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1.
Artigo em Inglês | MEDLINE | ID: mdl-34492260

RESUMO

BACKGROUND: SARS-CoV-2 vaccination is recommended in patients with inborn errors of immunity (IEIs); however, little is known about immunogenicity and safety in these patients. OBJECTIVE: We sought to evaluate the impact of genetic diagnosis, age, and treatment on antibody response to COVID-19 vaccine and related adverse events in a cohort of patients with IEIs. METHODS: Plasma was collected from 22 health care worker controls, 81 patients with IEIs, and 2 patients with thymoma; the plasma was collected before immunization, 1 to 6 days before the second dose of mRNA vaccine, and at a median of 30 days after completion of the immunization schedule with either mRNA vaccine or a single dose of Johnson & Johnson's Janssen vaccine. Anti-spike (anti-S) and anti-nucleocapsid antibody titers were measured by using a luciferase immunoprecipitation systems method. Information on T- and B-cell counts and use of immunosuppressive drugs was extracted from medical records, and information on vaccine-associated adverse events was collected after each dose. RESULTS: Anti-S antibodies were detected in 27 of 46 patients (58.7%) after 1 dose of mRNA vaccine and in 63 of 74 fully immunized patients (85.1%). A lower rate of seroconversion (7 of 11 [63.6%]) was observed in patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. Previous use of rituximab and baseline counts of less than 1000 CD3+ T cells/mL and less than 100 CD19+ B cells/mL were associated with lower anti-S IgG levels. No significant adverse events were reported. CONCLUSION: Vaccinating patients with IEIs is safe, but immunogenicity is affected by certain therapies and gene defects. These data may guide the counseling of patients with IEIs regarding prevention of SARS-CoV-2 infection and the need for subsequent boosts.

3.
Biol Sex Differ ; 12(1): 45, 2021 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-34380555

RESUMO

BACKGROUND: Coronavirus disease 2019 (COVID-19) severity seems to be influenced by genetic background, sex, age, and presence of specific comorbidities. So far, little attention has been paid to sex-specific variations of demographic, clinical, and laboratory features of COVID-19 patients referred to the same hospital in the two consecutive pandemic waves. METHODS: Demographic, clinical, and laboratory data were collected in 1000 COVID-19 patients (367 females and 633 males), 500 hospitalized in the first wave and 500 in the second one, at the ASST Spedali Civili of Brescia from March to December 2020. Statistical analyses have been employed to compare data obtained in females and males, taking into account their age, and during the first and second COVID-19 waves. RESULTS: The mean age at the time of hospitalization was similar in females and males but was significantly higher for both in the second wave; the time elapsed from symptom onset to hospital admission did not differ between sexes in the two waves, and no correlation was observed between delayed hospital admission and length of hospitalization. The number of multi-symptomatic males was higher than that of females, and patients with a higher number of comorbidities were more frequently admitted to intensive care unit (ICU) and more frequently died. Older males remained in the ICU longer than females and showed a longer disease duration, mainly the first wave. The highest levels of white blood cells, neutrophils, C-reactive protein, and fibrinogen were significantly higher in males and in the first, and along with higher levels of D-dimer, ferritin, lactate dehydrogenase, and procalcitonin which were preferentially documented in patients requiring ICU or died. While the rate of death in ICU was higher in males, the overall death rate did not differ between the sexes; however, the deceased women were older. CONCLUSIONS: These data indicate that once patients were hospitalized, the risk of dying was similar between females and males. Therefore, future studies should aim at understanding the reasons why, for a given number of SARS-CoV-2 infections, fewer females develop the disease requiring hospitalization. HIGHLIGHTS: Although the hospitalized males were significantly more, the similar number of hospitalizations of the > 75-year-old females and males could be due to the fact that in Brescia province, elderly women are about twice as many as men. Although males spent more days in the hospital, had a longer disease duration, developed a critical illness more frequently, and were admitted and died in the ICU more than females, the total rate of deaths among patients was not significantly different between sexes. Overall, the most frequent comorbidities were cardiovascular diseases, which were preferentially seen among patients hospitalized in the second wave; it is possible that the knowledge gained in the first wave concerning the association between certain comorbidities and worse disease evolution has guided the preferential hospitalization of patients with these predominant comorbidities.


