Medicine- Federal University of Rio de Janeiro
Pediatrician- Federal University of Rio de Janeiro (IPPMG/UFRJ)
Master- Fiocruz /RJ
PhD- Federal University of Rio de Janeiro
Pos-Doc- Hôpital Pitié- Salpêtrière Paris /France
RESEARCH, TEACHING, or OTHER INTERESTS
Medicine, Pediatrics, Perinatology and Child Health, Immunology and Allergy
15
Scopus Publications
Scopus Publications
Assessing whole-exome sequencing data from undiagnosed Brazilian patients to improve the diagnostic yield of inborn errors of immunity Cristina Santos Ferreira, Ronaldo da Silva Francisco Junior, Alexandra Lehmkuhl Gerber, Ana Paula de Campos Guimarães, Flávia Anisio Amendola, Fernanda Pinto-Mariz, Monica Soares de Souza, Patrícia Carvalho Batista Miranda, Zilton Farias Meira de Vasconcelos, Ekaterini Simões Goudouris, Ana Tereza Ribeiro Vasconcelos BMC Genomic Data, 2023 Objectives Inborn error of immunity (IEI) comprises a broad group of inherited immunological disorders that usually display an overlap in many clinical manifestations challenging their diagnosis. The identification of disease-causing variants from whole-exome sequencing (WES) data comprises the gold-standard approach to ascertain IEI diagnosis. The efforts to increase the availability of clinically relevant genomic data for these disorders constitute an important improvement in the study of rare genetic disorders. This work aims to make available WES data of Brazilian patients’ suspicion of IEI without a genetic diagnosis. We foresee a broad use of this dataset by the scientific community in order to provide a more accurate diagnosis of IEI disorders. Data description Twenty singleton unrelated patients treated at four different hospitals in the state of Rio de Janeiro, Brazil were enrolled in our study. Half of the patients were male with mean ages of 9 ± 3, while females were 12 ± 10 years old. The WES was performed in the Illumina NextSeq platform with at least 90% of sequenced bases with a minimum of 30 reads depth. Each sample had an average of 20,274 variants, comprising 116 classified as rare pathogenic or likely pathogenic according to American College of Medical Genetics and Genomics and the Association (ACMG) guidelines. The genotype-phenotype association was impaired by the lack of detailed clinical and laboratory information, besides the unavailability of molecular and functional studies which, comprise the limitations of this study. Overall, the access to clinical exome sequencing data is limited, challenging exploratory analyses and the understanding of genetic mechanisms underlying disorders. Therefore, by making these data available, we aim to increase the number of WES data from Brazilian samples despite contributing to the study of monogenic IEI-disorders.
Genetic screening in a Brazilian cohort with inborn errors of immunity Cristina Santos Ferreira, Ronaldo da Silva Francisco Junior, Alexandra Lehmkuhl Gerber, Ana Paula de Campos Guimarães, Flavia Amendola Anisio de Carvalho, Bárbara Carvalho Santos dos Reis, Fernanda Pinto-Mariz, Monica Soares de Souza, Zilton Farias Meira de Vasconcelos, Ekaterini Simões Goudouris, Ana Tereza Ribeiro Vasconcelos BMC Genomic Data, 2023 Background Inherited genetic defects in immune system-related genes can result in Inborn Errors of Immunity (IEI), also known as Primary Immunodeficiencies (PID). Diagnosis of IEI disorders is challenging due to overlapping clinical manifestations. Accurate identification of disease-causing germline variants is crucial for appropriate treatment, prognosis, and genetic counseling. However, genetic sequencing is challenging in low-income countries like Brazil. This study aimed to perform genetic screening on patients treated within Brazil's public Unified Health System to identify candidate genetic variants associated with the patient’s phenotype. Methods Thirteen singleton unrelated patients from three hospitals in Rio de Janeiro were enrolled in this study. Genomic DNA was extracted from the peripheral blood lymphocytes of each patient, and whole exome sequencing (WES) analyses were conducted using Illumina NextSeq. Germline genetic variants in IEI-related genes were prioritized using a computational framework considering their molecular consequence in coding regions; minor allele frequency ≤ 0.01; pathogenicity classification based on American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) guidelines gathered from the VarSome clinical database; and IEI-related phenotype using the Franklin tool. The genes classification into IEI categories follows internationally recognized guidelines informed by the International Union of Immunological Societies Expert Committee. Additional methods for confirmation of the variant included Sanger sequencing, phasing analysis, and splice site prediction. Results A total of 16 disease-causing variants in nine genes, encompassing six different IEI categories, were identified. X-Linked Agammaglobulinemia, caused by BTK variations, emerged as the most prevalent IEI disorder in the cohort. However, pathogenic and likely pathogenic variants were also reported in other known IEI-related genes, namely CD40LG, CARD11, WAS, CYBB, C6, and LRBA. Interestingly, two patients with suspected IEI exhibited pathogenic variants in non-IEI-related genes, ABCA12 and SLC25A13, potentially explaining their phenotypes. Conclusions Genetic screening through WES enabled the detection of potentially harmful variants associated with IEI disorders. These findings contribute to a better understanding of patients' clinical manifestations by elucidating the genetic basis underlying their phenotypes.
