Publications by authors named "Rita Carsetti"

120 Publications

Highly Specific Memory B Cells Generation after the 2nd Dose of BNT162b2 Vaccine Compensate for the Decline of Serum Antibodies and Absence of Mucosal IgA.

Cells 2021 Sep 26;10(10). Epub 2021 Sep 26.

Neonatal Intensive Care Unit and Human Milk Bank, Department of Neonatology, Bambino Gesù Children's Hospital, IRCSS, Piazza Sant'Onofrio, 4, 00165 Rome, Italy.

Specific memory B cells and antibodies are a reliable read-out of vaccine efficacy. We analysed these biomarkers after one and two doses of BNT162b2 vaccine. The second dose significantly increases the level of highly specific memory B cells and antibodies. Two months after the second dose, specific antibody levels decline, but highly specific memory B cells continue to increase, thus predicting a sustained protection from COVID-19. We show that although mucosal IgA is not induced by the vaccination, memory B cells migrate in response to inflammation and secrete IgA at mucosal sites. We show that the first vaccine dose may lead to an insufficient number of highly specific memory B cells and low concentration of serum antibodies, thus leaving vaccinees without the immune robustness needed to ensure viral elimination and herd immunity. We also clarify that the reduction of serum antibodies does not diminish the force and duration of the immune protection induced by vaccination. The vaccine does not induce sterilizing immunity. Infection after vaccination may be caused by the lack of local preventive immunity because of the absence of mucosal IgA.
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http://dx.doi.org/10.3390/cells10102541DOI Listing
September 2021

Impaired memory B-cell response to the Pfizer-BioNTech COVID-19 vaccine in patients with common variable immunodeficiency.

J Allergy Clin Immunol 2021 Oct 18. Epub 2021 Oct 18.

Diagnostic Immunology Research Unit, Multimodal Medicine Research Area, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy; Diagnostic Immunology Clinical Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy. Electronic address:

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http://dx.doi.org/10.1016/j.jaci.2021.08.031DOI Listing
October 2021

SARS-CoV-2 Vaccine Induced Atypical Immune Responses in Antibody Defects: Everybody Does their Best.

J Clin Immunol 2021 Oct 20. Epub 2021 Oct 20.

Department of Molecular Medicine, Sapienza University of Rome, Viale Dell'Università, 37, Rome, Italy.

Background: Data on immune responses to SARS-CoV-2 in patients with Primary Antibody Deficiencies (PAD) are limited to infected patients and to heterogeneous cohorts after immunization.

Methods: Forty-one patients with Common Variable Immune Deficiencies (CVID), six patients with X-linked Agammaglobulinemia (XLA), and 28 healthy age-matched controls (HD) were analyzed for anti-Spike and anti-receptor binding domain (RBD) antibody production, generation of Spike-specific memory B-cells, and Spike-specific T-cells before vaccination and one week after the second dose of BNT162b2 vaccine.

Results: The vaccine induced Spike-specific IgG and IgA antibody responses in all HD and in 20% of SARS-CoV-2 naive CVID patients. Anti-Spike IgG were detectable before vaccination in 4 out 7 CVID previously infected with SARS-CoV-2 and were boosted in six out of seven patients by the subsequent immunization raising higher levels than patients naïve to infection. While HD generated Spike-specific memory B-cells, and RBD-specific B-cells, CVID generated Spike-specific atypical B-cells, while RBD-specific B-cells were undetectable in all patients, indicating the incapability to generate this new specificity. Specific T-cell responses were evident in all HD and defective in 30% of CVID. All but one patient with XLA responded by specific T-cell only.

Conclusion: In PAD patients, early atypical immune responses after BNT162b2 immunization occurred, possibly by extra-follicular or incomplete germinal center reactions. If these responses to vaccination might result in a partial protection from infection or reinfection is now unknown. Our data suggests that SARS-CoV-2 infection more effectively primes the immune response than the immunization alone, possibly suggesting the need for a third vaccine dose for patients not previously infected.
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http://dx.doi.org/10.1007/s10875-021-01133-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8527979PMC
October 2021

Comprehensive phenotyping of human peripheral blood B lymphocytes in healthy conditions.