Assuntos
COVID-19/mortalidade , Hospitalização/estatística & dados numéricos , Caracteres Sexuais , Idoso , Feminino , Humanos , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
4.
Sci Immunol ; 6(62)2021 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-34413139

RESUMO

Circulating autoantibodies (auto-Abs) neutralizing high concentrations (10 ng/mL, in plasma diluted 1 to 10) of IFN-α and/or -ω are found in about 10% of patients with critical COVID-19 pneumonia, but not in subjects with asymptomatic infections. We detect auto-Abs neutralizing 100-fold lower, more physiological, concentrations of IFN-α and/or -ω (100 pg/mL, in 1/10 dilutions of plasma) in 13.6% of 3,595 patients with critical COVID-19, including 21% of 374 patients > 80 years, and 6.5% of 522 patients with severe COVID-19. These antibodies are also detected in 18% of the 1,124 deceased patients (aged 20 days-99 years; mean: 70 years). Moreover, another 1.3% of patients with critical COVID-19 and 0.9% of the deceased patients have auto-Abs neutralizing high concentrations of IFN-ß. We also show, in a sample of 34,159 uninfected subjects from the general population, that auto-Abs neutralizing high concentrations of IFN-α and/or -ω are present in 0.18% of individuals between 18 and 69 years, 1.1% between 70 and 79 years, and 3.4% >80 years. Moreover, the proportion of subjects carrying auto-Abs neutralizing lower concentrations is greater in a subsample of 10,778 uninfected individuals: 1% of individuals <70 years, 2.3% between 70 and 80 years, and 6.3% >80 years. By contrast, auto-Abs neutralizing IFN-ß do not become more frequent with age. Auto-Abs neutralizing type I IFNs predate SARS-CoV-2 infection and sharply increase in prevalence after the age of 70 years. They account for about 20% of both critical COVID-19 cases in the over-80s, and total fatal COVID-19 cases.


Assuntos
Autoanticorpos/imunologia , COVID-19/imunologia , Interferon Tipo I/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/imunologia , Autoanticorpos/sangue , COVID-19/mortalidade , Estudos de Casos e Controles , Criança , Pré-Escolar , Estado Terminal , Humanos , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Lactente , Recém-Nascido , Interferon-alfa/imunologia , Pessoa de Meia-Idade , Adulto Jovem
5.
Immunol Cell Biol ; 99(9): 917-921, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34309902

RESUMO

Type-I interferons (IFNs) mediate antiviral activity and have emerged as important immune mediators during coronavirus disease 19 (COVID-19). Several lines of evidence suggest that impaired type-I IFN signaling may predispose to severe COVID-19. However, the pathophysiologic mechanisms that contribute to illness severity remain unclear. In this study, our goal was to gain insight into how type-I IFNs influence outcomes in patients with COVID-19. To achieve this goal, we compared clinical outcomes between 26 patients with neutralizing type-I IFN autoantibodies (AAbs) and 192 patients without AAbs who were hospitalized for COVID-19 at three Italian hospitals. The presence of circulating AAbs to type-I IFNs was associated with an increased risk of admission to the intensive care unit and a delayed time to viral clearance. However, survival was not adversely affected by the presence of type-I IFN AAbs. Our findings provide further support for the role of type-I IFN AAbs in impairing host antiviral defense and promoting the development of critical COVID-19 pneumonia in severe acute respiratory syndrome coronavirus 2-infected individuals.


