Publications by authors named "Antonio Condino-Neto"

131 Publications

The network interplay of interferon and Toll-like receptor signaling pathways in the anti-Candida immune response.

Sci Rep 2021 Oct 13;11(1):20281. Epub 2021 Oct 13.

Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.

Fungal infections represent a major global health problem affecting over a billion people that kills more than 1.5 million annually. In this study, we employed an integrative approach to reveal the landscape of the human immune responses to Candida spp. through meta-analysis of microarray, bulk, and single-cell RNA sequencing (scRNA-seq) data for the blood transcriptome. We identified across these different studies a consistent interconnected network interplay of signaling molecules involved in both Toll-like receptor (TLR) and interferon (IFN) signaling cascades that is activated in response to different Candida species (C. albicans, C. auris, C. glabrata, C. parapsilosis, and C. tropicalis). Among these molecules are several types I IFN, indicating an overlap with antiviral immune responses. scRNA-seq data confirmed that genes commonly identified by the three transcriptomic methods show cell type-specific expression patterns in various innate and adaptive immune cells. These findings shed new light on the anti-Candida immune response, providing putative molecular pathways for therapeutic intervention.
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http://dx.doi.org/10.1038/s41598-021-99838-0DOI Listing
October 2021

Hematologically important mutations: The autosomal forms of chronic granulomatous disease (third update).

Blood Cells Mol Dis 2021 Jul 28;92:102596. Epub 2021 Jul 28.

Dept of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.

Chronic granulomatous disease (CGD) is an immunodeficiency disorder affecting about 1 in 250,000 individuals. CGD patients suffer from severe, recurrent bacterial and fungal infections. The disease is caused by mutations in the genes encoding the components of the leukocyte NADPH oxidase. This enzyme produces superoxide, which is subsequently metabolized to hydrogen peroxide and other reactive oxygen species (ROS). These products are essential for intracellular killing of pathogens by phagocytic leukocytes (neutrophils, eosinophils, monocytes and macrophages). The leukocyte NADPH oxidase is composed of five subunits, four of which are encoded by autosomal genes. These are CYBA, encoding p22, NCF1, encoding p47, NCF2, encoding p67 and NCF4, encoding p40. This article lists all mutations identified in these genes in CGD patients. In addition, cytochrome b chaperone-1 (CYBC1), recently recognized as an essential chaperone protein for the expression of the X-linked NADPH oxidase component gp91 (also called Nox2), is encoded by the autosomal gene CYBC1. Mutations in this gene also lead to CGD. Finally, RAC2, a small GTPase of the Rho family, is needed for activation of the NADPH oxidase, and mutations in the RAC2 gene therefore also induce CGD-like symptoms. Mutations in these last two genes are also listed in this article.
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http://dx.doi.org/10.1016/j.bcmd.2021.102596DOI Listing
July 2021

The relevance of primary immunodeficiency registries on a global perspective.

J Allergy Clin Immunol 2021 Sep 15. Epub 2021 Sep 15.

Division of Allergy and Immunology, Children's Hospital of Philadelphia, Philadelphia, Pa.

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http://dx.doi.org/10.1016/j.jaci.2021.08.023DOI Listing
September 2021

Serum Protein Electrophoresis May Be Used as a Screening Tool for Antibody Deficiency in Children and Adolescents.

Front Immunol 2021 23;12:712637. Epub 2021 Aug 23.

Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.

Background: Patients with antibody deficiency may experience exceptionally long diagnostic delays, increasing the risk of life-threatening infections, end-organ damage, mortality, and health costs.

Objective: This study aimed to analyze serum protein electrophoresis and verify the correlation between calculated globulin (CG, total protein minus albumin levels) or electrophoretically determined serum gamma globulin fraction (Gamma) with IgG levels in children and adolescents under 18 years old (yo).

Methods: We analyzed serum protein electrophoresis (GC or Gamma) and IgG levels from 1215 children and adolescents under 18 yo, classified into 5 age groups. We verified the correlation between CG or Gamma with serum IgG levels.

Results: Serum IgG levels varied according to age groups (from 4.3 ± 2.3 g/l in children under 6 months old to 11.4 ± 3.2 g/l in adolescents in the 10-<18 yo group). CG sensitivity and specificity to detect IgG below the reference range for all patients were 93.1% and 81.8%, respectively, and varied according to age group. Gamma sensitivity and specificity for all patients were 100% and 87.8%, respectively, and varied according to age group as well. We found serum IgG levels below the age reference level in 29 patients (2.4% of the cases) using CG or Gamma levels.

