiencia Variable Común/virología , Duodeno/virología , Enfermedades Intestinales/virología , Norovirus/genética , ARN Viral/análisis , Adulto , Anciano , Antivirales/uso terapéutico , Biopsia , Infecciones por Caliciviridae/complicaciones , Infecciones por Caliciviridae/tratamiento farmacológico , Infecciones por Caliciviridae/patología , Estudios de Casos y Controles , Enfermedad Crónica , Estudios de Cohortes , Inmunodeficiencia Variable Común/complicaciones , Inmunodeficiencia Variable Común/patología , Duodeno/patología , Heces/virología , Femenino , Humanos , Enfermedades Intestinales/complicaciones , Enfermedades Intestinales/patología , Intestino Delgado/patología , Intestino Delgado/virología , Masculino , Persona de Mediana Edad , Ribavirina/uso terapéuticoRESUMEN
Rare Epstein-Barr virus (EBV)+ smooth muscle tumours (SMT) manifest typically under immunosuppression. Three major subtypes are known: human immunodeficiency virus-associated (HIV-SMT), after transplantation (PTSMT) or associated with congenital immunodeficiency syndromes (CI-SMT). So far, there are no analyses which compare the clinico-pathological characteristics of all three subtypes. Case reports and case series on these three tumour types were collected (1990-2012). Meta-data analysis was performed for identification of similarities and differences. A total of 73 HIV-SMT, 66 PTSMT and 9 CI-SMT were evaluated. There was a slight female predominance (55-67%). Children were affected nearly equally in HIV-SMT (33%) and PTSMT (35%), while all CI-SMT occurred in children. HIV-SMT manifested preferentially in the central nervous system, gut/liver, skin, lungs/larynx/pharynx and adrenal glands. PTSMT were predominantly found in the liver, lungs/larynx/pharynx, gut/spleen and brain. CI-SMT were often found in lungs/larynx, brain, liver, adrenal glands and spleen. Antecedent EBV+ lymphoproliferations manifested more often in PTSMT. In all three tumour subtypes, survival analyses did not show any significant differences regarding surgical therapeutic approaches, the occurrence of multiple tumours, tumour size or sarcoma-like histological features. HIV-SMT had the poorest overall survival, which might be attributed to HIV-associated infectious complications.
Asunto(s)
VIH/aislamiento & purificación , Tumor de Músculo Liso/patología , Estudios de Cohortes , Inmunodeficiencia Variable Común/inmunología , Inmunodeficiencia Variable Común/patología , Inmunodeficiencia Variable Común/virología , Infecciones por Virus de Epstein-Barr/patología , Humanos , Pronóstico , Tumor de Músculo Liso/inmunología , Tumor de Músculo Liso/virologíaRESUMEN
Common variable immunodeficiency (CVID) is the most frequent clinically relevant primary immunodeficiency and shows enormous heterogeneity in clinical presentation. Despite clinical immunodeficiency, opportunistic infections are not a typical manifestation of CVID. A retrospective study of 32 patients followed up for 335 patient-years was performed to determine the frequency of cytomegalovirus (CMV) disease. Symptomatic CMV infection was documented in 3 CVID patients. Patients No. 1 and 2 suffered from CMV pneumonia, with complications due to atypical mycobacteriosis in patient No. 1. Patient No. 3 suffered from CMV enteritis. A history of cancer and chronic hepatitis C infection (patient No. 1), immunosuppressive therapy for interstitial lung disease (patient No. 2) and serious enteropathy complicated with malnutrition (patient No. 3) may have contributed to the complications despite only mild abnormalities in T-cell subpopulations. The direct detection of CMV in bronchoalveolar lavage, stool or tissue samples was the most beneficial diagnostic laboratory method, whereas the detection of CMV DNA in blood did not produce positive results. Adequate treatment of CMV disease led to significant clinical improvement in all 3 patients. The frequency of CMV disease appears to be higher than previously described. In our experience, the probability of opportunistic infections in CVID patients increases with secondary comorbidities and their management.
