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1.
Cell Rep ; 34(11): 108852, 2021 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-33730580

RESUMO

As the global COVID-19 pandemic progresses, it is paramount to gain knowledge on adaptive immunity to SARS-CoV-2 in children to define immune correlates of protection upon immunization or infection. We analyzed anti-SARS-CoV-2 antibodies and their neutralizing activity (PRNT) in 66 COVID-19-infected children at 7 (±2) days after symptom onset. Individuals with specific humoral responses presented faster virus clearance and lower viral load associated with a reduced in vitro infectivity. We demonstrated that the frequencies of SARS-CoV-2-specific CD4+CD40L+ T cells and Spike-specific B cells were associated with the anti-SARS-CoV-2 antibodies and the magnitude of neutralizing activity. The plasma proteome confirmed the association between cellular and humoral SARS-CoV-2 immunity, and PRNT+ patients show higher viral signal transduction molecules (SLAMF1, CD244, CLEC4G). This work sheds lights on cellular and humoral anti-SARS-CoV-2 responses in children, which may drive future vaccination trial endpoints and quarantine measures policies.


Assuntos
Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , /imunologia , Imunidade Adaptativa/imunologia , Linfócitos B/imunologia , Linfócitos T CD4-Positivos/imunologia , Criança , Humanos , Imunidade Humoral/imunologia , Proteoma/imunologia , Transdução de Sinais/imunologia , Carga Viral/imunologia
2.
Ital J Pediatr ; 47(1): 72, 2021 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-33761977

RESUMO

BACKGROUND: COVID-19 pandemic was responsible for disrupting routine immunization activities all over the world. Aim of the study was to investigate the reduced adherence to the national children vaccination schedule during the lockdown period in Italy. MATERIALS AND METHODS: Through social channels, the Italian Pediatric Society conducted a survey among Italian families on children vaccination during lockdown period. RESULTS: In the study period, 1474 responders were collected. More than one third (34%) of them skipped the vaccine appointment as they were afraid of SARS-CoV-2-virus (44%), vaccination services postponed the appointment (42%) or was closed to public (13%). DISCUSSION: Reduction in routine immunization coverage may represent a serious life-threating problem for unvaccinated or under-vaccinated children. CONCLUSIONS: Information on national and local preventive measures including physical distancing, handwashing, and proper coughing/sneezing hygiene should be spread among families in order to contrast vaccine hesitancy and maintain adequate coverage levels during COVID19 pandemic period.


Assuntos
Agendamento de Consultas , Esquemas de Imunização , Vacinação/estatística & dados numéricos , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Itália/epidemiologia , Masculino , Pandemias , Mídias Sociais , Sociedades Médicas , Inquéritos e Questionários
4.
Ital J Pediatr ; 47(1): 16, 2021 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-33494789

RESUMO

Aim of these revised recommendations for the general management of Kawasaki disease is to encourage its prompter recognition and warrant the most appropriate therapy, based on ascertained scientific data, raising awareness of the complications related to misdiagnosis or delayed treatment. A set of 20 synthetic operative statements is herein provided, including the definition of Kawasaki disease, its protean presentations, clinical course and seminal treatment modalities of all disease phases. The application of these recommendations should improve prognosis of Kawasaki disease and prevent the progression to permanent vascular abnormalities, thereby diminishing morbidity and mortality.

5.
Artigo em Inglês | MEDLINE | ID: mdl-33491084

RESUMO

Limited data exist regarding sex bias and viral decay in children with HIV. We investigated the sex differences in viral decay in 25 perinatally HIV-infected children. Females presented faster phase I viral decay regardless of their age at antiretroviral therapy (ART) initiation, baseline CD4 percentages, or baseline RNA levels. Also, for each month elapsed under ART, females had faster viral decay than males.