Conclusion: Both CG and Gamma levels may be of utility as a screening tool for earlier diagnosis of antibody deficiency in children and adolescents under 18 yo.
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http://dx.doi.org/10.3389/fimmu.2021.712637DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8419225PMC
August 2021

Autoantibodies neutralizing type I IFNs are present in 4% of uninfected individuals over 70 years old and account for 20% of COVID-19 deaths.

Sci Immunol 2021 08;6(62)

Joint Research Unit, Hospices Civils de Lyon-bio Mérieux, Hospices Civils de Lyon, Lyon Sud Hospital, Pierre-Bénite, France; International Center of Research in Infectiology, Lyon University, INSERM U1111, CNRS UMR 5308, ENS, UCBL, Lyon, France.

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-β. 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-β 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.
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http://dx.doi.org/10.1126/sciimmunol.abl4340DOI Listing
August 2021

Immunity and inflammatory biomarkers in COVID-19: A systematic review.

Rev Med Virol 2021 07 4;31(4):e2199. Epub 2020 Dec 4.

Genetics of Rare Diseases, Instituto de Pesquisa Pelé Pequeno Príncipe, Curitiba, Paraná, Brazil.

Coronavirus disease 2019 (COVID-19) is a clinical syndrome caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus. Patients can be asymptomatic or present respiratory and gastrointestinal symptoms, and even multiple-organ failure which can lead to death. The balance between an effective antiviral response and dysregulated immune response is the key factor determining the severity of COVID-19 progression. A systematic review was performed using the NCBI-PubMed database to find the articles related to COVID-19 immunity and inflammatory response published from 1 December 2019 to 15 April 2020. Haematological, immunological and biochemical parameters were extracted and correlated with disease severity, age and presence of comorbidities. Twelve articles were analysed comprising a total of 1042 hospitalized patients infected with SARS-CoV-2 and 95 different parameters. Total lymphocyte count and levels of CD3+ and CD4+ T cells were decreased in severe and critical cases. Neutrophilia was found in patients who progressed to acute respiratory distress syndrome (ARDS). Interleukin-six (IL-6) was high in mild and severe patients regardless of comorbidities. Erythrocyte sedimentation rate (ESR) and count and C-reactive protein (CRP) levels were increased regardless of disease severity or presence of comorbidities. High levels of D-dimer and lactate dehydrogenase were present in diabetic patients and patients who developed ARDS. Procalcitonin levels were elevated to varying degrees in severe and critical patients. We conclude that the total lymphocyte count, CD3+ and CD4+ T cells are low, especially in severe and critical COVID-19 patients; ESR, CRP and IL-6 were elevated, independent of the severity of disease. Understanding the inflammatory response of COVID-19 patients is essential for the development of better therapeutic and management strategies.
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http://dx.doi.org/10.1002/rmv.2199DOI Listing
July 2021

CD40L modulates transcriptional signatures of neutrophils in the bone marrow associated with development and trafficking.

JCI Insight 2021 Aug 23;6(16). Epub 2021 Aug 23.

Department of Immunology, Institute of Biomedical Science, University of São Paulo, São Paulo, São Paulo, Brazil.

Neutrophils are produced in the BM in a process called granulopoiesis, in which progenitor cells sequentially develop into mature neutrophils. During the developmental process, which is finely regulated by distinct transcription factors, neutrophils acquire the ability to exit the BM, properly distribute throughout the body, and migrate to infection sites. Previous studies have demonstrated that CD40 ligand (CD40L) influences hematopoiesis and granulopoiesis. Here, we investigate the effect of CD40L on neutrophil development and trafficking by performing functional and transcriptome analyses. We found that CD40L signaling plays an essential role in the early stages of neutrophil generation and development in the BM. Moreover, CD40L modulates transcriptional signatures, indicating that this molecule enables neutrophils to traffic throughout the body and to migrate in response to inflammatory signals. Thus, our study provides insights into the complex relationships between CD40L signaling and granulopoiesis, and it suggests a potentially novel and nonredundant role of CD40L signaling in neutrophil development and function.
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http://dx.doi.org/10.1172/jci.insight.148652DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8410015PMC
August 2021

Toxicological insights of Spike fragments SARS-CoV-2 by exposure environment: A threat to aquatic health?

J Hazard Mater 2021 10 25;419:126463. Epub 2021 Jun 25.