Asunto(s)
Inmunodeficiencia Variable Común/diagnóstico , Infecciones por Citomegalovirus/diagnóstico , ADN Viral/aislamiento & purificación , Enteritis/diagnóstico , Infecciones por Mycobacterium no Tuberculosas/diagnóstico , Neumonía Viral/diagnóstico , Líquido del Lavado Bronquioalveolar/virología , Inmunodeficiencia Variable Común/complicaciones , Inmunodeficiencia Variable Común/patología , Inmunodeficiencia Variable Común/virología , Citomegalovirus , Infecciones por Citomegalovirus/complicaciones , Infecciones por Citomegalovirus/patología , Infecciones por Citomegalovirus/virología , Enteritis/complicaciones , Enteritis/patología , Enteritis/virología , Heces/virología , Femenino , Humanos , Persona de Mediana Edad , Infecciones por Mycobacterium no Tuberculosas/complicaciones , Infecciones por Mycobacterium no Tuberculosas/patología , Infecciones por Mycobacterium no Tuberculosas/virología , Neumonía Viral/complicaciones , Neumonía Viral/patología , Neumonía Viral/virologíaRESUMEN
Viral infections remain a major cause of morbidity in patients with immunodeficiency, such as recipients of hemopoietic stem cell transplantation. Adoptive transfer of donor-derived virus-specific cytotoxic T lymphocytes is a strategy to restore virus-specific immunity to prevent or treat viral diseases and has been tested in the clinical setting for more than 20 years. Several different groups have used expanded virus-specific T-cell products specific for one or multiple viruses to both reconstitute antiviral immunity after transplantation and to treat active viral infections. Response rates are encouraging, although resistance has been seen when the infused cell population has had restricted specificity or has targeted antigens expressed in donor-infected but not virally infected recipient cells. The goal of current trials is to make this approach more broadly applicable using more rapidly available products from the donor, such as directly selected or briefly expanded cells or closely matched banked cells.
Asunto(s)
Traslado Adoptivo , Trasplante de Células Madre Hematopoyéticas , Linfocitos T Citotóxicos , Virosis , Inmunodeficiencia Variable Común/inmunología , Inmunodeficiencia Variable Común/mortalidad , Inmunodeficiencia Variable Común/virología , Humanos , Linfocitos T Citotóxicos/inmunología , Linfocitos T Citotóxicos/trasplante , Virosis/inmunología , Virosis/mortalidad , Virosis/terapiaRESUMEN
Smooth muscle tumours (SMT) after transplantation (PTSMT) or associated with congenital immunodeficiency syndromes (CI-SMT) and human immunodeficiency virus (HIV-SMT) are rare. The majority of PTSMT and CI-SMT are associated with Epstein-Barr virus (EBV), while some HIV-SMT can be EBV-negative. SMT in immunodeficient states may present with unspecific symptoms which are mainly related to tumour localisation. In PTSMT, >50% of tumours manifest in the liver/transplant liver, but in general PTSMT, HIV-SMT and CI-SMT can occur at any site as single or multiple tumours. Multiple tumour manifestations do not define metastatic disease as PTSMT can occur synchronously and/or metachronously. PTSMT can originate from the recipient as well as from the donor. Morphologically, most tumours, in particular PTSMT, lack marked histological atypia or tumour necrosis, while some HIV-SMT and CI-SMT can present as sarcoma-like variants, but histomorphology does not predict clinical aggressiveness or tumourbiological behaviour. In PTSMT, surgery and reduced immunosuppression show comparable overall survival rates, while poor prognosis is mainly associated with intracranial manifestation and non-resectable tumours. In HIV-SMT and CI-SMT, surgery should be performed. In all 3 tumour types, adverse prognosis is mainly related to comorbidities associated with immunosuppression but not with the extent of histological atypia or tumour size.