Clinical and genetic findings in two siblings with X-Linked agammaglobulinemia and bronchiolitis obliterans: a case report Ronaldo da Silva Francisco Junior, Guilherme Loss de Morais, Joseane Biso de Carvalho, Cristina dos Santos Ferreira, Alexandra Lehmkuhl Gerber, Ana Paula de C Guimarães, Flávia Anisio Amendola, Fernanda Pinto-Mariz, Zilton Farias Meira de Vasconcelos, Ekaterini Simões Goudouris, Ana Tereza Ribeiro de Vasconcelos BMC Pediatrics, 2022 BackgroundX-linked agammaglobulinemia (XLA) is an Inborn Errors of Immunity (IEI) characterized by pan-hypogammaglobulinemia and low numbers of B lymphocytes due to mutations inBTKgene. Usually, XLA patients are not susceptible to respiratory tract infections by viruses and do not present interstitial lung disease (ILD) such as bronchiolitis obliterans (BO) as a consequence of acute or chronic bacterial infections of the respiratory tract. Although many pathogenic variants have already been described in XLA, the heterogeneous clinical presentations in affected patients suggest a more complex genetic landscape underlying this disorder.Case presentationWe report two pediatric cases from male siblings with X-Linked Agammaglobulinemia and bronchiolitis obliterans, a phenotype not often observed in XLA phenotype. The whole-exome sequencing (WES) analysis showed a rare hemizygous missense variant NM_000061.2(BTK):c.1751G>A(p.Gly584Glu) in BTKgene of both patients. We also identified a gain-of-function mutation inTGFβ1(rs1800471) previously associated with transforming growth factor-beta1 production, fibrotic lung disease, and graft fibrosis after lung transplantation. TGFβ1 plays a key role in the regulation of immune processes and inflammatory response associated with pulmonary impairment.ConclusionsOur report illustrates a possible role for WES in patients with known inborn errors of immunity, but uncommon clinical presentations, providing a personalized understanding of genetic basis, with possible implications in the identification of potential treatments, and prognosis for patients and their families.
CD40 Ligand Deficiency in Latin America: Clinical, Immunological, and Genetic Characteristics Tábata Takahashi França, Lucila Akune Barreiros, Ranieri Coelho Salgado, Sarah Maria da Silva Napoleão, Lillian Nunes Gomes, Janáira Fernandes Severo Ferreira, Carolina Prando, Cristina Worm Weber, Regina Sumiko Watanabe Di Gesu, Cecilia Montenegro, Carolina Sanchez Aranda, Gisele Kuntze, Aidé Tamara Staines-Boone, Edna Venegas-Montoya, Juan Carlos Aldave Becerra, Liliana Bezrodnik, Daniela Di Giovanni, Ileana Moreira, Gisela Analia Seminario, Andrea Cecilia Gómez Raccio, Mayra de Barros Dorna, Nelson Augusto Rosário-Filho, Herberto Jose Chong-Neto, Elisa de Carvalho, Milena Baptistella Grotta, Julio Cesar Orellana, Miguel Garcia Dominguez, Oscar Porras, Laura Sasia, Karina Salvucci, Emilio Garip, Luiz Fernando Bacarini Leite, Wilma Carvalho Neves Forte, Fernanda Pinto-Mariz, Ekaterini Goudouris, María Enriqueta Nuñez Nuñez, Magdalena Schelotto, Laura Berrón Ruiz, Diana Inés Liberatore, Hans D. Ochs, Otavio Cabral-Marques, Antonio Condino-Neto Journal of Clinical Immunology, 2022 CD40 ligand (CD40L) deficiency is a rare inborn error of immunity presenting with heterogeneous clinical manifestations. While a detailed characterization of patients affected by CD40L deficiency is essential to an accurate diagnosis and management, information about this disorder in Latin American patients is limited. We retrospectively analyzed data from 50 patients collected by the Latin American Society for Immunodeficiencies registry or provided by affiliated physicians to characterize the clinical, laboratory, and molecular features of Latin American patients with CD40L deficiency. The median age at