Percorrer por autor "Pinto, Marta Valente"
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- Antiviral responses induced by Tdap-IPV vaccination are associated with persistent humoral immunity to Bordetella pertussisPublication . Gillard, Joshua; Suffiotti, Madeleine; Brazda, Peter; Venkatasubramanian, Prashanna B.; Versteegen, Pauline; Jonge, Marien I. de; Kelly, Dominic; Bibi, Sagida; Pinto, Marta Valente; Simonetti, Elles; Babiceanu, Mihaela; Kettring, Andrew; Teodosio, Cristina; Groot, Ronald de; Berbers, Guy; Stunnenberg, Hendrik G.; Schanen, Brian; Fenwick, Craig; Huynen, Martijn A.; Diavatopoulos, Dimitri A.Many countries continue to experience pertussis epidemics despite widespread vaccination. Waning protection after booster vaccination has highlighted the need for a better understanding of the immunological factors that promote durable protection. Here we apply systems vaccinology to investigate antibody responses in adolescents in the Netherlands (N = 14; NL) and the United Kingdom (N = 12; UK) receiving a tetanus-diphtheria-acellular pertussis-inactivated poliovirus (Tdap-IPV) vaccine. We report that early antiviral and interferon gene expression signatures in blood correlate to persistence of pertussis-specific antibody responses. Single-cell analyses of the innate response identified monocytes and myeloid dendritic cells (MoDC) as principal responders that upregulate antiviral gene expression and type-I interferon cytokine production. With public data, we show that Tdap vaccination stimulates significantly lower antiviral/type-I interferon responses than Tdap-IPV, suggesting that IPV may promote antiviral gene expression. Subsequent in vitro stimulation experiments demonstrate TLR-dependent, IPV-specific activation of the pro-inflammatory p38 MAP kinase pathway in MoDCs. Together, our data provide insights into the molecular host response to pertussis booster vaccination and demonstrate that IPV enhances innate immune activity associated with persistent, pertussis-specific antibody responses.
- Case report : hypomorphic ligase 4 deficiency – a paradigm of immunodysregulationPublication . Andrade, Catarina; Cordeiro, Ana Isabel; Pinto, Marta Valente; Neves, Conceição; Martins, Catarina; Villartay, Jean-Pierre; Neves, João FarelaDNA Ligase 4 is critical to nonhomologous end joining, necessary for V(D)J recombination in T and B cell development. Ligase 4 deficiency is a rare autosomal recessive disorder caused by hypomorphic mutations in the DNA Ligase 4 gene, that can lead to a wide range of phenotypes. We describe a case of Ligase 4 deficiency causing a type of T-B-NK+ atypical SCID, highlighting the clinical and immunologic manifestations. An eight-year-old female, from São Nicolau Island (Cape Verde), presented at our hospital with a history of recurrent pneumonia and suppurative otitis, multiple skin lesions attributed to fungal and bacterial infections since the age of two, and recurrent diarrhea and growth impairment, beginning at the age of four. The laboratory workup showed almost absent B cells, marked hypogammaglobulinemia, and an impaired response to protein antigens. Flow cytometry revealed normal NK and T cell counts, but with nearly absent naïve T cells and TCR-Va7 expressing T lymphocytes, and reduced proliferative responses to mitogens and antigens. An oligoclonal Vβ repertoire was identified by FACS, and PROMIDISa analysis revealed a skewed TCRa repertoire signature. A 477 PID-related genes NGS panel identified a homozygous R278H mutation in the DNA Ligase 4 gene, previously reported to cause Ligase 4 deficiency. Immunoglobulin replacement and prophylactic therapies were started while waiting for hematopoietic stem cell transplantation. She has experienced fluctuating transaminase levels. The cutaneous biopsy was suggestive of lupus pernio. She has shown recurrent inflammatory signs in her limbs, with documented tenosynovitis on ultrasound. Homozygous R278H in Ligase 4 has been linked to various ranges of manifestations in Ligase 4 deficient patients. In our report, this genotype resulted in T-B-NK+ atypical SCID, that after proper prophylaxis has a predominant autoimmune phenotype.
- Case report : patient with deficiency of ADA2 presenting leukocytoclastic vasculitis and pericarditis during infliximab treatmentPublication . Raimundo, Diana Simão; Cordeiro, Ana Isabel; Freixo, João Parente; Pinto, Marta Valente; Neves, Conceição; Neves, João FarelaDeficiency of adenosine deaminase 2 (DADA2), first reported in 2014, is a disease with great phenotypic variability, which has been increasingly reported. Therapeutic response depends on the phenotype. We present a case of an adolescent with recurrent fever, oral aphthous ulcers, and lymphadenopathy from 8 to 12 years of age and subsequently presented with symptomatic neutropenia. After the diagnosis of DADA2, therapy with infliximab was started, but after the second dose, she developed leukocytoclastic vasculitis and showed symptoms of myopericarditis. Infliximab was switched to etanercept, with no relapses. Despite the safety of tumor necrosis factor alpha inhibitors (TNFi), paradoxical adverse effects have been increasingly reported. The differential diagnosis between disease new-onset manifestations of DADA2 and side effects of TNFi can be challenging and warrants further clarification.