Assuntos
Autoanticorpos/imunologia , COVID-19 , Interferon Tipo I/imunologia , Anticorpos Neutralizantes/imunologia , COVID-19/imunologia , Humanos , Unidades de Terapia Intensiva , Itália
6.
Front Immunol ; 12: 673487, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33936120

RESUMO

DOCK8 deficiency is a combined immunodeficiency due to biallelic variants in dedicator of cytokinesis 8 (DOCK8) gene. The disease has a wide clinical spectrum encompassing recurrent infections (candidiasis, viral and bacterial infections), virally driven malignancies and immune dysregulatory features, including autoimmune (cytopenia and vasculitis) as well as allergic disorders (eczema, asthma, and food allergy). Hypomorphic function and somatic reversion of DOCK8 has been reported to result in incomplete phenotype without IgE overproduction. Here we describe a case of DOCK8 deficiency in a 8-year-old Caucasian girl. The patient's disease was initially classified as autoimmune thrombocytopenia, which then evolved toward a combined immunodeficiency phenotype with recurrent infections, persistent EBV infection and lymphoproliferation. Two novel variants (one deletion and one premature stop codon) were characterized, resulting in markedly reduced, but not absent, DOCK8 expression. Somatic reversion of the DOCK8 deletion was identified in T cells. Hypomorphic function and somatic reversion were associated with restricted T cell repertoire, decreased STAT5 phosphorylation and impaired immune synapse functioning in T cells. Although the patient presented with incomplete phenotype (absence of markedly increase IgE and eosinophil count), sclerosing cholangitis was incidentally detected, thus indicating that hypomorphic function and somatic reversion of DOCK8 may delay disease progression but do not necessarily prevent from severe complications.

7.
Cell ; 184(7): 1836-1857.e22, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33713619

RESUMO

COVID-19 exhibits extensive patient-to-patient heterogeneity. To link immune response variation to disease severity and outcome over time, we longitudinally assessed circulating proteins as well as 188 surface protein markers, transcriptome, and T cell receptor sequence simultaneously in single peripheral immune cells from COVID-19 patients. Conditional-independence network analysis revealed primary correlates of disease severity, including gene expression signatures of apoptosis in plasmacytoid dendritic cells and attenuated inflammation but increased fatty acid metabolism in CD56dimCD16hi NK cells linked positively to circulating interleukin (IL)-15. CD8+ T cell activation was apparent without signs of exhaustion. Although cellular inflammation was depressed in severe patients early after hospitalization, it became elevated by days 17-23 post symptom onset, suggestive of a late wave of inflammatory responses. Furthermore, circulating protein trajectories at this time were divergent between and predictive of recovery versus fatal outcomes. Our findings stress the importance of timing in the analysis, clinical monitoring, and therapeutic intervention of COVID-19.


Assuntos
COVID-19/imunologia , Citocinas/metabolismo , Células Dendríticas/metabolismo , Expressão Gênica/imunologia , Células Matadoras Naturais/metabolismo , Índice de Gravidade de Doença , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/metabolismo , COVID-19/mortalidade , Estudos de Casos e Controles , Células Dendríticas/citologia , Feminino , Humanos , Células Matadoras Naturais/citologia , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Transcriptoma/imunologia , Adulto Jovem
8.
J Neurosurg Sci ; 65(2): 207-210, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29480693

RESUMO

Cryptococcal meningoencephalitis is the most common infective complication observed in patients with CD4 lymphocytopenia, including sarcoidosis. T-cell immunity is well characterized in HIV-related infections and data regarding immunity in cryptococcosis animal models is now available; on the contrary, little is known about the immune status in non-HIV-related infections. We report on reduced production of new T cells observed in a patient with sarcoidosis, CD4 lymphocytopenia, and cryptococcal-related meningoencephalitis. Although T cells presented with an intact proliferative capacity, they were oligoclonally expanded showing an effector memory phenotype. However, the deleterious activity of effector memory cells could have been controlled by the expansion of the regulatory T cell subset with the highest suppressive capability. This information provides a better understanding of the immune response to Cryptococcus occurring in non-HIV-associated cases, the predisposition to infection, and the role of different cell subtypes in controlling the disease in humans.