6.
Sci Rep ; 10(1): 17836, 2020 10 20.
Artigo em Inglês | MEDLINE | ID: mdl-33082466

RESUMO

Infections are most frequent at the extremes of life, especially among newborns, reflecting age-specific differences in immunity. Monocytes maintain tissue-homeostasis and defence-readiness by escaping circulation in the absence of inflammation to become tissue-resident antigen presenting cells in vivo. Despite equivalent circulating levels, neonates demonstrate lower presence of monocytes inside peripheral tissues as compared to adults. To study the ability of monocytes to undergo autonomous transendothelial extravasation under biologically accurate circumstances we engineered a three-dimensional human vascular-interstitial model including collagen, fibronectin, primary endothelial cells and autologous untreated plasma. This microphysiological tissue construct enabled age-specific autonomous extravasation of monocytes through a confluent human endothelium in the absence of exogenous chemokines and activation. Both CD16- and CD16+ newborn monocytes demonstrated lower adherence and extravasation as compared to adults. In contrast, pre-activated tissue constructs were colonized by newborn monocytes at the same frequency than adult monocytes, suggesting that neonatal monocytes are capable of colonizing inflamed tissues. The presence of autologous plasma neither improved newborn homeostatic extravasation nor shaped age-specific differences in endothelial cytokines that could account for this impairment. Newborn monocytes demonstrated significantly lower surface expression of CD31 and CD11b, and mechanistic experiments using blocking antibodies confirmed a functional role for CD31 and CD54 in neonatal homeostatic extravasation. Our data suggests that newborn monocytes are intrinsically impaired in extravasation through quiescent endothelia, a phenomenon that could contribute to the divergent immune responsiveness to vaccines and susceptibility to infection observed during early life.

7.
Front Immunol ; 11: 559590, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33123133

RESUMO

The number of patients affected by chronic diseases with special vaccination needs is burgeoning. In this scenario, predictive markers of immunogenicity, as well as signatures of immune responses are typically missing even though it would especially improve the identification of personalized immunization practices in these populations. We aimed to develop a predictive score of immunogenicity to Influenza Trivalent Inactivated Vaccination (TIV) by applying deep machine learning algorithms using transcriptional data from sort-purified lymphocyte subsets after in vitro stimulation. Peripheral blood mononuclear cells (PBMCs) collected before TIV from 23 vertically HIV infected children under ART and virally controlled were stimulated in vitro with p09/H1N1 peptides (stim) or left unstimulated (med). A multiplexed-qPCR for 96 genes was made on fixed numbers of 3 B cell subsets, 3 T cell subsets and total PBMCs. The ability to respond to TIV was assessed through hemagglutination Inhibition Assay (HIV) and ELIspot and patients were classified as Responders (R) and Non Responders (NR). A predictive modeling framework was applied to the data set in order to define genes and conditions with the higher predicted probability able to inform the final score. Twelve NR and 11 R were analyzed for gene expression differences in all subsets and 3 conditions [med, stim or Δ (stim-med)]. Differentially expressed genes between R and NR were selected and tested with the Adaptive Boosting Model to build a prediction score. The score obtained from subsets revealed the best prediction score from 46 genes from 5 different subsets and conditions. Calculating a combined score based on these 5 categories, we achieved a model accuracy of 95.6% and only one misclassified patient. These data show how a predictive bioinformatic model applied to transcriptional analysis deriving from in-vitro stimulated lymphocytes subsets may predict poor or protective vaccination immune response in vulnerable populations, such as HIV-infected individuals. Future studies on larger cohorts are needed to validate such strategy in the context of vaccination trials.

9.
Cell ; 183(4): 968-981.e7, 2020 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-32966765

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is typically very mild and often asymptomatic in children. A complication is the rare multisystem inflammatory syndrome in children (MIS-C) associated with COVID-19, presenting 4-6 weeks after infection as high fever, organ dysfunction, and strongly elevated markers of inflammation. The pathogenesis is unclear but has overlapping features with Kawasaki disease suggestive of vasculitis and a likely autoimmune etiology. We apply systems-level analyses of blood immune cells, cytokines, and autoantibodies in healthy children, children with Kawasaki disease enrolled prior to COVID-19, children infected with SARS-CoV-2, and children presenting with MIS-C. We find that the inflammatory response in MIS-C differs from the cytokine storm of severe acute COVID-19, shares several features with Kawasaki disease, but also differs from this condition with respect to T cell subsets, interleukin (IL)-17A, and biomarkers associated with arterial damage. Finally, autoantibody profiling suggests multiple autoantibodies that could be involved in the pathogenesis of MIS-C.