Cytometry A 2021 Oct 18. Epub 2021 Oct 18.

Diagnostic Immunology Research Unit, Multimodal Medicine Research Area, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.

The B cell compartment provides innate and adaptive immune defenses against pathogens. Different B cell subsets, reflecting the maturation stages of B cells, have noninterchangeable functions and roles in innate and adaptive immune responses. In this review, we provide an overview of the B cell subsets present in peripheral blood of healthy individuals. A specific gating strategy is also described to clearly and univocally identify B cell subsets based on the their phenotypic traits by flow cytometric analysis.
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http://dx.doi.org/10.1002/cyto.a.24507DOI Listing
October 2021

Circulating plasmablasts in children with steroid-sensitive nephrotic syndrome.

Pediatr Nephrol 2021 Oct 18. Epub 2021 Oct 18.

Renal Diseases Research Unit, Genetics and Rare Diseases Research Area, Bambino Gesù Children's Hospital, IRCCS, Viale S. Paolo 15, 00146, Rome, Italy.

Background: The therapeutic efficacy of B cell-depleting anti-CD20 treatment in both pediatric and adult steroid-sensitive nephrotic syndromes (SSNS) suggests that B cells play a pathogenic role in the disease. In adults with minimal change disease (MCD), only circulating plasmablasts are increased during the active phase of the disease, among B cell subsets. These cells have not been studied yet in children with SSNS.

Methods: We retrospectively quantified by flow cytometry analysis circulating plasmablasts in 107 pediatric patients with SSNS (51 at disease onset, 27 during relapse, and 29 in remission). Data were compared with an equal number of age- and sex-matched healthy donors (HD).

Results: Circulating plasmablast levels, expressed as percentage of total CD19 B cells or as percentage of total lymphocytes, were normal in all SSNS subgroups, compared to HD. Patients in remission had significantly fewer circulating plasmablasts compared to patients at disease onset. No significant correlation was observed between plasmablast levels and proteinuria or serum proteins, at onset. Treatment with prednisone and mycophenolate mofetil significantly reduced circulating levels of plasmablasts, unlike treatment with prednisone and calcineurin inhibitors.

Conclusions: The B cell phenotype of children with SSNS differs from that of adults with MCD. This may justify different therapeutic approaches.
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http://dx.doi.org/10.1007/s00467-021-05273-8DOI Listing
October 2021

Recurrence, Reactivation, or Inflammatory Rebound of SARS-CoV-2 Infection With Acute Vestibular Symptoms: A Case Report and Revision of Literature.

Front Hum Neurosci 2021 11;15:666468. Epub 2021 Aug 11.

Health Directorate, Occupational Medicine Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.

A case of recurrent coronavirus disease 2019 (COVID-19) with neurovestibular symptoms was reported. In March 2020, a physician working in an Italian pediatric hospital had flu-like symptoms with anosmia and dysgeusia, and following a reverse transcription PCR (RT/PCR) test with a nasopharyngeal swab tested positive for SARS-CoV-2. After home quarantine, 21 days from the beginning of the symptoms, the patient tested negative in two subsequent swabs and was declared healed and readmitted to work. Serological testing showed a low level of immunoglobulin G (IgG) antibody title and absence of immunoglobulin M (IgM). However, 2 weeks later, before resuming work, the patient complained of acute vestibular syndrome, and the RT/PCR test with mucosal swab turned positive. On the basis of the literature examined and reviewed for recurrence cases and vestibular symptoms during COVID-19, to our knowledge this case is the first case of recurrence with vestibular impairment as a neurological symptom, and we defined it as probably a viral reactivation. The PCR retest positivity cannot differentiate re-infectivity, relapse, and dead-viral RNA detection. Serological antibody testing and viral genome sequencing could be always performed in recurrence cases.
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http://dx.doi.org/10.3389/fnhum.2021.666468DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8385757PMC
August 2021

Evolution of Human Memory B Cells From Childhood to Old Age.