9.
JCI Insight ; 6(1)2021 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-33232303

RESUMO

Immune and inflammatory responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) contribute to disease severity of coronavirus disease 2019 (COVID-19). However, the utility of specific immune-based biomarkers to predict clinical outcome remains elusive. Here, we analyzed levels of 66 soluble biomarkers in 175 Italian patients with COVID-19 ranging from mild/moderate to critical severity and assessed type I IFN-, type II IFN-, and NF-κB-dependent whole-blood transcriptional signatures. A broad inflammatory signature was observed, implicating activation of various immune and nonhematopoietic cell subsets. Discordance between IFN-α2a protein and IFNA2 transcript levels in blood suggests that type I IFNs during COVID-19 may be primarily produced by tissue-resident cells. Multivariable analysis of patients' first samples revealed 12 biomarkers (CCL2, IL-15, soluble ST2 [sST2], NGAL, sTNFRSF1A, ferritin, IL-6, S100A9, MMP-9, IL-2, sVEGFR1, IL-10) that when increased were independently associated with mortality. Multivariate analyses of longitudinal biomarker trajectories identified 8 of the aforementioned biomarkers (IL-15, IL-2, NGAL, CCL2, MMP-9, sTNFRSF1A, sST2, IL-10) and 2 additional biomarkers (lactoferrin, CXCL9) that were substantially associated with mortality when increased, while IL-1α was associated with mortality when decreased. Among these, sST2, sTNFRSF1A, IL-10, and IL-15 were consistently higher throughout the hospitalization in patients who died versus those who recovered, suggesting that these biomarkers may provide an early warning of eventual disease outcome.


Assuntos
COVID-19/imunologia , COVID-19/mortalidade , Corticosteroides/uso terapêutico , Adulto , Idoso , Antibacterianos/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Antivirais/uso terapêutico , Azitromicina/uso terapêutico , Biomarcadores , COVID-19/genética , COVID-19/terapia , Calgranulina B/genética , Calgranulina B/imunologia , Estudos de Casos e Controles , Quimiocina CCL2/genética , Quimiocina CCL2/imunologia , Quimiocina CXCL9/genética , Quimiocina CXCL9/imunologia , Inibidores Enzimáticos/uso terapêutico , Feminino , Ferritinas/genética , Ferritinas/imunologia , Perfilação da Expressão Gênica , Humanos , Hidroxicloroquina/uso terapêutico , Fatores Imunológicos/uso terapêutico , Interferon Tipo I/genética , Interferon Tipo I/imunologia , Interferon gama/genética , Interferon gama/imunologia , Proteína 1 Semelhante a Receptor de Interleucina-1/genética , Proteína 1 Semelhante a Receptor de Interleucina-1/imunologia , Interleucina-10/genética , Interleucina-10/imunologia , Interleucina-15/genética , Interleucina-15/imunologia , Interleucina-2/genética , Interleucina-2/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Lactoferrina/genética , Lactoferrina/imunologia , Lipocalina-2/genética , Lipocalina-2/imunologia , Masculino , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/imunologia , Pessoa de Meia-Idade , Análise Multivariada , NF-kappa B/genética , NF-kappa B/imunologia
11.
medRxiv ; 2020 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-32908997

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the pandemic respiratory infectious disease COVID-19. However, clinical manifestations and outcomes differ significantly among COVID-19 patients, ranging from asymptomatic to extremely severe, and it remains unclear what drives these disparities. Here, we studied 159 hospitalized Italian patients with pneumonia from the NIAID-NCI COVID-19 Consortium using a phage-display method to characterize circulating antibodies binding to 93,904 viral peptides encoded by 1,276 strains of human viruses. SARS-CoV-2 infection was associated with a marked increase in individual's immune memory antibody repertoires linked to trajectories of disease severity from the longitudinal analysis also including anti-spike protein antibodies. By applying a machine-learning-based strategy, we developed a viral exposure signature predictive of COVID-19-related disease severity linked to patient survival. These results provide a basis for understanding the roles of memory B-cell repertoires in COVID-19-related symptoms as well as a predictive tool for monitoring its clinical severity.