Assuntos
Infecções por Coronavirus/patologia , Pneumonia Viral/patologia , Síndrome de Resposta Inflamatória Sistêmica/patologia , Autoanticorpos/sangue , Betacoronavirus/isolamento & purificação , Criança , Pré-Escolar , Infecções por Coronavirus/complicações , Infecções por Coronavirus/virologia , Citocinas/metabolismo , Feminino , Humanos , Imunidade Humoral , Lactente , Masculino , Síndrome de Linfonodos Mucocutâneos/complicações , Síndrome de Linfonodos Mucocutâneos/imunologia , Síndrome de Linfonodos Mucocutâneos/patologia , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/virologia , Análise de Componente Principal , Proteoma/análise , Índice de Gravidade de Doença , Síndrome de Resposta Inflamatória Sistêmica/etiologia , Síndrome de Resposta Inflamatória Sistêmica/imunologia , Subpopulações de Linfócitos T/citologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo
10.
Artigo em Inglês | MEDLINE | ID: mdl-32678875

RESUMO

BACKGROUND: Strategies aimed at antiretroviral therapy (ART)-free remission will target individuals with a limited viral reservoir. We investigated factors associated with low reservoir measured as total human immunodeficiency virus type 1 (HIV-1) DNA in peripheral blood mononuclear cells (PBMCs) in perinatal infection (PaHIV). METHODS: Children from 7 European centers in the Early Treated Perinatally HIV Infected Individuals: Improving Children's Actual Life (EPIICAL) consortium who commenced ART aged <2 years, and remained suppressed (viral load [VL] <50 copies/mL) for >5 years were included. Total HIV-1 DNA was measured by quantitative polymerase chain reaction per million PBMCs. Factors associated with total HIV-1 DNA were analyzed using generalized additive models. Age, VL at ART initiation, and baseline CD4% effects were tested including smoothing splines to test nonlinear association. RESULTS: Forty PaHIV, 27 (67.5%) female 21 (52.5%) Black/Black African, had total HIV-1 DNA measured; median 12 (IQR, 7.3-15.4) years after ART initiation. Eleven had total HIV-1 DNA <10 copies/106 PBMCs. HIV-1 DNA levels were positively associated with age and VL at ART initiation, baseline CD4%, and Western blot antibody score. Age at ART initiation presented a linear association (coefficient = 0.10 ± 0.001, P ≤ .001), the effect of VL (coefficient = 0.35 ± 0.1, P ≤ .001) noticeable >6 logs. The effect of CD4% (coefficient = 0.03 ± 0.01, P = .049) was not maintained >40%. CONCLUSIONS: In this PaHIV cohort, reduced total HIV-1 DNA levels were associated with younger age and lower VL at ART initiation. The impact of early-infant treatment on reservoir size persists after a decade of suppressive therapy.