Front Immunol 2021 23;12:690534. Epub 2021 Jul 23.

Diagnostic Immunology Research Unit, Multimodal Medicine Research Area, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.

High quality medical assistance and preventive strategies, including pursuing a healthy lifestyle, result in a progressively growing percentage of older people. The population and workforce is aging in all countries of the world. It is widely recognized that older individuals show an increased susceptibility to infections and a reduced response to vaccination suggesting that the aged immune system is less able to react and consequently protect the organism. The SARS-CoV-2 pandemic is dramatically showing us that the organism reacts to novel pathogens in an age-dependent manner. The decline of the immune system observed in aging remains unclear. We aimed to understand the role of B cells. We analyzed peripheral blood from children (4-18 years); young people (23-60 years) and elderly people (65-91 years) by flow cytometry. We also measured antibody secretion by ELISA following a T-independent stimulation. Here we show that the elderly have a significant reduction of CD27 memory B cells, a population that bridges innate and adaptive immune functions. In older people, memory B cells are mostly high specialized antigen-selected CD27. Moreover, after stimulation with CpG, B cells from older individuals produced significantly fewer IgM and IgA antibodies compared to younger individuals. Aging is a complex process characterized by a functional decline in multiple physiological systems. The immune system of older people is well equipped to react to often encountered antigens but has a low ability to respond to new pathogens.
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http://dx.doi.org/10.3389/fimmu.2021.690534DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8343175PMC
August 2021

Cryptococcal Meningitis and Post-Infectious Inflammatory Response Syndrome in a Patient With X-Linked Hyper IgM Syndrome: A Case Report and Review of the Literature.

Front Immunol 2021 15;12:708837. Epub 2021 Jul 15.

Unit of Immune and Infectious Diseases, Bambino Gesu' Children's Hospital, IRCCS, Rome, Italy.

The hyper IgM syndromes are a rare group of primary immunodeficiency. The X-linked Hyper IgM syndrome (HIGM), due to a gene defect in CD40L, is the commonest variant; it is characterized by an increased susceptibility to a narrow spectrum of opportunistic infection. A few cases of HIGM patients with Cryptococcal meningoencephalitis (CM) have been described in the literature. Herein we report the case of a young male diagnosed in infancy with HIGM who developed CM complicated by a post-infectious inflammatory response syndrome (PIIRS), despite regular immunoglobulin replacement therapy and appropriate antimicrobial prophylaxis. The patient was admitted because of a headache and CM was diagnosed through detection of in the cerebrospinal fluid. Despite the antifungal therapy resulting to negative CSF culture, the patient exhibited persistent headaches and developed diplopia. An analysis of inflammatory cytokines on CSF, as well as the brain MRI, suggested a diagnosis of PIIRS. Therefore, a prolonged corticosteroids therapy was started obtaining a complete resolution of symptoms without any relapse.
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http://dx.doi.org/10.3389/fimmu.2021.708837DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8320724PMC
July 2021

The Protective Role of Maternal Immunization in Early Life.

Front Pediatr 2021 28;9:638871. Epub 2021 Apr 28.

Department of Maternal and Child Health and Urological Sciences, Policlinico Umberto I, Sapienza University of Rome, Rome, Italy.