12.
Drugs Aging ; 37(10): 739-746, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32761321

RESUMO

BACKGROUND: Patients with multiple sclerosis exhibit the same qualitative and quantitative changes in immune system cells observed in aging. In the last 20 years, multiple sclerosis patients have shown an increase in life expectancy and average age, but clinical trial inclusion criteria typically exclude patients over the age of 55 years. Therefore, disease-modifying therapies are likely administered to patients older than those enrolled in clinical trials. OBJECTIVE: In order to investigate whether disease-modifying therapies for multiple sclerosis induce modifications to the immune system that may have (super)additive effects resulting in an acceleration of immunosenescence, we quantified the number of T-cell receptor excision circles (TRECs) and K-deleting recombination excision circles (KRECs). These molecules are contained in new T and B lymphocytes released by the thymus and bone marrow and are considered molecular age-related markers. METHODS: The markers of aging were measured by a multiplex quantitative real-time PCR assay in 122 patients who had started therapy with interferon-beta (IFN-ß), fingolimod, alemtuzumab, or natalizumab. Samples were obtained before the therapy and at 6 and 12 months of treatment. Comparisons between the variables were performed by a non-parametric statistical analysis. RESULTS: In therapy-naive patients, a significant and direct correlation was found between a lower number of newly produced T and B cells and older age. Although disease-modifying therapies induced different changes (both increases and decreases) in the production of new T and B lymphocytes, 12 months of therapy with IFN-ß or natalizumab did not affect the correlations found at baseline between the release of lymphocytes containing TRECs or KRECs and age. On the contrary, in patients treated with alemtuzumab, both correlations were lost, while in fingolimod-treated patients, only the correlation between TRECs and age disappeared. CONCLUSIONS: This observational study indicated that different age-related changes of the new T and B lymphocyte production could be one of the reasons for the emergence, in the real-world setting, of adverse events not otherwise observed in clinical trials; thus, caution is advised when choosing disease-modifying therapies for multiple sclerosis patients.


Assuntos
Linfócitos B/efeitos dos fármacos , Imunossupressores/uso terapêutico , Esclerose Múltipla/tratamento farmacológico , Receptores de Antígenos de Linfócitos T/genética , Linfócitos T/efeitos dos fármacos , Fatores Etários , Idoso , Linfócitos B/citologia , Linfócitos B/imunologia , Medula Óssea/efeitos dos fármacos , Medula Óssea/imunologia , Feminino , Humanos , Imunossenescência/efeitos dos fármacos , Imunossenescência/genética , Masculino , Esclerose Múltipla/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Recombinação Genética , Linfócitos T/citologia , Linfócitos T/imunologia , Timo/efeitos dos fármacos , Timo/imunologia
13.
medRxiv ; 2020 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-32793919