11.
J AAPOS ; 24(4): 212-215, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32531341

RESUMO

PURPOSE: To evaluate ocular manifestations and severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) prevalence in the tears of children with coronavirus disease 2019 (COVID-19). METHODS: A total of 27 pediatric patients with confirmed COVID-19 infection hospitalized from March 16 to April 15, 2020, at the Bambino Gesù Children's Hospital were enrolled in the study. At admission, all patients showed ocular manifestations. Reverse transcriptase-polymerase chain reaction from nasopharyngeal and conjunctival swabs were performed every 2-3 days before discharge. RESULTS: Of the 27 patients, 4 (15%) were asymptomatic, 15 (56%) showed respiratory symptoms, and 8 (30%) had gastrointestinal symptoms. At admission, nasopharyngeal swabs were positive for COVID-19 in all patients; on the second swabs, 7 children (26%) tested negative, and 20 remained positive for COVID-19. Ocular manifestations consistent with mild viral conjunctivitis were observed in 4 patients (15%). At first conjunctival swab, 3 patients (11%), 1 symptomatic and 2 asymptomatic for ocular infection, had positive findings for COVID-19; 2 became negative on the second test and 1 on the third. CONCLUSIONS: In our study cohort, ocular manifestations of COVID-19 seem to have had a milder clinical course in pediatric patients than in adults. Despite the low prevalence and rapid regression of viral presence in the conjunctiva, SARS-CoV-2 transmission through tears may be possible, even in patients without apparent ocular involvement.

12.
Lancet HIV ; 7(5): e359-e365, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32386722

RESUMO

Several assays have been developed to measure and characterise the replication-competent HIV-1 reservoir, which constitutes the barrier to cure. To date, the application of these assays to studies in children and in limited-resource settings has been minimal, primarily because of their expense, the large required blood volumes, and labour-intensive technologies. For children vertically infected with HIV-1 who initiated suppressive antiretroviral therapy (ART) regimens in infancy, HIV-1-specific antibody concentrations are associated with viral persistence and could be used to estimate the size of the residual latent reservoir on ART. This strategy could be particularly useful for screening children on suppressive ART for enrolment into therapeutic vaccine trials and other protocols aimed at achieving HIV-1 remission.


Assuntos
Anticorpos Anti-HIV/sangue , Infecções por HIV/imunologia , Infecções por HIV/virologia , HIV-1/imunologia , Transmissão Vertical de Doença Infecciosa , Carga Viral , Fármacos Anti-HIV/uso terapêutico , DNA Viral/sangue , Infecções por HIV/tratamento farmacológico , Infecções por HIV/transmissão , Humanos , Lactente
13.
J Leukoc Biol ; 108(2): 739-748, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32392633

RESUMO

X-linked severe combined immunodeficiency (X-SCID) caused by full mutation of the IL2RG gene leads to T- B+ NK- phenotype and is usually associated with severe opportunistic infections, diarrhea, and failure to thrive. When IL2RG hypomorphic mutation occurs, diagnosis could be delayed and challenging since only moderate reduction of T and NK cells may be present. Here, we explored phenotypic insights and the impact of the p.R222C hypomorphic mutation (IL2RGR222C ) in distinct cell subsets in an 8-month-old patient with atypical X-SCID. We found reduced CD4+ T cell counts, a decreased frequency of naïve CD4+ and CD8+ T cells, and an expansion of B cells. Ex vivo STAT5 phosphorylation was impaired in CD4+ CD45RO+ T cells, yet compensated by supraphysiological doses of IL-2. Sanger sequencing on purified cell subsets showed a partial reversion of the mutation in total CD3+ cells, specifically in recent thymic emigrants (RTE), effector memory (EM), and CD45RA+ terminally differentiated EM (EMRA) CD4+ T cells. Of note, patient's NK cells had a normal frequency compared to age-matched healthy subjects, but displayed an expansion of CD56bright cells with higher perforin content and cytotoxic potential, associated with accumulation of NK-cell stimulatory cytokines (IL-2, IL-7, IL-15). Overall, this report highlights an alteration in the NK-cell compartment that, together with the high disease-phenotype variability, should be considered in the suspicion of X-SCID with hypomorphic IL2RG mutation.