Post-graduation Program in Biotechnology and Biodiversity, Goiano Federal Institution and Federal University of Goiás, GO, Brazil; Biological Research Laboratory, Post-graduation Program in Conservation of Cerrado Natural Resources, Goiano Federal Institute - Urata Campus, GO, Brazil. Electronic address:

The Spike protein (S protein) is a critical component in the infection of the new coronavirus (SARS-CoV-2). The objective of this work was to evaluate whether peptides from S protein could cause negative impact in the aquatic animals. The aquatic toxicity of SARS-CoV-2 Spike protein peptides derivatives has been evaluated in tadpoles (n = 50 tadpoles/5 replicates of 10 animals) from species Physalaemus cuvieri (Leptodactylidae). After synthesis, purification, and characterization of peptides (PSDP2001, PSDP2002, PSDP2003) an aquatic contamination has been simulated with these peptides during 24 h of exposure in two concentrations (100 and 500 ng/mL). The control group ("C") was composed of tadpoles kept in polyethylene containers containing de-chlorinated water. Oxidative stress, antioxidant biomarkers and AChE activity were assessed. In both concentrations, PSPD2002 and PSPD2003 increased catalase and superoxide dismutase antioxidants enzymes activities, as well as oxidative stress (nitrite levels, hydrogen peroxide and reactive oxygen species). All three peptides also increased acetylcholinesterase activity in the highest concentration. These peptides showed molecular interactions in silico with acetylcholinesterase and antioxidant enzymes. Aquatic particle contamination of SARS-CoV-2 has cholinesterasic effect in P. cuvieri tadpoles. These findings indicate that the COVID-19 can constitute environmental impact or biological damage potential.
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http://dx.doi.org/10.1016/j.jhazmat.2021.126463DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8226002PMC
October 2021

Hematologically important mutations: X-linked chronic granulomatous disease (fourth update).

Blood Cells Mol Dis 2021 09 2;90:102587. Epub 2021 Jun 2.

Dept of Pediatrics and Laboratory for Leukocyte Function, Meir Medical Centre, Kfar Saba, Israel.

Chronic granulomatous disease (CGD) is an immunodeficiency disorder affecting about 1 in 250,000 individuals. CGD patients suffer from severe bacterial and fungal infections. The disease is caused by a lack of superoxide production by the leukocyte enzyme NADPH oxidase. Superoxide and subsequently formed other reactive oxygen species (ROS) are instrumental in killing phagocytosed micro-organisms in neutrophils, eosinophils, monocytes and macrophages. The leukocyte NADPH oxidase is composed of five subunits, of which the enzymatic component is gp91, also called Nox2. This protein is encoded by the CYBB gene on the X chromosome. Mutations in this gene are found in about 70% of all CGD patients in Europe and in about 20% in countries with a high ratio of parental consanguinity. This article lists all mutations identified in CYBB and should therefore help in genetic counseling of X-CGD patients' families. Moreover, apparently benign polymorphisms in CYBB are also given, which should facilitate the recognition of disease-causing mutations. In addition, we also include some mutations in G6PD, the gene on the X chromosome that encodes glucose-6-phosphate dehydrogenase, because inactivity of this enzyme may lead to shortage of NADPH and thus to insufficient activity of NADPH oxidase. Severe G6PD deficiency can induce CGD-like symptoms.
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http://dx.doi.org/10.1016/j.bcmd.2021.102587DOI Listing
September 2021

Outcome of SARS-CoV-2 Infection in 121 Patients with Inborn Errors of Immunity: A Cross-Sectional Study.

J Clin Immunol 2021 10 23;41(7):1479-1489. Epub 2021 Jun 23.

Universidade Federal de Goias (UFG), Goiânia, GO, Brazil.

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).
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http://dx.doi.org/10.1007/s10875-021-01066-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8221557PMC
October 2021

The relationship between cytokine and neutrophil gene network distinguishes SARS-CoV-2-infected patients by sex and age.

JCI Insight 2021 05 24;6(10). Epub 2021 May 24.

Department of Immunology, Institute of Biomedical Sciences, and.

The fact that the COVID-19 fatality rate varies by sex and age is poorly understood. Notably, the outcome of SARS-CoV-2 infections mostly depends on the control of cytokine storm and the increasingly recognized pathological role of uncontrolled neutrophil activation. Here, we used an integrative approach with publicly available RNA-Seq data sets of nasopharyngeal swabs and peripheral blood leukocytes from patients with SARS-CoV-2, according to sex and age. Female and young patients infected by SARS-CoV-2 exhibited a larger number of differentially expressed genes (DEGs) compared with male and elderly patients, indicating a stronger immune modulation. Among them, we found an association between upregulated cytokine/chemokine- and downregulated neutrophil-related DEGs. This was correlated with a closer relationship between female and young subjects, while the relationship between male and elderly patients was closer still. The association between these cytokine/chemokines and neutrophil DEGs is marked by a strongly correlated interferome network. Here, female patients exhibited reduced transcriptional levels of key proinflammatory/neutrophil-related genes, such as CXCL8 receptors (CXCR1 and CXCR2), IL-1β, S100A9, ITGAM, and DBNL, compared with male patients. These genes are well known to be protective against inflammatory damage. Therefore, our work suggests specific immune-regulatory pathways associated with sex and age of patients infected with SARS-CoV-2 and provides a possible association between inverse modulation of cytokine/chemokine and neutrophil transcriptional signatures.
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http://dx.doi.org/10.1172/jci.insight.147535DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8262322PMC
May 2021