- A novel whole blood assay to quantify the release of T cell associated cytokines in response to Bordetella pertussis antigensPublication . Pinto, Marta Valente; Barkoff, Alex-Mikael; Bibi, Sagida; Knuutila, Aapo; Teräsjärvi, Johanna; Clutterbuck, Elizabeth; Gimenez-Fourage, Sophie; Pagnon, Anke; Gaans-van den Brink, Jacqueline A.M. van; Corbiere, Veronique; Montfort, Aymeric De; Saso, Anja; Jobe, Haddijatou; Roetynck, Sophie; Kampmann, Beate; Simonetti, Elles; Diavatopoulos, Dimitri; Lambert, Eleonora E.; Mertsola, Jussi; Blanc, Pascal; Els, Cécile A.C.M. van; Kelly, Dominic; He, Qiushui; The PERISCOPE ConsortiumBackground: Bordetella pertussis continues to cause whooping cough globally even in countries with high immunisation coverage. Booster vaccinations with acellular pertussis vaccines are thus used in children, adolescents, and adults. T cell immunity is crucial for orchestrating the immune response after vaccination. However, T cell assays can be expensive and difficult to implement in large clinical trials. In this study, a whole blood (WB) stimulation assay was developed to identify secreted T cell associated cytokines in different age groups after acellular pertussis booster vaccination. Material and methods: Longitudinal WB samples were collected from a small set of subjects (n = 38) aged 7–70 years participating in a larger ongoing clinical trial. For assay development, samples were diluted and incubated with purified inactivated pertussis toxin (PT), filamentous haemagglutinin (FHA), inactivated B. pertussis lysate, and complete medium (M) as stimulating conditions, with anti-CD28 and anti-CD49d as co-stimulants. Different timepoints around the vaccination (D0, D7, D14, D28), WB dilution factor (1:2, 1:4) and incubation time (24 h, 48 h, 72 h) were compared. Responses to 15 cytokines were tested with Luminex/multiplex immunoassay. Results: The optimized assay consisted of WB incubation with M, PT, and FHA (including the two co-stimulants). After 48 h incubation, supernatants were collected for measurement of seven selected T cell associated cytokines (IL-2, IL-5, IL-10, IL-13, IL-17 A, IL-17F, and IFN-y) from samples before and 28 days after vaccination. PT stimulation showed a trend for upregulation of IL-2, IL-13, and IL-17 A/F for adult subjects, whereas the responses of all cytokines were downregulated for the paediatric subjects. Furthermore, PT and FHA-stimulated WB showed diverse cytokine producing profiles. Conclusions: The developed WB-based cytokine assay was shown to be less costly, easy to perform, and functional in differently aged individuals. Further, it requires only a small amount of fresh blood, which is beneficial especially for studies including infants. Our results support the use of this assay for other immunological studies in the future.
- Post-varicella vaccination uveitis in a child with nephrotic syndrome receiving immunosuppressive treatment : a case reportPublication . Andrade, Catarina; Cordeiro, Miguel de Almeida; Baptista, Rute Baeta; Nunes, Beatriz Sousa; Garcia, Ana Margarida; Silva, Tiago Milheiro; Pinto, Marta ValentePatients with nephrotic syndrome are at heightened risk of infections due to the underlying disease pathophysiology and the effects of immunosuppressive therapies. Varicella-zoster virus (VZV) infection can cause severe complications in immunocompromised individuals. Concerns about the safety of live attenuated vaccines in this population persist. Emerging vaccination strategies incorporate pre-vaccination risk stratification algorithms based on immunological criteria. We present a case of a five-year-old male with corticosteroid-dependent nephrotic syndrome, in complete remission on mycophenolate mofetil therapy, who received the varicella vaccine after meeting immunocompetence criteria. Fourteen days post-vaccination, he developed scant vesicular lesions, with VZV DNA detected by PCR via swab. By day 16 post-vaccination, he presented with left-eye panuveitis. VZV DNA was also detected in the blood by PCR. Differentiation of VZV vaccine strains from wild-type strains was not possible. Additionally, molecular testing for VZV in the aqueous humor was not performed. However, given the temporal association with varicella vaccination, the detection of VZV in the blood and cutaneous lesions, and most importantly, the immunosuppression of the patient, post-vaccination ocular varicella was assumed even without an epidemiological history of varicella exposure. This case highlights the importance of a thorough immunocompetence assessment before administering live vaccines to immunosuppressed patients, as well as close post-vaccine monitoring and a high index of suspicion for complications to optimize vaccine safety in this vulnerable group. Patients with nephrotic syndrome require vaccination strategies tailored to their individual risk.
- Precision medicine : the use of tailored therapy in primary immunodeficienciesPublication . Pinto, Marta Valente; Neves, João FarelaPrimary immunodeficiencies (PID) are rare, complex diseases that can be characterised by a spectrum of phenotypes, from increased susceptibility to infections to autoimmunity, allergy, auto-inflammatory diseases and predisposition to malignancy. With the introduction of genetic testing in these patients and wider use of next-Generation sequencing techniques, a higher number of pathogenic genetic variants and conditions have been identified, allowing the development of new, targeted treatments in PID. The concept of precision medicine, that aims to tailor the medical interventions to each patient, allows to perform more precise diagnosis and more importantly the use of treatments directed to a specific defect, with the objective to cure or achieve long-term remission, minimising the number and type of side effects. This approach takes particular importance in PID, considering the nature of causative defects, disease severity, short- and long-term complications of disease but also of the available treatments, with impact in life-expectancy and quality of life. In this review we revisit how this approach can or is already being implemented in PID and provide a summary of the most relevant treatments applied to specific diseases.