14.
Clin Immunol ; 215: 108440, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32330555

RESUMO

Perinatally HIV-infected children (PHIV), despite successful antiretroviral therapy, present suboptimal responses to vaccinations compared to healthy-controls (HC). Here we investigated phenotypic and transcriptional signatures of H1N1-specific B-cells (H1N1-Sp) in PHIV, differentially responding to trivalent-influenza-vaccine (TIV), and HC. Patients were categorized in responders (R) and non-responders (NR) according to hemagglutination-inhibition-assay at baseline and 21 days after TIV. No differences in H1N1-Sp frequencies were found between groups. H1N1-Sp transcriptional analysis revealed a distinct signature between PHIV and HC. NR presented higher PIK3C2B and NOD2 expression compared to R, confirmed by downregulation of PIK3C2B in resting-memory of R after H1N1 in-vitro stimulation. In conclusion this study confirms that qualitative rather than quantitative analyses are needed to characterize immune responses in PHIV. These results further suggest that higher PIK3C2B in H1N1-Sp of NR is associated with lower H1N1 immunogenicity and may be targeted by future modulating strategies to improve TIV responses in PHIV.

15.
AIDS ; 34(5): 669-680, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32167989

RESUMO

OBJECTIVE: To investigate long-term persistence of HIV-specific lymphocyte immunity in perinatally HIV-infected children treated within the first year of life. DESIGN: Twenty perinatally HIV-infected children who received ART therapy within the first year of life (early treated) and with stable viral control (>5 years) were grouped according to their serological response to HIV. METHODS: Western blot analysis and ELISA defined 14 HIV-seropositive and six seronegative patients. Frequencies of gp140-specific T-cell and B-cell, and T-cell cytokine production were quantified by flow cytometry in both seronegatives and seropositives. Transcriptional signatures in purified gp140-specific B-cell subsets, in response to in-vitro stimulation with HIV peptides was evaluated by multiplex RT-PCR. RESULTS: Gp140-specific T cells and B cells persist at similar levels in both groups. A higher production of IL-21 in gp140-specific T cells was found in seropositives vs. seronegatives (P = 0.003). Gene expression in switched IgM-IgD- gp140-specific memory B cells after stimulation with HIV peptides in vitro demonstrated a differential expression of genes involved in signal transduction and activation after BCR/TLR triggering and B-cell activation. Genes relating to antibody production (PRDM1) and T-B cognate stimulation (CXCR4, IL21R) were differentially induced after in-vitro stimulation in seronegatives vs. seropositives suggesting a truncated process of B-cell maturation. CONCLUSION: HIV-specific memory B and T cells persist in early treated regardless their serological status. Seronegatives and seropositives are distinguished by gp140-specific T-cell function and by distinct transcriptional signatures of gp140-specific B cells after in-vitro stimulation, presumably because of a different antigen exposure. Such qualitative insights may inform future immunotherapeutic interventions.

16.
J Immunol ; 204(3): 540-549, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31889024

RESUMO

Early initiation of antiretroviral therapy (ART) in vertically HIV-infected children limits the size of the virus reservoir, but whether the time of treatment initiation (TI) can durably impact host immune responses associated with HIV infection is still unknown. This study was conducted in PBMC of 20 HIV-infected virally suppressed children on ART (mean age 9.4 y), classified as early treated (ET; age at ART initiation ≤0.5 y, n = 14) or late treated (LT; age at ART initiation 1-10 y, n = 6). Frequencies and functions of Ag-specific CD4 (CD40L+) and CD8 (CD69+) T cells were evaluated by intracellular IL-2, IFN-γ, and TNF-α production with IL-21 in CD4 or CD107a, granzyme B and perforin in CD8 T cells following stimulation with HIV gp140 protein (ENV) or GAG peptides by multiparameter flow cytometry. ET showed a higher proportion of cytokine-producing ENV- and GAG-specific CD4 and CD8 T cells compared with LT. In particular, ET were enriched in polyfunctional T cells. RNA sequencing analysis showed upregulation of immune activation pathways in LT compared with ET. Our results suggest that timing of TI in HIV-infected children has a long-term and measurable impact on the quality of the HIV-specific T cell immune responses and transcriptional profiles of PBMC, reinforcing the importance of early TI.