A simplified alternative diagnostic algorithm for SARS-CoV-2 suspected symptomatic patients and confirmed close contacts (asymptomatic): A consensus of Latin American experts.

Int J Infect Dis 2021 May 19. Epub 2021 May 19.

Department of Immunology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil.

Introduction: Latin America accounts for one-quarter of global COVID-19 cases and one-third of deaths. Inequalities in the region lead to barriers regarding the best use of diagnostic tests during the pandemic. There is a need for a simplified guideline, considering the region's health resources' low availability, international guidelines, medical literature, and local expertise.

Methods: Nine experts from Latin American countries developed a simplified algorithm for COVID-19 diagnosis, using a modified Delphi method. Twenty-four questions related to diagnostic settings were proposed, followed by discussion of the literature and experts' experience.

Results: The algorithm considers three timeframes (≤7 days, 8-13 days, and ≥ 14 days) and discusses diagnostic options for each one. SARS-CoV-2 rRT-PCR is the test of choice from day 1 to day 14 after symptom onset or close contact, although antigen testing may be used in particular situations, from days 5 to 7. Antibody assays may be used for confirmation, mainly after day 14. If the clinical suspicion is very high, but other tests are negative, these assays may be used as an adjunct to decision-making from day 8 to day 13.

Conclusion: The proposed algorithm aims to support COVID-19 diagnosis decision-making in Latin America.
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http://dx.doi.org/10.1016/j.ijid.2021.05.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8133827PMC
May 2021

Socialization During the COVID-19 Pandemic: The Role of Social and Scientific Networks During Social Distancing.

Adv Exp Med Biol 2021 ;1318:911-921

Herbal and Traditional Medicines Research Center, Kerman University of Medical Sciences, Kerman, Iran.

In the COVID-19 era, while we are encouraged to be physically far away from each other, social and scientific networking is needed more than ever. The dire consequences of social distancing can be diminished by social networking. Social media, a quintessential component of social networking, facilitates the dissemination of reliable information and fighting against misinformation by health authorities. Distance learning, telemedicine, and telehealth are among the most prominent applications of networking during this pandemic. Additionally, the COVID-19 pandemic highlights the importance of collaborative scientific efforts. In this chapter, we summarize the advantages of harnessing both social and scientific networking in minimizing the harms of this pandemic. We also discuss the extra collaborative measures we can take in our fight against COVID-19, particularly in the scientific field.
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http://dx.doi.org/10.1007/978-3-030-63761-3_51DOI Listing
May 2021

Editorial: The Complexity of Primary Antibody Deficiencies.

Front Immunol 2021 21;12:635482. Epub 2021 Apr 21.

Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.

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http://dx.doi.org/10.3389/fimmu.2021.635482DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8097173PMC
September 2021

Primary Immunodeficiencies: A Decade of Progress and a Promising Future.

Front Immunol 2020 18;11:625753. Epub 2021 Feb 18.

International Patient Organisation for Primary Immunodeficiencies (IPOPI), Ixelles, Belgium.

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http://dx.doi.org/10.3389/fimmu.2020.625753DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7935502PMC
March 2021

Extreme phenotypes approach to investigate host genetics and COVID-19 outcomes.

Genet Mol Biol 2021 1;44(1 Suppl 1):e20200302. Epub 2021 Mar 1.

Universidade de São Paulo, Instituto de Biociências, Departamento de Genética e Biologia Evolutiva, Centro de Pesquisa sobre o Genoma Humano e Células-Tronco, São Paulo, SP, Brazil.