RESUMO

T cells are involved in the early identification and clearance of viral infections and also support the development of antibodies by B cells. This central role for T cells makes them a desirable target for assessing the immune response to SARS-CoV-2 infection. Here, we combined two high-throughput immune profiling methods to create a quantitative picture of the T-cell response to SARS-CoV-2. First, at the individual level, we deeply characterized 3 acutely infected and 58 recovered COVID-19 subjects by experimentally mapping their CD8 T-cell response through antigen stimulation to 545 Human Leukocyte Antigen (HLA) class I presented viral peptides (class II data in a forthcoming study). Then, at the population level, we performed T-cell repertoire sequencing on 1,015 samples (from 827 COVID-19 subjects) as well as 3,500 controls to identify shared "public" T-cell receptors (TCRs) associated with SARS-CoV-2 infection from both CD8 and CD4 T cells. Collectively, our data reveal that CD8 T-cell responses are often driven by a few immunodominant, HLA-restricted epitopes. As expected, the T-cell response to SARS-CoV-2 peaks about one to two weeks after infection and is detectable for several months after recovery. As an application of these data, we trained a classifier to diagnose SARS-CoV-2 infection based solely on TCR sequencing from blood samples, and observed, at 99.8% specificity, high early sensitivity soon after diagnosis (Day 3-7 = 83.8% [95% CI = 77.6-89.4]; Day 8-14 = 92.4% [87.6-96.6]) as well as lasting sensitivity after recovery (Day 29+/convalescent = 96.7% [93.0-99.2]). These results demonstrate an approach to reliably assess the adaptive immune response both soon after viral antigenic exposure (before antibodies are typically detectable) as well as at later time points. This blood-based molecular approach to characterizing the cellular immune response has applications in vaccine development as well as clinical diagnostics and monitoring.

14.
Eur J Immunol ; 50(9): 1412-1414, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32592406

RESUMO

Study of immunological features of immune response in 14 children (aged from 12 days up to 15 years) and of 10 adults who developed COVID-19 show increased number of activated CD4 and CD8 cells expressing DR and higher plasmatic levels of IL-12 and IL-1ß in adults with COVID-19, but not in children. In addition, plasmatic levels of CCL5/RANTES are higher in children and adults with COVID-19, while CXCL9/MIG was only increased in adults. Higher number of activated T cells and expression of IL-12 and CXCL9 suggest prominent Th1 polarization of immune response against SARS-CoV2 in infected adults as compared with children.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , COVID-19/sangue , Quimiocinas/sangue , SARS-CoV-2/imunologia , Adolescente , COVID-19/imunologia , COVID-19/patologia , Quimiocina CCL2/sangue , Quimiocina CCL5/sangue , Quimiocina CXCL10/sangue , Quimiocina CXCL9/sangue , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Interleucina-8/sangue , Ativação Linfocitária , Contagem de Linfócitos , Linfopenia/patologia , Masculino , Subpopulações de Linfócitos T/imunologia
15.
J Neuroimmunol ; 345: 577282, 2020 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-32505908

RESUMO

A multiple sclerosis patient infected by SARS-CoV-2 during fingolimod therapy was hospitalized with moderate clinical features, and recovered in 15 days. High levels of CCL5 and CCL10 chemokines and of antibody-secreting B cells were detected, while the levels other B- and T-cell subsets were comparable to that of appropriate controls. However, CD4+ and CD8+ cells were oligoclonally expanded and prone to apoptosis when stimulated in vitro. This study suggests that fingolimod-immunosuppressed patients, despite the low circulating lymphocytes, may rapidly expand antibody-secreting cells and mount an effective immune response that favors COVID-19 recovery after drug discontinuation.


Assuntos
Infecções por Coronavirus/complicações , Infecções por Coronavirus/imunologia , Hospedeiro Imunocomprometido , Esclerose Múltipla Recidivante-Remitente/imunologia , Esclerose Múltipla Recidivante-Remitente/virologia , Pneumonia Viral/complicações , Pneumonia Viral/imunologia , Betacoronavirus , COVID-19 , Feminino , Cloridrato de Fingolimode/uso terapêutico , Humanos , Imunossupressores/uso terapêutico , Pessoa de Meia-Idade , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Pandemias , SARS-CoV-2
16.
Sci Rep ; 10(1): 10057, 2020 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-32572110