Assuntos
Antirretrovirais/uso terapêutico , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Infecções por HIV/tratamento farmacológico , HIV-1/fisiologia , Adolescente , Criança , Pré-Escolar , Feminino , Granzimas/metabolismo , Antígenos HIV/imunologia , Humanos , Recém-Nascido , Ativação Linfocitária , Masculino , Produtos do Gene gag do Vírus da Imunodeficiência Humana/imunologia
17.
Front Immunol ; 10: 2735, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31849946

RESUMO

Multiparametric flow cytometry (MFC) represents a rapid, highly reproducible, and sensitive diagnostic technology for primary immunodeficiencies (PIDs), which are characterized by a wide range of T cell perturbations and a broad clinical and genetic heterogeneity. MFC data from CD4+ and CD8+ T cell subsets were examined in 100 patients referred for Primary Immunodeficiencies to our center. Naïve, central memory, effector memory, and terminal effector memory cell differentiation stages were defined by the combined expression CD45RA/CD27 for CD4 and CD45RA/CCR7 for CD8. Principal component analysis (PCA), a non-hypothesis driven statistical analysis, was applied to analyze MFC data in order to distinguish the diverse PIDs. Among severe lymphopenic patients, those affected by severe combined and combined immunodeficiency (SCID and CID) segregated in a specific area, reflecting a homogenous, and a more severe T cell impairment, compared to other lymphopenic PID, such as thymectomized and partial DiGeorge syndrome patients. PID patients with predominantly antibody defects were distributed in a heterogeneous pattern, but unexpectedly PCA was able to cluster some patients' resembling CID, hence warning for additional and more extensive diagnostic tests and a diverse clinical management. In conclusion, PCA applied to T cell MFC data might help the physician to estimate the severity of specific PID and to diversify the clinical and diagnostic approach of the patients.


Assuntos
Diferenciação Celular , Imunofenotipagem , Fenótipo , Subpopulações de Linfócitos T/citologia , Subpopulações de Linfócitos T/metabolismo , Adolescente , Biomarcadores , Diferenciação Celular/imunologia , Criança , Análise de Dados , Diagnóstico Diferencial , Feminino , Humanos , Imunofenotipagem/métodos , Ativação Linfocitária , Contagem de Linfócitos , Masculino , Técnicas de Diagnóstico Molecular , Doenças da Imunodeficiência Primária/diagnóstico , Doenças da Imunodeficiência Primária/etiologia , Doenças da Imunodeficiência Primária/metabolismo , Prognóstico , Subpopulações de Linfócitos T/imunologia
18.
J Acquir Immune Defic Syndr ; 82(5): 483-490, 2019 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-31714427

RESUMO

There are limited data on infants with HIV starting antiretroviral therapy (ART) in the neonatal period. We investigated the association between the timing of ART initiation and time-to-suppression among infants who tested HIV-positive and initiated ART within the first 28 days of life. The effect was estimated using cumulative probability flexible parametric spline models and a multivariable generalized additive mixed model was performed to test nonlinear associations. Forty-four neonates were included. Nineteen (43.2%) initiated ART within 7 days of life and 25 (56.8%) from 8 to 28 days. Infants treated within 7 days were 4-fold more likely to suppress earlier than those treated after 7 days [Hazard ratio (HR) 4.01 (1.7-9.5)]. For each week the ART initiation was delayed, the probability of suppression decreased by 35% (HR 0.65 [0.46-0.92]). Age at ART start was linearly associated with time-to-suppression. However, a linear association with normally distributed residuals was not found between baseline viral load and time-to-suppression, with no association found when baseline viral loads were ≤5 log(10) copies/mL, but with exponential increase in time-to-suppression with > log5 copies/mL at baseline. Starting ART within 7 days of life led to 4-fold faster time to viral suppression, in comparison to initiation from 8 to 28 days.