COVID-19 comprises clinical outcomes of SARS-CoV-2 infection and is highly heterogeneous, ranging from asymptomatic individuals to deceased young adults without comorbidities. There is growing evidence that host genetics play an important role in COVID-19 severity, including inborn errors of immunity, age-related inflammation and immunosenescence. Here we present a brief review on the known order of events from infection to severe system-wide disturbance due to COVID-19 and summarize potential candidate genes and pathways. Finally, we propose a strategy of subject's ascertainment based on phenotypic extremes to take part in genomic studies and elucidate intrinsic risk factors involved in COVID-19 severe outcomes.
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http://dx.doi.org/10.1590/1678-4685-GMB-2020-0302DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7924362PMC
March 2021

Antibodies to Der p 1 and Der p 2 in allergic patients.

Allergol Immunopathol (Madr) 2021 1;49(2):46-52. Epub 2021 Mar 1.

Laboratory of Human Immunology, Department of Immunology, Institute of Biomedical Sciences IV, Universidade de São Paulo, São Paulo, Brazil.

Introduction And Objectives: Atopic individuals are characterized by increased IgE production and Th2 response if exposed to certain antigens. It is known that the mother transfers anti-mite antibodies to the fetus and newborn, IgG thru the placenta, and IgA thru breastfeeding, but it is not clear whether there is a protective mechanism mediated by them concerning the development of future allergies. This study aimed to compare the levels of IgA, IgG, and IgE antibodies specific to Der p 1 and Der p 2 between atopic and healthy individuals.

Methods: Serum samples of 98 patients and 44 healthy controls were subjected to quantification for specific IgE, IgG, and IgA antibodies against Der p 1 and Der p 2 by ImmunoCap and ELISA, and subjected to statistical analysis as indicated.

Results: Atopic patients had higher serum levels of IgE, IgG, and IgA specific to Der p 1 and Der p 2. The correlation was more robust between IgE and IgG antibodies.

Conclusions: Allergic patients produce higher levels of antibodies against Der p 1 and Der p 2 compared with healthy individuals. The mechanisms involved still require detailed studies.
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http://dx.doi.org/10.15586/aei.v49i2.59DOI Listing
March 2021

Editorial: Screening for Primary Immunodeficiency Disorders (PIDDs) in Neonates.

Front Immunol 2020 18;11:633266. Epub 2020 Dec 18.

Division of Pediatric Allergy and Immunology, University of South Florida, Tampa, FL, United States.

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http://dx.doi.org/10.3389/fimmu.2020.633266DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7793736PMC
June 2021

Inherited GATA2 Deficiency Is Dominant by Haploinsufficiency and Displays Incomplete Clinical Penetrance.

J Clin Immunol 2021 04 8;41(3):639-657. Epub 2021 Jan 8.

Allergy and Clinical Immunology Service at the XXI Century National Medical Center, Mexican Institute of Social Security (IMSS), Mexico City, Mexico.

Purpose: Germline heterozygous mutations of GATA2 underlie a variety of hematological and clinical phenotypes. The genetic, immunological, and clinical features of GATA2-deficient patients with mycobacterial diseases in the familial context remain largely unknown.

Methods: We enrolled 15 GATA2 index cases referred for mycobacterial disease. We describe their genetic and clinical features including their relatives.

Results: We identified 12 heterozygous GATA2 mutations, two of which had not been reported. Eight of these mutations were loss-of-function, and four were hypomorphic. None was dominant-negative in vitro, and the GATA2 locus was found to be subject to purifying selection, strongly suggesting a mechanism of haploinsufficiency. Three relatives of index cases had mycobacterial disease and were also heterozygous, resulting in 18 patients in total. Mycobacterial infection was the first clinical manifestation in 11 patients, at a mean age of 22.5 years (range: 12 to 42 years). Most patients also suffered from other infections, monocytopenia, or myelodysplasia. Strikingly, the clinical penetrance was incomplete (32.9% by age 40 years), as 16 heterozygous relatives aged between 6 and 78 years, including 4 older than 60 years, were completely asymptomatic.

Conclusion: Clinical penetrance for mycobacterial disease was found to be similar to other GATA2 deficiency-related manifestations. These observations suggest that other mechanisms contribute to the phenotypic expression of GATA2 deficiency. A diagnosis of autosomal dominant GATA2 deficiency should be considered in patients with mycobacterial infections and/or other GATA2 deficiency-related phenotypes at any age in life. Moreover, all direct relatives should be genotyped at the GATA2 locus.
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http://dx.doi.org/10.1007/s10875-020-00930-3DOI Listing
April 2021

The First Iranian Cohort of Pediatric Patients with Activated Phosphoinositide 3-Kinase-δ (PI3Kδ) Syndrome (APDS).

Immunol Invest 2021 Jan 6:1-16. Epub 2021 Jan 6.

Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Science, Tehran, Iran.