With birth, the newborn is transferred from a quasi-sterile environment to the outside world. At this time, the neonatal immune system is inexperienced and continuously subject to a process of development as it encounters different antigenic stimuli after birth. It is initially characterized by a bias toward T helper 2 phenotype, reduced T helper 1, and cytotoxic responses to microbial stimuli, low levels of memory, and effector T and B cells and a high production of suppressive T regulatory cells. The aim of this setting, during fetal life, is to maintain an anti-inflammatory state and immune-tolerance. Maternal antibodies are transferred during pregnancy through the placenta and, in the first weeks of life of the newborn, they represent a powerful tool for protection. Thus, optimization of vaccination in pregnancy represents an important strategy to reduce the burden of neonatal infections and sepsis. Beneficial effects of maternal immunization are universally recognized, although the optimal timing of vaccination in pregnancy remains to be defined. Interestingly, the dynamic exchange that takes place at the fetal-maternal interface allows the transfer not only of antibodies, but also of maternal antigen presenting cells, probably in order to stimulate the developing fetal immune system in a harmless way. There are still controversial effects related to maternal immunization including the so called "immunology blunting," i.e., a dampened antibody production following infant's vaccination in those infants who received placentally transferred maternal immunity. However, clinical relevance of this phenomenon is still not clear. This review will provide an overview of the evolution of the immune system in early life and discuss the benefits of maternal vaccination. Current maternal vaccination policies and their rationale will be summarized on the road to promising approaches to enhance immunity in the neonate.
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http://dx.doi.org/10.3389/fped.2021.638871DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8113393PMC
April 2021

IgA Antibodies and IgA Deficiency in SARS-CoV-2 Infection.

Front Cell Infect Microbiol 2021 6;11:655896. Epub 2021 Apr 6.

Department of Laboratory Medicine, Research Area Multimodal Medicine, Diagnostic Immunology and Research Unit, Bambino Gesù Children's Hospital IRCCS, Rome, Italy.

A large repertoire of IgA is produced by B lymphocytes with T-independent and T-dependent mechanisms useful in defense against pathogenic microorganisms and to reduce immune activation. IgA is active against several pathogens, including rotavirus, poliovirus, influenza virus, and SARS-CoV-2. It protects the epithelial barriers from pathogens and modulates excessive immune responses in inflammatory diseases. An early SARS-CoV-2 specific humoral response is dominated by IgA antibodies responses greatly contributing to virus neutralization. The lack of anti-SARS-Cov-2 IgA and secretory IgA (sIgA) might represent a possible cause of COVID-19 severity, vaccine failure, and possible cause of prolonged viral shedding in patients with Primary Antibody Deficiencies, including patients with Selective IgA Deficiency. Differently from other primary antibody deficiency entities, Selective IgA Deficiency occurs in the vast majority of patients as an asymptomatic condition, and it is often an unrecognized, Studies are needed to clarify the open questions raised by possible consequences of a lack of an IgA response to SARS-CoV-2.
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http://dx.doi.org/10.3389/fcimb.2021.655896DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8057809PMC
May 2021

Evaluation of Immune and Vaccine Competence in Steroid-Sensitive Nephrotic Syndrome Pediatric Patients.

Front Immunol 2021 12;12:602826. Epub 2021 Mar 12.

Renal Diseases Research Unit, Genetics and Rare Diseases Research Area, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.

Idiopathic nephrotic syndrome is a childhood renal disease characterized by a damage of the glomerular filtration barrier leading to an intense leakage of proteins into the urine. This severe proteinuria causes a transient but strong reduction of serum IgG. Therefore, evaluation of vaccine competence by measuring serum levels of protective antibodies can be misleading in nephrotic syndrome, especially during the active phase of disease. To overcome this issue, in parallel to measuring serum antigen-specific IgG, we quantified by ELISPOT the number of antigen-specific memory B cells induced by previous immunization with tetanus and hepatitis B virus (HBV) in 11 steroid-sensitive nephrotic syndrome (SSNS) pediatric patients at onset before any immunosuppressive treatment (mean age 5.1±0.9 years). Five age-matched children with non-immunomediated nephro-urologic disorders were also enrolled as controls (mean age 6.9±2.3 years). Low total serum IgG levels (<520 mg/dl) were found in all the analyzed SSNS patients. In parallel, median levels of anti-tetanus and anti-HBV IgG were significantly reduced compared to controls [0.05 (0.03-0.16) vs. 0.45 (0.29-3.10) IU/ml and 0.0 (0.0-0.5) vs. 30.3 (5.5-400.8) mIU/ml, respectively; = 0.02 for both], with serum IgG titers below protective threshold in 7/11 SSNS patients for tetanus and in 9/11 SSNS patients for HBV. In contrast, all SSNS patients had a competent B-cell response, showing an amount of total IgG-secreting B cells >1,000 counts/10 stimulated cells. The amount of anti-tetanus and anti-HBV IgG-secreting B cells was also comparable to that of controls ( = 0.24, = 0.32, respectively), with a frequency of memory anti-tetanus and anti-HBV IgG secreting B cells >0.1% of total IgG secreting B cells. In conclusion, SSNS children at disease onset pre-immunosuppressive therapy showed a competent immune and vaccine response against tetanus and HBV, which can be correctly evaluated by quantification of antigen-specific memory B cells rather than by measuring serum IgG levels. This approach allows early identification of the impairment of immune and vaccine competence, which may derive from protracted use of different immunosuppressive drugs during disease course.
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http://dx.doi.org/10.3389/fimmu.2021.602826DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7994282PMC
June 2021