Asunto(s)
Inmunodeficiencia Variable Común/complicaciones , Infecciones por Virus de Epstein-Barr/complicaciones , Infecciones por VIH/complicaciones , Herpesvirus Humano 4/aislamiento & purificación , Neoplasias de los Músculos/complicaciones , Músculo Liso/patología , Adolescente , Inmunodeficiencia Variable Común/congénito , Inmunodeficiencia Variable Común/virología , Infecciones por Virus de Epstein-Barr/virología , Femenino , Infecciones por VIH/virología , Humanos , Terapia de Inmunosupresión , Neoplasias de los Músculos/patología , Neoplasias de los Músculos/terapia , Neoplasias de los Músculos/virología , Trasplante de Órganos , Pronóstico , Factores de RiesgoRESUMEN
Encephalitis due to BK virus is a rare condition. Here, we describe a young male patient with common variable immunodeficiency who developed fatal encephalitis due to BK virus. The patient presented initially with ocular symptoms that were followed by behavioral changes and spastic quadriparesis. Diagnosis was made by the compatible clinical findings and detection of viral DNA by polymerase chain reaction in the cerebrospinal fluid. To the best of our knowledge, this is the first report of BK virus encephalitis in a patient with common variable immunodeficiency. We suggest that BK virus should be suspected in cases of encephalitis; particularly in patients with immunodeficiency.
Asunto(s)
Virus BK/aislamiento & purificación , Inmunodeficiencia Variable Común/virología , Encefalitis Viral/inmunología , Encefalitis Viral/virología , Infecciones por Polyomavirus/inmunología , Infecciones Tumorales por Virus/inmunología , Adulto , Virus BK/genética , Inmunodeficiencia Variable Común/inmunología , ADN Viral/genética , Humanos , Masculino , Infecciones por Polyomavirus/virología , Infecciones Tumorales por Virus/virología , Adulto JovenRESUMEN
The shedding of human rhinovirus (HRV) after an acute, naturally acquired infection has not been described in detail. We determined the duration of HRV shedding in immunocompetent children and adults, and in patients with primary hypogammaglobulinaemia. Subjects with symptoms of respiratory tract infection, and their household contacts, were screened for HRV by reverse transcription PCR. They were followed by serial, self-collected nasal swab specimens until negative for HRV or infected by another HRV type. We followed 62 HRV infections in 54 subjects. The mean (95% CI) duration of HRV shedding was 11.4 (8.2-14.7) days in children, 10.1 (7.4-12.9) days in adults, and 40.9 (26.4-55.4) days in patients with hypogammaglobulinaemia (p <0.001). The duration of respiratory tract symptoms correlated with the duration of virus shedding (p 0.002). A new infection by another HRV type soon after the first episode was common. We conclude that the shedding times of HRV are relatively short in otherwise healthy individuals. In contrast, prolonged shedding over 28 days is frequent in patients with hypogammaglobulinaemia despite immunoglobulin replacement therapy.
Asunto(s)
Inmunodeficiencia Variable Común/complicaciones , Infecciones por Picornaviridae/virología , Infecciones del Sistema Respiratorio/virología , Rhinovirus/aislamiento & purificación , Esparcimiento de Virus , Adulto , Niño , Preescolar , Inmunodeficiencia Variable Común/virología , Estudios de Seguimiento , Humanos , Lactante , Persona de Mediana Edad , Mucosa Nasal/virología , Infecciones por Picornaviridae/inmunología , ARN Viral/genética , ARN Viral/aislamiento & purificación , Infecciones del Sistema Respiratorio/inmunología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factores de TiempoRESUMEN
The inhibition of death-receptor apoptosis is a conserved viral function. The murine cytomegalovirus (MCMV) gene M36 is a sequence and functional homologue of the human cytomegalovirus gene UL36, and it encodes an inhibitor of apoptosis that binds to caspase-8, blocks downstream signaling and thus contributes to viral fitness in macrophages and in vivo. Here we show a direct link between the inability of mutants lacking the M36 gene (ΔM36) to inhibit apoptosis, poor viral growth in macrophage cell cultures and viral in vivo fitness and virulence. ΔM36 grew poorly in RAG1 knockout mice and in RAG/IL-2-receptor common gamma chain double knockout mice (RAGγC(-/-)), but the depletion of macrophages in either mouse strain rescued the growth of ΔM36 to almost wild-type levels. This was consistent with the observation that activated macrophages were sufficient to impair ΔM36 growth in vitro. Namely, spiking fibroblast cell cultures with activated macrophages had a suppressive effect on ΔM36 growth, which could be reverted by z-VAD-fmk, a chemical apoptosis inhibitor. TNFα from activated macrophages synergized with IFNγ in target cells to inhibit ΔM36 growth. Hence, our data show that poor ΔM36 growth in macrophages does not reflect a defect in tropism, but rather a defect in the suppression of antiviral mediators secreted by macrophages. To the best of our knowledge, this shows for the first time an immune evasion mechanism that protects MCMV selectively from the antiviral activity of macrophages, and thus critically contributes to viral pathogenicity in the immunocompromised host devoid of the adaptive immune system.