Assuntos
Fármacos Anti-HIV/administração & dosagem , Infecções por HIV/tratamento farmacológico , Infecções por HIV/transmissão , Transmissão Vertical de Doença Infecciosa , Fármacos Anti-HIV/uso terapêutico , Contagem de Linfócito CD4 , Criança , Pré-Escolar , Quimioterapia Combinada , Feminino , Seguimentos , Infecções por HIV/congênito , Infecções por HIV/imunologia , Inibidores da Protease de HIV/uso terapêutico , Humanos , Lactente , Recém-Nascido , Masculino , Estudos Retrospectivos , Inibidores da Transcriptase Reversa/uso terapêutico , Fatores de Tempo , Carga Viral
19.
Front Immunol ; 10: 2471, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31736942

RESUMO

Patients with severe combined immunodeficiency (SCID) exhibit T lymphopenia and profound impairments in cellular and humoral immunity. IL-7 receptor α (IL-7Rα) deficiency is a rare form of SCID that usually presents in the first months of life with severe and opportunistic infections, failure to thrive and high risk of mortality unless treated. Here, we reported an atypical and delayed onset of IL7Rα-SCID in a 15-month-old girl presenting with thrombocytopenia. Immunological investigations showed a normal lymphocyte count with isolated CD4-penia, absence of naïve T cells, marked hypergammaglobulinemia, and maternal T cell engraftment. Targeted next generation sequencing (NGS) revealed two novel compound heterozygous mutations in the IL-7Rα gene: c.160T>C (p.S54P) and c.245G>T (p.C82F). The atypical onset and the unusual immunological phenotype expressed by our patient highlights the diagnostic challenge in the field of primary immunodeficiencies (PID) and in particular in SCID patients where prompt diagnosis and therapy greatly affects survival.


Assuntos
Heterozigoto , Mutação , Receptores de Interleucina-7/genética , Linfócitos T/imunologia , Linfócitos T/metabolismo , Trombocitopenia/diagnóstico , Trombocitopenia/etiologia , Biomarcadores , Feminino , Humanos , Imunofenotipagem , Lactente , Contagem de Linfócitos , Linhagem , Fenótipo , Imunodeficiência Combinada Severa/complicações , Imunodeficiência Combinada Severa/diagnóstico , Imunodeficiência Combinada Severa/genética , Trombocitopenia/sangue
20.
J Exp Med ; 216(12): 2778-2799, 2019 12 02.
Artigo em Inglês | MEDLINE | ID: mdl-31601675

RESUMO

Hemophagocytic lymphohistiocytosis (HLH) is characterized by immune dysregulation due to inadequate restraint of overactivated immune cells and is associated with a variable clinical spectrum having overlap with more common pathophysiologies. HLH is difficult to diagnose and can be part of inflammatory syndromes. Here, we identify a novel hematological/autoinflammatory condition (NOCARH syndrome) in four unrelated patients with superimposable features, including neonatal-onset cytopenia with dyshematopoiesis, autoinflammation, rash, and HLH. Patients shared the same de novo CDC42 mutation (Chr1:22417990C>T, p.R186C) and altered hematopoietic compartment, immune dysregulation, and inflammation. CDC42 mutations had been associated with syndromic neurodevelopmental disorders. In vitro and in vivo assays documented unique effects of p.R186C on CDC42 localization and function, correlating with the distinctiveness of the trait. Emapalumab was critical to the survival of one patient, who underwent successful bone marrow transplantation. Early recognition of the disorder and establishment of treatment followed by bone marrow transplant are important to survival.


Assuntos
Suscetibilidade a Doenças , Linfo-Histiocitose Hemofagocítica/diagnóstico , Linfo-Histiocitose Hemofagocítica/genética , Fenótipo , Proteína cdc42 de Ligação ao GTP/genética , Proteína cdc42 de Ligação ao GTP/metabolismo , Alelos , Substituição de Aminoácidos , Animais , Sítios de Ligação , Linhagem Celular Tumoral , Criança , Feminino , Estudos de Associação Genética , Genótipo , Humanos , Lactente , Masculino , Camundongos , Modelos Moleculares , Conformação Molecular , Mutação , Ligação Proteica , Proteína cdc42 de Ligação ao GTP/química
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