: Activated phosphoinositide 3-kinase δ syndrome (APDS) is a recently defined combined primary immunodeficiency disease (PID) characterized by recurrent respiratory tract infections, lymphoproliferation, autoimmunity and lymphoma. Gain-of-function mutations in and loss-of-function of genes lead to APDS1 and APDS2, respectively.: Demographic, clinical, immunological and genetic data were collected from medical records of 15 pediatric patients, who were genetically identified using the whole-exome sequencing method.: Fifteen patients (6 APDS1 and 9 APDS2) were enrolled in this study. Recurrent respiratory tract infections followed by lymphoproliferation and autoimmunity were the most common manifestations (86.7%, 53.3% and 26.7%, respectively). Five patients (33.3%) had a Hyper-IgM-syndrome-like immunoglobulin profile. In the APDS1 group, splice site and missense mutations were found in half of the patients and the C-lobe domain of was the most affected region (50%). In the APDS2 group, splice site mutation was the most frequent mutation (77.8%) and the inter-SH2 domain was the most affected region of (66.7%). Mortality rate was significantly higher in APDS2 group ( = .02) mainly due to chronic lung infections.: Respiratory tract infections and humoral immunodeficiency are commonly the most important complication in pediatric APDS patients, and they can be fatal by ultimately causing catastrophic damage to the structure of lungs. Hence, physicians should be aware of its significance and further work-up of patients with recurrent respiratory tract infections especially in patients with lymphoproliferation. Moreover, delineation of genotype-phenotype associations with disease severity could be helpful in the timely application of appropriate management and patients' survival.
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http://dx.doi.org/10.1080/08820139.2020.1863982DOI Listing
January 2021

Immunological deficiencies: more frequent than they seem to be.

J Pediatr (Rio J) 2021 Mar-Apr;97 Suppl 1:S49-S58. Epub 2020 Nov 22.

Universidade de São Paulo (USP), Instituto de Ciências Biomédicas, Departamento de Imunologia, São Paulo, SP, Brazil.

Objective: A review article was carried out, addressing the clinical and epidemiological characteristics of immune system deficiencies, which are associated with or predispose to recurrent infectious processes, autoimmune diseases, auto inflammatory diseases, or neoplasms, and which are classified as inborn errors of immunity (IEI) and secondary immunodeficiencies (SID). Emphasis was placed on the classification of the main signs and symptoms for each organ and system, which will serve as warning signs, to guide the pediatrician in the investigation of the main IEI. In addition, the main secondary changes in the immune system triggered by infections (with emphasis on COVID-19), drugs, chronic diseases, metabolic and nutritional disorders were identified.

Sources Of Data: This review included articles published in the last five years and that were identified in the MEDLINE platform (PubMed).

Summary Of Findings: The recurrence of infectious processes, associated with the severity of the condition and/or unusual profile of the infectious agent, always related to the age range of symptom onset, are the most important findings for suspected diagnosis.

Conclusions: Considering this scenario, immunity disorders should be part of the investigation carried out by the general pediatrician, whether they are the innate errors of immunity (primary immunodeficiencies) or secondary immunodeficiencies, so that the diagnosis is attained as early as possible and therapeutic measures are implemented, reducing the morbidity and mortality of these patients.
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http://dx.doi.org/10.1016/j.jped.2020.10.009DOI Listing
March 2021

Algorithms for testing COVID-19 focused on use of RT-PCR and high-affinity serological testing: A consensus statement from a panel of Latin American experts.

Int J Infect Dis 2021 Feb 21;103:260-267. Epub 2020 Nov 21.

Institute of Biomedical Sciences, University of São Paulo, Brazil; Director of the Jeffrey Modell Center for Immunodeficiencies, São Paulo, Brazil.

The COVID-19 pandemic has caused an unprecedented public health, social, and economic crisis. Improving understanding on available tests for detecting COVID-19 is critical for effective management of the pandemic. We proposed that a multidisciplinary expert panel can establish recommendations on ideal use of diagnostic tools, with a focus on RT-PCR and serological high-affinity antibodies (both IgM and IgG) tests for the Latin America region.

Study Design: A collaborative multidisciplinary panel of 5 recognized experts in Latin America (an infectious disease specialist, three pathologists, and an immunologist) was convened and supported by Roche Diagnostics to develop standard guidelines and an evidence-based document of best practices on the use of diagnostic tools for COVID-19.

Results: The authors reached consensus on the applicability of diagnostic tools to provide testing algorithms for the use of RT-PCR and serological high-affinity antibodies (both IgM and IgG) tests in three settings: 1) For asymptomatic subjects exposed to a SARS-CoV-2 infected person; 2) For epidemiological purposes and; 3) For symptomatic subjects.