Asunto(s)
Inmunidad Adaptativa , Inmunodeficiencia Variable Común/inmunología , Infecciones por Herpesviridae/inmunología , Macrófagos/inmunología , Muromegalovirus/inmunología , Clorometilcetonas de Aminoácidos/farmacología , Animales , Línea Celular , Inmunodeficiencia Variable Común/genética , Inmunodeficiencia Variable Común/patología , Inmunodeficiencia Variable Común/virología , Inhibidores de Cisteína Proteinasa/farmacología , Fibroblastos/inmunología , Fibroblastos/patología , Fibroblastos/virología , Infecciones por Herpesviridae/genética , Infecciones por Herpesviridae/patología , Humanos , Interferón gamma/genética , Interferón gamma/inmunología , Macrófagos/patología , Macrófagos/virología , Ratones , Ratones Noqueados , Muromegalovirus/genética , Proteínas Virales/genética , Proteínas Virales/inmunologíaRESUMEN
BACKGROUND: A subset of patients with common variable immunodeficiency (CVID) have debilitating inflammatory complications strongly associated with cytomegalovirus (CMV) infection and a hyperproliferative CMV-specific T-cell response. OBJECTIVES: We studied the T-cell response to CMV and the global effect of this virus on immune effector cell populations in patients with CVID. METHODS: Antibody staining, peptide stimulation, and proliferation assays were used to profile CMV-specific T-cell function. RESULTS: CMV infection drives the CD4/CD8 ratio inversion that is characteristic of CVID. The late effector CD8(+) T-cell subset is expanded in CMV-infected patients with CVID. This expansion is largely attributable to CMV-specific cells and correlates with inflammatory disease; within the CMV-specific population, the frequency of late effector cells correlates inversely with the frequency of cells expressing programmed death 1. Supernatants from proliferating CMV-specific CD8(+) cells from patients with inflammatory disease can confer proliferative potential on cells from patients with noninflammatory CVID and healthy subjects. Blocking experiments showed that this proliferation is mediated in part by IFN-γ and TNF-α. CONCLUSIONS: These data strengthen the association of CMV with inflammatory pathology in patients with CVID, explain some of the well-known T-cell abnormalities associated with this condition, and provide a plausible mechanism for the documented therapeutic activity of anti-TNF-α and antiviral chemotherapy in managing CVID-associated inflammatory disease.
Asunto(s)
Linfocitos T CD8-positivos/metabolismo , Inmunodeficiencia Variable Común/inmunología , Infecciones por Citomegalovirus/inmunología , Citomegalovirus/inmunología , Receptor de Muerte Celular Programada 1/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Bloqueadores/farmacología , Relación CD4-CD8 , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/patología , Linfocitos T CD8-positivos/virología , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Inmunodeficiencia Variable Común/tratamiento farmacológico , Inmunodeficiencia Variable Común/virología , Citomegalovirus/patogenicidad , Infecciones por Citomegalovirus/complicaciones , Infecciones por Citomegalovirus/tratamiento farmacológico , Infecciones por Citomegalovirus/virología , Femenino , Humanos , Inmunofenotipificación , Interferón gamma/inmunología , Interferón gamma/metabolismo , Masculino , Persona de Mediana Edad , Receptor de Muerte Celular Programada 1/genética , Receptor de Muerte Celular Programada 1/inmunología , Factor de Necrosis Tumoral alfa/inmunología , Factor de Necrosis Tumoral alfa/metabolismo , Adulto JovenRESUMEN
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.