COVID-19 - pathogenesis and immunological findings across the clinical manifestation spectrum.

Curr Opin Pulm Med 2021 05;27(3):193-198

Department of Hematology/Oncology, Bambino Gesù Children Hospital, IRCCS.

Purpose Of Review: The wide spectrum of COVID-19 clinical manifestations demonstrates the determinant role played by the individual immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the course of the disease. Thanks to the large number of published data, we are beginning to understand the logic of the human response to a virus adapted to bat immunity.

Recent Findings: Impairment of types I and III interferon responses may facilitate the occurrence of severe COVID-19 with reduced antiviral activity associated to potent inflammation. The human T and B-cell germline repertoire contain the specificities able to react against SARS-CoV-2 antigens. Although inflammation disrupts the structure of germinal centers, memory T and B cells can be found in the blood of patients after mild and severe COVID 19.

Summary: Further studies are indispensable to better understand the human immune response to SARS-CoV-2. The diversity of the individual reaction may contribute to explain the clinical manifestation spectrum. Immunological memory can be demonstrated in patients, convalescent from mild, moderate, or severe COVID-19, but we do not know whether asymptomatic individuals have memory of the virus. Tailored vaccination protocols may be needed for individuals with previous SAS-CoV-2 infection.
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http://dx.doi.org/10.1097/MCP.0000000000000775DOI Listing
May 2021

Follow-up evaluation of the immunological status of children admitted for acute cerebral nervous system infections: a retrospective study.

Ital J Pediatr 2021 Feb 2;47(1):22. Epub 2021 Feb 2.

University/Hospital Department of Pediatrics, Pediatric and Infectious Diseases Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.

Background: Acute Cerebral Nervous System Infections (ACNS) may cause death or severe complications even to promptly treated children. The role of the immune system in influencing the course and the outcome of meningitis has been studied but it is not yet completely understood. The aim of the research is to ascertain whether children who experienced ACNS infection had a normal immune system.

Methods: Patients under 18 years of age admitted at Bambino Gesù Children from January 2006 till June 2016 for meningitis were asked to participate to the follow-up study. The immune status was evaluated both clinically and by laboratory investigations.

Results: Most of the patients over 3 years at follow up had at least one immunological alteration at follow-up evaluation (74%). Considering ACNS infection etiology, certain pathogens were almost exclusive of patients affected by some immunological alteration, regardless of their age.

Discussion: Our preliminary results indicate that sub-clinical immunological defects may be associated to ACNS pediatric infections. Moreover, to the best of our knowledges, this is the first study correlating pathogens to immune evaluation in ACNS infections. It is, however, important to underline the high frequency of persistent immunological alterations in the analyzed patients. Further studies are needed to confirm our conclusions.

Conclusions: We recommend an immunological assessment at follow up evaluation in children who experienced an ACNS infection.
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http://dx.doi.org/10.1186/s13052-021-00973-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7851811PMC
February 2021

Purification and Characterization of Murine MZ and T2-MZP Cells.