Conclusion: The serological high-affinity SARS-CoV-2 antibodies (both IgM and IgG) tests play a key role in COVID-19 diagnosis. These tests can be applied for suspected false-negative RT-PCR results and for individual determination of response. The use of these tests can also contribute greatly to public health strategies, such as population screening and supporting vaccination planning. Serological status for high-affinity antibodies (both IgM and IgG) should be performed ideally 21 days after potential infectious contact, given that the majority of exposed individuals will have seroconverted.
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http://dx.doi.org/10.1016/j.ijid.2020.11.173DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7834199PMC
February 2021

Treatment of patients with immunodeficiency: Medication, gene therapy, and transplantation.

J Pediatr (Rio J) 2021 Mar-Apr;97 Suppl 1:S17-S23. Epub 2020 Nov 9.

Universidade de São Paulo, Instituto de Ciências Biomédicas, Departamento de Imunologia, São Paulo, SP, Brazil.

Objectives: To provide an overview of drug treatment, transplantation, and gene therapy for patients with primary immunodeficiencies.

Source Of Data: Non-systematic review of the literature in the English language carried out at PubMed.

Synthesis Of Data: The treatment of patients with primary immunodeficiencies aims to control their disease, especially the treatment and prevention of infections through antibiotic prophylaxis and/or immunoglobulin replacement therapy. In several diseases, it is possible to use specific medications for the affected pathway with control of the condition, especially in autoimmune or autoinflammatory processes associated with inborn immunity errors. In some diseases, treatment can be curative through hematopoietic stem cell transplantation (HSCT); more recently, gene therapy has opened new horizons through new technologies.

Conclusions: Immunoglobulin replacement therapy remains the main therapeutic tool. Precision medicine with specific drugs for altered immune pathways is already a reality for several immune defects. Advances in the management of HSCT and gene therapy have expanded the capacity for curative treatments in patients with primary immunodeficiencies.
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http://dx.doi.org/10.1016/j.jped.2020.10.005DOI Listing
May 2021

Global systematic review of primary immunodeficiency registries.

Expert Rev Clin Immunol 2020 07;16(7):717-732

Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences , Tehran, Iran.

Introduction: During the last 4 decades, registration of patients with primary immunodeficiencies (PID) has played an essential role in different aspects of these diseases worldwide including epidemiological indexes, policymaking, quality controls of care/life, facilitation of genetic studies and clinical trials as well as improving our understanding about the natural history of the disease and the immune system function. However, due to the limitation of sustainable resources supporting these registries, inconsistency in diagnostic criteria and lack of molecular diagnosis as well as difficulties in the documentation and designing any universal platform, the global perspective of these diseases remains unclear.

Areas Covered: Published and unpublished studies from January 1981 to June 2020 were systematically reviewed on PubMed, Web of Science and Scopus. Additionally, the reference list of all studies was hand-searched for additional studies. This effort identified a total of 104614 registered patients and suggests identification of at least 10590 additional PID patients, mainly from countries located in Asia and Africa. Molecular defects in genes known to cause PID were identified and reported in 13852 (13.2% of all registered) patients.

Expert Opinion: Although these data suggest some progress in the identification and documentation of PID patients worldwide, achieving the basic requirement for the global PID burden estimation and registration of undiagnosed patients will require more reinforcement of the progress, involving both improved diagnostic facilities and neonatal screening.
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http://dx.doi.org/10.1080/1744666X.2020.1801422DOI Listing
July 2020

Humoral deficiency in a novel GATA2 mutation: A new clinical presentation successfully treated with hematopoietic stem cell transplantation.

Pediatr Blood Cancer 2020 09 18;67(9):e28374. Epub 2020 Jun 18.

Department of Internal Medicine, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.

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http://dx.doi.org/10.1002/pbc.28374DOI Listing
September 2020

Lentiviral gene therapy rescues p47 chronic granulomatous disease and the ability to fight Salmonella infection in mice.

Gene Ther 2020 09 12;27(9):459-469. Epub 2020 Jun 12.

Molecular and Cellular Immunology Unit, UCL Great Ormond Street Institute of Child Health, University College London, London, UK.