RESUMO

Perinatally HIV-infected patients face the consequences of both chronic infection effects per se and long-term combination antiretroviral therapy (cART) on immunosenescence. Aims of our study were to evaluate which factors independently contribute to immunosenescence in HIV-infected young adults with a very different HIV infection duration (perinatally HIV-infected young individuals -pHIVy- and age-matched non perinatally HIV-infected youths -npHIVy), after durable  efficient cART. We considered low thymic and bone marrow output, respectively evaluated by quantifying T-cell receptor excision circles (TRECs), K-deleting recombination excision circles (KRECs), and shorter telomeres lenght (TL) as surrogate biomarkers of immunosenescence. Twenty-one pHIVy and 19 npHIVy (with a mean HIV duration of 3-8 years) were included; mean age was 27 years for both groups. Immunosenescence biomarkers were comparable between pHIVy and npHIVy (despite longer HIV-infection, higher frequency of AIDS events, past cART-free periods and concomitant chronic viral infections in pHIVy). At the multivariate analysis, CD4+ was the only variable independently associated with TRECs and TL. Our data suggest that a good level of thymic activity can compensate the deleterious effects of past periods without cART, if HIV replication is suppressed for a sufficient time.


Assuntos
Terapia Antirretroviral de Alta Atividade/métodos , Linfócitos T CD4-Positivos/metabolismo , Infecções por HIV/tratamento farmacológico , Efeitos Tardios da Exposição Pré-Natal/virologia , Medula Óssea/imunologia , Estudos Transversais , Feminino , Infecções por HIV/imunologia , Humanos , Imunossenescência , Masculino , Gravidez , Efeitos Tardios da Exposição Pré-Natal/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Encurtamento do Telômero , Timo/imunologia , Replicação Viral , Adulto Jovem
18.
J Transl Med ; 18(1): 169, 2020 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-32299447

RESUMO

BACKGROUND: The mechanisms underlying the therapeutic activity of interferon-ß in multiple sclerosis are still not completely understood. In the present study, we evaluated the short and long-term effects of interferon-ß treatment on different subsets of regulatory T cells in relapsing-remitting multiple sclerosis patients biologically responsive to treatment because of mixovirus resistance protein A inducibility. METHODS: In this prospective longitudinal study, subsets of natural regulatory T cells (naïve, central memory and effector memory) and inducible regulatory T cells (Tr1), as well as in vitro-induced regulatory T cells (Tr1-like cells), were simultaneously quantified by flow cytometry in samples prepared from 148 therapy-naïve multiple sclerosis patients obtained before and after 6, 12, 18, and 24 months of interferon-ß-1a treatment. mRNA for interleukin-10 and Tr1-related genes (CD18, CD49b, and CD46, together with Cyt-1 and Cyt-2 CD46-associated isoforms) were quantified in Tr1-like cells. RESULTS: Despite profound inter-individual variations in the modulation of all regulatory T-cell subsets, the percentage of natural regulatory T cells increased after 6, 12, and 24 months of interferon-ß treatment. This increase was characterized by the expansion of central and effector memory regulatory T-cell subsets. The percentage of Tr1 significantly enhanced at 12 months of therapy and continued to be high at the subsequent evaluation points. Patients experiencing relapses displayed a higher percentage of naïve regulatory T cells and a lower percentage of central memory regulatory T cells and of Tr1 before starting interferon-ß therapy. In addition, an increase over time of central memory and of Tr1 was observed only in patients with stable disease. However, in vitro-induced Tr1-like cells, prepared from patients treated for 24 months, produced less amount of interleukin-10 mRNA compared with pre-treatment Tr1-like cells. CONCLUSION: Interferon-ß induces the expansion of T regulatory subsets endowed with a high suppressive activity, especially in clinically stable patients. The overall concurrent modulation of natural and inducible regulatory T-cell subsets might explain the therapeutic effects of interferon-ß in multiple sclerosis patients.