Methods Mol Biol 2021 ;2270:3-25

B Cell Physiopathology Unit, Immunology Research Area, Bambino Gesù Children Hospital, Rome, Italy.

The spleen is the second major reservoir of B cells in the adult. In the spleen, cells, generated in the bone marrow, are selected, mature, and become part of the peripheral B-cell pool. Murine spleen comprises several B-cell subsets representing various maturation stages and/or cell functions. The spleen is a complex lymphoid organ organized into two main structures with different functions: the red and white pulp. The red pulp is flowed with blood while the white pulp is organized in primary follicles, with a B-cell area composed of follicular B cells and a T-cell area surrounding a periarterial lymphatic sheath. The frontier between the red and white pulp is defined as the marginal zone (MZ) and contains the MZ B cells. Because B cells, localized in different areas, are characterized by distinct expression levels of B-cell receptor (BCR) and of other surface markers, splenic B-cell subsets can be easily identified and purified by flow cytometry analyses and fluorescence-activated cell sorting (FACS).Here, we will focus on MZ B cells and on their precursors, giving some experimental hints to identify, generate, and isolate these cells. We will combine the use of FACS analysis and confocal microscopy to visualize MZ B cells in cell suspensions and in tissue sections, respectively. We will also give some clues to analyze B-cell repertoire on isolated MZ-B cells.
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http://dx.doi.org/10.1007/978-1-0716-1237-8_1DOI Listing
April 2021

Editorial: Challenges in Vaccinology.

Front Immunol 2020 17;11:632537. Epub 2020 Dec 17.

Institute of Specific Prophylaxis and Tropical Medicine, Center of Pathophysiology, Infectiology & Immunology, Medical University Vienna, Vienna, Austria.

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http://dx.doi.org/10.3389/fimmu.2020.632537DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7773695PMC
June 2021

Different Innate and Adaptive Immune Responses to SARS-CoV-2 Infection of Asymptomatic, Mild, and Severe Cases.

Front Immunol 2020 16;11:610300. Epub 2020 Dec 16.

Department of Hematology/Oncology, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.

SARS-CoV-2 is a novel coronavirus, not encountered before by humans. The wide spectrum of clinical expression of SARS-CoV-2 illness suggests that individual immune responses to SARS-CoV-2 play a crucial role in determining the clinical course after first infection. Immunological studies have focused on patients with moderate to severe disease, demonstrating excessive inflammation in tissues and organ damage. In order to understand the basis of the protective immune response in COVID-19, we performed a longitudinal follow-up, flow-cytometric and serological analysis of innate and adaptive immunity in adults with a spectrum of clinical presentations: healthy SARS-CoV-2-negative contacts of COVID-19 cases; asymptomatic SARS-CoV-2-infected cases; patients with Mild COVID-19 disease and cases of Severe COVID-19 disease. Our data show that high frequency of NK cells and early and transient increase of specific IgA, IgM and, to a lower extent, IgG are associated with asymptomatic SARS-CoV-2 infection. By contrast, monocyte expansion and high and persistent levels of IgA and IgG, produced relatively late in the course of the infection, characterize severe disease. Modest increase of monocytes and different kinetics of antibodies are detected in mild COVID-19. The importance of innate NK cells and the short-lived antibody response of asymptomatic individuals and patients with mild disease suggest that only severe COVID-19 may result in protective memory established by the adaptive immune response.
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http://dx.doi.org/10.3389/fimmu.2020.610300DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7772470PMC
January 2021

Hyperinflammation in Two Severe Acute Respiratory Syndrome Coronavirus 2-Infected Adolescents Successfully Treated With the Interleukin-1 Inhibitor Anakinra and Glucocorticoids.

Front Pediatr 2020 30;8:576912. Epub 2020 Nov 30.

Academic Department of Pediatrics, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.