Chronic granulomatous disease (CGD) is an inherited primary immunodeficiency disorder characterised by recurrent and often life-threatening infections and hyperinflammation. It is caused by defects of the phagocytic NADPH oxidase, a multicomponent enzyme system responsible for effective pathogen killing. A phase I/II clinical trial of lentiviral gene therapy is underway for the most common form of CGD, X-linked, caused by mutations in the gp91 subunit of the NADPH oxidase. We propose to use a similar strategy to tackle p47-deficient CGD, caused by mutations in NCF1, which encodes the p47 cytosolic component of the enzymatic complex. We generated a pCCLCHIM-p47 lentiviral vector, containing the chimeric Cathepsin G/FES myeloid promoter and a codon-optimised version of the human NCF1 cDNA. Here we show that transduction with the pCCLCHIM-p47 vector efficiently restores p47 expression and biochemical NADPH oxidase function in p47-deficient human and murine cells. We also tested the ability of our gene therapy approach to control infection by challenging p47-null mice with Salmonella Typhimurium, a leading cause of sepsis in CGD patients, and found that mice reconstituted with lentivirus-transduced hematopoietic stem cells had a reduced bacterial load compared with untreated mice. Overall, our results potentially support the clinical development of a gene therapy approach using the pCCLCHIM-p47 vector.
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http://dx.doi.org/10.1038/s41434-020-0164-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7500983PMC
September 2020

Primary Immunodeficiencies in a Mesoregion of São Paulo, Brazil: Epidemiologic, Clinical, and Geospatial Approach.

Front Immunol 2020 12;11:862. Epub 2020 May 12.

Imunnodeficiencies Outpatient Clinic, Regional Hospital of Presidente Prudente, Presidente Prudente, Brazil.

Primary immunodeficiencies (PIDs) are rare genetic disorders leading to immunologic abnormalities that can affect different organs and systems. We determined the epidemiology, clinical, and geospatial characteristics of PID disorders among patients diagnosed over a 5 year period in a reference hospital covering a mesoregion in São Paulo, Brazil. A retrospective analysis of 39 patients with recognizable PIDs according to the criteria of the European Society of Primary Immunodeficiencies were enrolled. Thirty-four patients came from outpatient immunodeficiency clinics and five patients from active search. Demographic, clinical, and immunologic data were collected, and maps were constructed using a geographic information system. The ratio of females to males was 1.4:1, and 48.7% of patients were younger than 17 years of age. The mean age at the onset of symptoms in children was 2.0 years [standard error of the mean (SEM), 1.7 years] and the diagnosis lag was 5.1 years (SEM, 3.1 years); the mean age at diagnosis in adults was 16.3 years (SEM, 11.8 years) and the lag was 10.8 years (SEM, 10.9 years). Antibody deficiency and common variable immunodeficiencies were the most common categories and phenotypes, respectively. The need for intravenous antibiotics and respiratory tract infections were the most prevalent warning signs, with an overall mortality rate of 15.3%. Autoimmune diseases were diagnosed in 56.4% and visceral leishmaniasis in 5.1% of patients. In the active search, 29 patients were investigated and 17.2% were diagnosed; early diagnosis, the involvement of multidisciplinary professionals, and dissemination of knowledge achieved milestone benefits. The distribution of PID networks in Brazil shows great asymmetry between regions and at a regional level; it was shown that the patients lived mainly in Presidente Prudente municipality. The implementation of an immunodeficiency outpatient clinic in a referral hospital covering a mesoregion with a large population has led to the generation of policies and practices to improve the diagnosis, quality of life, and care of patients with PIDs and their families. Furthermore, the search for hospitalized patients with warning signs for PIDs showed great benefits. Inequality in the distribution of PID network centers in Brazil was demonstrated.
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http://dx.doi.org/10.3389/fimmu.2020.00862DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7235164PMC
April 2021

All together to Fight COVID-19.

Am J Trop Med Hyg 2020 06;102(6):1181-1183

School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.

Novel coronavirus disease (COVID-19), named a pandemic by the WHO, is the current global health crisis. National and international collaboration are indispensable for combating COVID-19 and other similar potential outbreaks. International efforts to tackle this complex problem have led to remarkable scientific advances. Yet, as a global society, we can and must take additional measures to fight this pandemic. Undoubtedly, our approach toward COVID-19 was not perfect, and testing has not been deployed fast enough to arrest the epidemic early on. It is critical that we revise our approaches to be more prepared for pandemics as a united body by promoting global cooperation and commitment.
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http://dx.doi.org/10.4269/ajtmh.20-0281DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7253116PMC
June 2020

Editorial: Primary Immunodeficiencies Worldwide.

Front Immunol 2019 22;10:3148. Epub 2020 Jan 22.

Department of Immunology, Institut Pasteur de Tunis, University Tunis El-Manar, Tunis, Tunisia.

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http://dx.doi.org/10.3389/fimmu.2019.03148DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6987400PMC
November 2020
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