Assuntos
Esclerose Múltipla Recidivante-Remitente , Esclerose Múltipla , Humanos , Interferon beta/uso terapêutico , Estudos Longitudinais , Esclerose Múltipla/tratamento farmacológico , Estudos Prospectivos , Subpopulações de Linfócitos T , Linfócitos T Reguladores
19.
J Neurovirol ; 26(1): 133-137, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31468472

RESUMO

Natalizumab is effective against relapsing-remitting multiple sclerosis (MS) but increases the risk of progressive multifocal leukoencephalopathy (PML), which is caused by the activation of the JCV polyomavirus. SF2/ASF (splicing factor2/alternative splicing factor) is a potent cellular inhibitor of JCV replication and large T-antigen (T-Ag) expression. We reported that SF2/ASF levels in blood cells increase during the first year of natalizumab therapy and decrease thereafter, inversely related to T-Ag expression, and suggested a correlation with JCV reactivation. Here, we report SF2/ASF levels of longitudinal blood samples of two patients undergoing natalizumab therapy, who developed PML while monitored, in comparison to natalizumab-treated controls and to one-off PML samples. After 6 months of therapy, SF2/ASF levels of the two cases were reduced, instead of increased, and their overall SF2/ASF levels were lower than those from natalizumab controls. Since SF2/ASF inhibits JCV, its early reduction might have a role in subsequent PML. We are aware of the limitations of the study, but the uniqueness of serial blood samples collected before and after PML onset in natalizumab-treated patients must be stressed. If confirmed in other patients, SF2/ASF evaluation could be a new and early biomarker of natalizumab-associated PML risk, allowing an 18-24-month interval before PML onset (presently ~ 5 months), in which clinicians could evaluate other risk factors and change therapy.


Assuntos
Fatores Imunológicos/efeitos adversos , Leucoencefalopatia Multifocal Progressiva/imunologia , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Natalizumab/efeitos adversos , Fatores de Processamento de Serina-Arginina/sangue , Feminino , Humanos , Hospedeiro Imunocomprometido , Vírus JC , Leucoencefalopatia Multifocal Progressiva/sangue , Esclerose Múltipla Recidivante-Remitente/virologia , Adulto Jovem
20.
Sci Rep ; 9(1): 16605, 2019 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-31719595

RESUMO

Progressive multifocal leukoencephalopathy (PML) is a rare, potentially devastating myelin-degrading disease caused by the JC virus. PML occurs preferentially in patients with compromised immune system, but has been also observed in multiple sclerosis (MS) patients treated with disease-modifying drugs. We characterized T and B cells in 5 MS patients that developed PML, 4 during natalizumab therapy and one after alemtuzumab treatment, and in treated patients who did not develop the disease. Results revealed that: i) thymic and bone marrow output was impaired in 4 out 5 patients at the time of PML development; ii) T-cell repertoire was restricted; iii) clonally expanded T cells were present in all patients. However, common usage or pairings of T-cell receptor beta variable or joining genes, specific clonotypes or obvious "public" T-cell response were not detected at the moment of PML onset. Similarly, common restrictions were not found in the immunoglobulin heavy chain repertoire. The data indicate that no JCV-related specific T- and B-cell expansions were mounted at the time of PML. The current results enhance our understanding of JC virus infection and PML, and should be taken into account when choosing targeted therapies.


Assuntos
Linfócitos B/imunologia , Células Clonais/imunologia , Vírus JC/imunologia , Leucoencefalopatia Multifocal Progressiva/imunologia , Esclerose Múltipla/imunologia , Linfócitos T Citotóxicos/imunologia , Linfócitos T/imunologia , Genes Codificadores da Cadeia beta de Receptores de Linfócitos T/genética , Humanos , Região Variável de Imunoglobulina/genética , Fatores Imunológicos/farmacologia , Leucoencefalopatia Multifocal Progressiva/tratamento farmacológico , Leucoencefalopatia Multifocal Progressiva/patologia , Leucoencefalopatia Multifocal Progressiva/virologia , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/patologia , Esclerose Múltipla/virologia , Natalizumab/farmacologia , Infecções por Polyomavirus/imunologia , Infecções por Polyomavirus/virologia , Infecções Tumorais por Vírus/imunologia , Infecções Tumorais por Vírus/virologia , Carga Viral
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