Asunto(s)
Infecciones por Papillomavirus/complicaciones , Verrugas/complicaciones , Inmunodeficiencia Variable Común/complicaciones , Inmunodeficiencia Variable Común/terapia , Inmunodeficiencia Variable Común/virología , Infecciones por VIH/complicaciones , Humanos , Síndrome de Inmunodeficiencia con Hiper-IgM/complicaciones , Síndrome de Inmunodeficiencia con Hiper-IgM/terapia , Síndrome de Inmunodeficiencia con Hiper-IgM/virología , Síndromes de Inmunodeficiencia/complicaciones , Síndromes de Inmunodeficiencia/terapia , Terapia de Inmunosupresión/efectos adversos , Papillomaviridae/genética , Infecciones por Papillomavirus/terapia , Infecciones por Papillomavirus/virología , Enfermedades de Inmunodeficiencia Primaria , Inmunodeficiencia Combinada Grave/complicaciones , Inmunodeficiencia Combinada Grave/terapia , Inmunodeficiencia Combinada Grave/virología , Linfocitopenia-T Idiopática CD4-Positiva/complicaciones , Linfocitopenia-T Idiopática CD4-Positiva/terapia , Verrugas/terapia , Verrugas/virologíaRESUMEN
Secondary immunodeficiency can be caused by multiple factors. We studied whether there is a relationship between secondary immunodeficiency and Epstein-Barr virus (EBV) infection in children and adolescents. The study group included 845 patients with common variable immunodeficiency aged from 2 to 18 years and 394 age-matched healthy controls. IgM and IgG antibodies against viral capsid antigen (VCA) and IgG antibodies against Epstein-Barr virus nuclear antigen 1 (EBNA-1) were quantitated by an enzyme-linked immunosorbent assay. A statistically significant difference (p = 0.004) in the prevalence of EBV infection was found between the immunodeficient children and controls, both aged 2 to 6 years. The statistically significant difference was confirmed in boys (p = 0.003), but not in girls of this age group.
Asunto(s)
Anticuerpos Antivirales/sangre , Inmunodeficiencia Variable Común/virología , Herpesvirus Humano 4/inmunología , Adolescente , Antígenos Virales/inmunología , Proteínas de la Cápside/inmunología , Niño , Antígenos Nucleares del Virus de Epstein-Barr/inmunología , Femenino , Humanos , MasculinoRESUMEN
Cytomegalovirus (CMV) reactivation was analyzed in 92 recipients of allogeneic hematopoietic stem cell transplantation (HSCT) in relation to the proportion of CD4(+) lymphocytes in blood and a microsatellite polymorphism within the first intron of the interferon-gamma (IFNG) gene. CMV reactivation was found in 50% of the HSCT recipients; in 30% of these individuals, the level of CMV copies exceeded 100 per 10(5) peripheral blood (PB) cells on at least one occasion during the 100-day post-HSCT observation period. This high CMV copy level was most frequently found between 31 and 60 days post-HSCT (P = .021). Patients with > or = 100 CMV copies/10(5) cells were characterized by poorer overall survival (OS) compared with those lacking CMV copies or having < 100 CMV copies/10(5) cells (P = .04), and they suffered from severe post-HSCT complications, including acute graft-versus-host disease (aGVHD) and relapse. Thus, patients with > or = 100 CMV copies/10(5) cells were designated as having clinically significant CMV reactivation. Patients with < 10% CD4(+) lymphocytes had a higher number of CMV DNA copies than those with higher proportions of CD4(+) lymphocytes (0.62 vs 0.21, P = .001; mean +/- SEM, 4422 +/- 1667 vs 937 +/- 662 CMV copies/10(5) cells, P < .001, for the proportion of cases with reactivation and numbers of copies, respectively). Similarly, patients carrying 2 IFNG 13-CA-repeat alleles (homozygotes) had more frequent CMV reactivation (0.50 vs 0.26; P = .039) and a higher CMV load (4111 +/- 1699 vs 950+/-591 CMV copies/10(5) cells; P = .041) compared with those with other IFNG microsatellite allele constellations. Multivariate analysis demonstrated that the IFNG 13-CA-repeat homozygous genotype (odds ratio [OR] = 0.221; P = .044), a low proportion of CD4(+) lymphocytes (OR = 0.276; P = .050), and a lack of optimal (10/10 alleles) donor-recipient HLA match (OR = 15.19; P = .006) were independent risk factors for CMV reactivation with a high number of copies.