disease onset and diagnosis was 7 months and 17 months, respectively, with a median diagnosis delay of 1 year. Forty-seven patients were genetically characterized revealing 6 novel mutations in the CD40LG gene. Pneumonia was the most common first symptom reported (66%). Initial immunoglobulin levels were variable among patients. Pneumonia (86%), upper respiratory tract infections (70%), neutropenia (70%), and gastrointestinal manifestations (60%) were the most prevalent clinical symptoms throughout life. Thirty-five infectious agents were reported, five of which were not previously described in CD40L deficient patients, representing the largest number of pathogens reported to date in a cohort of CD40L deficient patients. The characterization of the largest cohort of Latin American patients with CD40L deficiency adds novel insights to the recognition of this disorder, helping to fulfill unmet needs and gaps in the diagnosis and management of patients with CD40L deficiency.
Outcome of SARS-CoV-2 Infection in 121 Patients with Inborn Errors of Immunity: A Cross-Sectional Study Ekaterini Simões Goudouris, Fernanda Pinto-Mariz, Leonardo Oliveira Mendonça, Carolina Sanchez Aranda, Rafaela Rolla Guimarães, Cristina Kokron, Myrthes Toledo Barros, Flávia Anísio, Maria Luiza Oliva Alonso, Fernanda Marcelino, Solange Oliveira Rodrigues Valle, Sergio Dortas Junior, Irma Douglas Paes Barreto, Janáira Fernandes Severo Ferreira, Pérsio Roxo-Junior, Almerinda Maria do Rego Silva, Fernanda Lugão Campinhos, Carmem Bonfim, Gisele Loth, Juliana Folloni Fernandes, Julia Lopes Garcia, Albertina Capelo, Olga Akiko Takano, Maria Isabel Valdomir Nadaf, Eliana C. Toledo, Luciana Araújo Oliveira Cunha, Regina Sumiko Watanabe Di Gesu, Laire Schidlowski, Priscila Fillipo, Daniélli C. Bichuetti-Silva, Gustavo Soldateli, Natasha Rebouças Ferraroni, Ellen de Oliveira Dantas, Simone Pestana, Eli Mansour, Raisa Gusso Ulaf, Carolina Prando, Antonio Condino-Neto, Anete Sevciovic Grumach Journal of Clinical Immunology, 2021 Purpose There is still scarce data on SARS-CoV-2 infection in patients with Inborn Errors of Immunity (IEI) and many unresolved questions. We aimed to describe the clinical outcome of SARS-CoV-2 infection in Brazilian IEI patients and identify factors influencing the infection. Methods We did a cross-sectional, multicenter study that included patients of any age affected by IEI and SARS-CoV-2 infection. The variables studied were sex, age, type of IEI, comorbidities (number and type), treatment in use for IEI, clinical manifestations and severity of SARS-CoV-2 infection. Results 121 patients were included: 55.4% female, ages from six months to 74 yo (median age = 25.1 yo). Most patients had predominantly antibody deficiency (n = 53). The infection was mostly asymptomatic (n = 21) and mild (n = 66), and one child had multisystem inflammatory syndrome (MIS-C). We could not observe sex-related susceptibility, and there was a weak correlation between age and severity of infection. The number of comorbidities was higher in severe cases, particularly bronchiectasis and cardiopathy. There were no severe cases in hereditary angioedema patients. Six patients aged 2 to 74 years died, three of them with antibody deficiency. Conclusion The outcome was mild in most patients, but the Case Fatality Ratio was higher than in the general population. However, the type of IEI was not a determining factor for severity, except for complement deficiencies linked to milder COVID-19. The severity of SARS-CoV-2 infection seems to be more related to older age, a higher number of comorbidities and type of comorbidities (bronchiectasis and cardiopathy). Supplementary Information The online version contains supplementary material available at 10.1007/s10875-021-01066-8.