In severe acute respiratory syndrome-related coronavirus (SARS-CoV-2) critically ill adults, hyperinflammation plays a key role in disease progression. The clinical manifestations of SARS-CoV-2 infection among children are much less severe compared with adult patients and usually associated with a good prognosis. However, hyperinflammation in SARS-CoV-2-infected pediatric patients has been described as pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 or as Kawasaki-like disease but is still little known, and optimal management has to be defined. The World Health Organization (WHO) on the 15th of May 2020 has developed a preliminary case definition for multisystem inflammatory disorder in children and adolescents with coronavirus disease 2019 (COVID-19) and stated for an urgent need to collect data on this condition. Here, we report two adolescent patients affected by COVID-19 presenting with multisystem inflammatory disorder, 3-4 weeks after the first symptoms of SARS-CoV-2 infection, treated with the interleukin-1 receptor antagonist anakinra and glucocorticoids with good clinical response. We report two patients chronically ill appearing, with high fever, severe gastrointestinal involvement, and increased biomarkers of inflammation onset 3-4 weeks after paucisymptomatic SARS-CoV-2 infection. They had no lung involvement, but abdominal ultrasound and CT scan showed thickening of the bowel wall. SARS-CoV-2 PCR was positive on ileum biopsy in both patients, whereas it was negative on other common sampled sites. They have been admitted to the pediatric intensive care unit and have been treated with a combination of anakinra 6-8 mg/kg/day i.v. and a standard dose of methylprednisolone 2 mg/kg/day in addition to lopinavir/ritonavir 400 mg q12h and low molecular weight heparin 100 UI/kg q12h with good clinical response.
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http://dx.doi.org/10.3389/fped.2020.576912DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7734022PMC
November 2020

Case Report: A Case of X-Linked Agammaglobulinemia With High Serum IgE Levels and Allergic Rhinitis.

Front Immunol 2020 5;11:582376. Epub 2020 Nov 5.

Department of Pediatrics, Policlinico Umberto I, Sapienza University of Rome, Rome, Italy.

X-linked Agammaglobulinemia (XLA) is a rare genetic disorder of B-lymphocyte differentiation, characterized by the absence or paucity of circulating B cells, markedly reduced levels of all serum immunoglobulin isotypes and lack of specific antibody production. Bruton Tyrosine Kinase () gene encodes a cytoplasmic tyrosine kinase involved in the B cell maturation and its mutation, blocking B cell differentiation at the pre-B cell stage, and is responsible for XLA. All domains may be affected by the mutation, and the many genotypes are associated with a wide range of clinical presentations. Little is known about genotype-phenotype correlation in this disorder, and factors influencing the phenotype of XLA are not clearly understood. In this report we present a unique case of a young patient affected by XLA. The disease was genetically diagnosed at birth due to a family history of XLA, but during follow up, it was characterized by a CD19+ B cell percentage consistently greater than 2%. He never suffered severe infections, but at two years of age, he developed persistent rhinitis. Thus, total serum IgE levels were measured and detected over the normal range, and specific allergic investigations showed sensitization to dust mites. Further immunological tests (BTK expression, functional "" B cell proliferation upon CpG stimulation, B cell subset analysis) explained these findings as possible manifestations of a mild XLA phenotype. XLA patients rarely present with allergic manifestations, which could warrant further investigation. High serum IgE levels could be a sign of a mild phenotype, but their role and the mechanisms underlying their production in XLA need to be clarified.
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http://dx.doi.org/10.3389/fimmu.2020.582376DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7674281PMC
June 2021

IgM on the surface of T cells: a novel biomarker of pediatric-onset systemic lupus erythematosus.

Pediatr Nephrol 2021 04 6;36(4):909-916. Epub 2020 Oct 6.

Division of Nephrology, Department of Pediatric Subspecialties, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.

Background: Children with systemic lupus erythematosus (SLE) frequently have kidney involvement. Lupus nephritis sometimes presents alone, without systemic SLE features, representing the so-called full-house nephropathy (FHN). Distinguishing patients with SLE or FHN has therapeutic and prognostic implications.