Failure of immunological competence: when to suspect? Fernanda Pinto-Mariz Jornal De Pediatria, 2021 OBJECTIVES: To draw physicians' attention to the different warning signs of diseases of inborn errors of immunity. DATA SOURCES: A non-systematic review of the literature was carried out in the PubMed, LILACS, and SciELO databases, in addition to consultation of reference textbooks. SUMMARY OF THE FINDINGS: It is known that the lack of immunological competence observed in patients with inborn errors of immunity diseases causes particularly serious and/or recurrent infections. However, manifestations related to autoimmunity, inflammation, allergies, and malignancy can also occur. Aiming at the early identification of these patients, a list of warning signs for inborn errors of immunity was created, in which the need for intravenous antibiotics or prolonged antibiotics use to control infection, failure to thrive, and positive family history for this group of diseases are considered the most sensitive. Regarding non-infectious manifestations, early onset, difficulty in controlling with the usual treatments, atypical presentations or association with other warning signs are noteworthy, and investigation for inborn errors of immunity in these situations is recommended. CONCLUSIONS: This article highlights the importance of considering this group of diseases even in the face of patients with non-infectious manifestations. Disclosure of inborn errors of immunity diseases, especially to non-specialists, is essential for early diagnosis and, consequently, for the reduction of these patients' morbidity and mortality.
Crosstalk Between Innate and T Cell Adaptive Immunity With(in) the Muscle Adriana C. Bonomo, Fernanda Pinto-Mariz, Ingo Riederer, Claudia F. Benjamim, Gillian Butler-Browne, Vincent Mouly, Wilson Savino Frontiers in Physiology, 2020 Growing evidence demonstrates a continuous interaction between the immune system and the skeletal muscle in inflammatory diseases of different pathogenetic origins, in dystrophic conditions such as Duchenne Muscular Dystrophy as well as during normal muscle regeneration. Although one component of the innate immunity, the macrophage, has been extensively studied both in disease conditions and during cell or gene therapy strategies aiming at restoring muscular functions, much less is known about dendritic cells and their primary immunological targets, the T lymphocytes. This review will focus on the dendritic cells and T lymphocytes (including effector and regulatory T-cells), emphasizing the potential cross talk between these cell types and their influence on the structure and function of skeletal muscle.
CD49d is a disease progression biomarker and a potential target for immunotherapy in Duchenne muscular dystrophy Fernanda Pinto-Mariz, Luciana Rodrigues Carvalho, Alexandra Prufer De Queiroz Campos Araujo, Wallace De Mello, Márcia Gonçalves Ribeiro, Maria Do Carmo Soares Alves Cunha, Pedro Hernan Cabello, Ingo Riederer, Elisa Negroni, Isabelle Desguerre, Mariana Veras, Erica Yada, Yves Allenbach, Olivier Benveniste, Thomas Voit, Vincent Mouly, Suse Dayse Silva-Barbosa, Gillian Butler-Browne, Wilson Savino Skeletal Muscle, 2015 BACKGROUND: Duchenne muscular dystrophy (DMD) is caused by mutations in the dystrophin gene. The immune inflammatory response also contributes to disease progression in DMD patients. In a previous study, we demonstrated higher levels of circulating CD49dhi and CD49ehi T cells in DMD patients compared to healthy control. DMD patients are clinically heterogeneous and the functional defect cannot be correlated with genotype. Therefore, it is important to be able to define reliable noninvasive biomarkers to better define the disease progression at the beginning of clinical trials. RESULTS: We studied 75 DMD patients at different stages of their disease and observed that increased percentages of circulating CD4(+)CD49d(hi) and CD8(+)CD49d(hi) T lymphocytes were correlated with both severity and a more rapid progression of the disease. Moreover, T(+)CD49d(+) cells were also found in muscular inflammatory infiltrates. Functionally, T cells from severely affected patients exhibited higher transendothelial and fibronectin-driven migratory responses and increased adhesion to myotubes, when compared to control individuals. These responses could be blocked with an anti-CD49d monoclonal antibody. CONCLUSION: CD49d can be used as a novel biomarker to stratify DMD patients by predicting disease progression for clinical trials. Moreover, anti-CD49d peptides or antibodies can be used as a therapeutic approach to decrease inflammation-mediated tissue damage in DMD.
Predictive markers of clinical outcome in the GRMD dog model of Duchenne muscular dystrophy Inès Barthélémy, Fernanda Pinto-Mariz, Erica Yada, Loïc Desquilbet, Wilson Savino, Suse Dayse Silva-Barbosa, Anne-Marie Faussat, Vincent Mouly, Thomas Voit, Stéphane Blot, Gillian Butler-Browne Dmm Disease Models and Mechanisms, 2014 In the translational process of developing innovative therapies for DMD (Duchenne muscular dystrophy), the last pre-clinical validation step is often carried out in the most relevant animal model of this human disease namely the GRMD (Golden retriever muscular dystrophy) dog. GRMD dogs mimic the human disease,DMD, in many aspects including the inter-individual heterogeneity. This last point can be seen as a drawback for an animal model but is inherently related to its close resemblance to DMD patients. In order to improve the management of this inter-individual heterogeneity we have screened a combination of biomarkers in 61 two month-old GRMD dogs at the onset of the disease and a posteriori we addressed their predictive value on the severity of the disease. Three non-invasive biomarkers obtained at early stages of the disease were found to be highly predictive for the loss of ambulation before 6 months of age. An elevation in the number of circulating CD4+CD49dHi T-lymphocytes, and a decreased stride frequency resulting in a reduced spontaneous speed were found to be strongly associated with the severe clinical form of the disease. These factors can be used as predictive tests to screen dogs to separate them into groups with slow or fast disease progression before their inclusion into a therapeutic pre-clinical trial and therefore improve the reliability and translational value of the trials carried out on this invaluable large animal model. These same biomarkers have also been described to be predictive for the time to loss of ambulation in DMD boys, strengthening the relevance of GRMD dogs as pre-clinical models of this devastating muscle disease.
First report of the hyper-IgM syndrome registry of the latin american society for immunodeficiencies: Novel mutations, unique infections, and outcomes Otavio Cabral-Marques, Stefanie Klaver, Lena F Schimke, Évelyn H Ascendino, Taj Ali Khan, Paulo Vítor Soeiro Pereira, Angela Falcai, Alexander Vargas-Hernández, Leopoldo Santos-Argumedo, Liliana Bezrodnik, Ileana Moreira, Gisela Seminario, Daniela Di Giovanni, Andrea Gómez Raccio, Oscar Porras, Cristina Worm Weber, Janaíra Fernandes Ferreira, Fabiola Scancetti Tavares, Elisa de Carvalho, Claudia França Cavalcante Valente, Gisele Kuntze, Miguel Galicchio, Alejandra King, Nelson Augusto Rosário-Filho, Milena Baptistella Grota, Maria Marluce dos Santos Vilela, Regina Sumiko Watanabe Di Gesu, Simone Lima, Leiva de Souza Moura, Eduardo Talesnik, Eli Mansour, Pérsio Roxo-Junior, Juan Carlos Aldave, Ekaterine Goudouris, Fernanda Pinto-Mariz, Laura Berrón-Ruiz, Tamara Staines-Boone, Wilmer O. Córdova Calderón, María del Carmen Zarate-Hernández, Anete S. Grumach, Ricardo Sorensen, Anne Durandy, Troy R. Torgerson, Beatriz Tavares Costa Carvalho, Francisco Espinosa-Rosales, Hans D. Ochs, Antonio Condino-Neto Journal of Clinical Immunology, 2014
Differential integrin expression by T lymphocytes: Potential role in DMD muscle damage Fernanda Pinto-Mariz, Luciana Rodrigues Carvalho, Wallace de Mello, Alexandra de Queiroz Campos Araújo, Márcia Gonçalves Ribeiro, Maria do Carmo Soares Alves Cunha, Thomas Voit, Gillian Butler-Browne, Suse Dayse Silva-Barbosa, Wilson Savino Journal of Neuroimmunology, 2010
Immune allergic response in Asperger syndrome Elizabeth S. Magalhães, Fernanda Pinto-Mariz, Sandra Bastos-Pinto, Adailton T. Pontes, Evandro A. Prado, Leonardo C. deAzevedo Journal of Neuroimmunology, 2009