Methods: In this retrospective observational study, we determined the presence of IgM on the surface of T cells (T cell IgM) by flow cytometry and characterized its ability in distinguishing SLE and FHN patients in a large pediatric cohort (n = 84). Fifty-seven patients with SLE (≥ 4 SLICC criteria at disease onset or during the follow-up) and 27 patients with FHN (3 or less SLICC criteria) were enrolled.

Results: Elevated T cell IgM levels were found in 24/25 SLE patients in active phase of disease and in 29/45 SLE patients in remission. In contrast, among FHN patients, only 1/9 presented this characteristic in active phase of disease and 0/20 in remission. Compared with standardized SLICC laboratory parameters, i.e., autoantibody titers and hypocomplementemia, T cell IgM positivity showed an extremely high sensitivity and specificity for the diagnosis of SLE, with the highest area under the curve (0.97, p < 0.001) by receiver operating characteristic analysis, similar to ANA (0.96, p < 0.001) and anti-dsDNA (0.90, p < 0.001) autoantibodies.

Conclusions: Altogether, our data indicate that T cell IgM intensity may be a useful tool to correctly classify patients with lupus nephritis as SLE or FHN since disease onset.
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http://dx.doi.org/10.1007/s00467-020-04761-7DOI Listing
April 2021

HLA allele frequencies and susceptibility to COVID-19 in a group of 99 Italian patients.

HLA 2020 11 3;96(5):610-614. Epub 2020 Sep 3.

Department of Haematology and Oncology, Bambino Gesù Children's Hospital, IRCCS, Rome.

With the aim to individuate alleles that may reflect a higher susceptibility to the disease, in the present study we analyzed the HLA allele frequency distribution in a group of 99 Italian patients affected by a severe or extremely severe form of COVID-19. After the application of Bonferroni's correction for multiple tests, a significant association was found for HLA-DRB1*15:01, -DQB1*06:02 and -B*27:07, after comparing the results to a reference group of 1017 Italian individuals, previously typed in our laboratory. The increased frequencies observed may contribute to identify potential markers of susceptibility to the disease, although controversial results on the role of single HLA alleles in COVID-19 patients have been recently reported.
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http://dx.doi.org/10.1111/tan.14047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7461491PMC
November 2020

A 23-Year Follow-Up of a Patient with Gain-of-Function IkB-Alpha Mutation and Stable Full Chimerism After Hematopoietic Stem Cell Transplantation.

J Clin Immunol 2020 08 2;40(6):927-933. Epub 2020 Jul 2.

University Department of Pediatrics, Unit of Immune and Infectious Diseases, Childrens' Hospital Bambino Gesù, Piazza S. Onofrio 4, Rome, Italy.

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http://dx.doi.org/10.1007/s10875-020-00780-zDOI Listing
August 2020

ImmunizziAMO: A School-Based Field Trial to Teach New Generations the Importance of Vaccination through Games and to Fight Vaccine Hesitancy in Italy.

Vaccines (Basel) 2020 Jun 5;8(2). Epub 2020 Jun 5.

Giochiamo Collaborative Group, Sapienza University of Rome, 00185 Rome, Italy.

Background: Vaccines simulate the first contact with infectious agents and evoke the immunological response without causing the disease and its complications. High rates of immunization among the population guarantee the interruption of the transmission chain of infectious diseases. Therefore, the population should be aware of the value of vaccination and motivated. In order to implement the spread of a correct culture about these issues, schools were recognized as a privileged operational setting. The aim of this project was to transmit knowledge and convey educational messages on the importance of vaccines, through the use of games, in elementary school children, their families and teachers.

Materials And Methods: A field trial study was implemented between April and October 2019. Sample size calculations highlighted the need to recruit at least 136 students in the schools. The intervention involved 10 classes (five first grade and five s grade classes) and was structured in frontal teaching sessions and gaming sessions. Knowledge was assessed comparing the results of a questionnaire administered before and after the intervention. The questionnaires referred to the following items: dangerousness of bacteria and viruses; capability of defending from microorganisms; the role of antibodies; functioning of the vaccine in a child; type of disease for which a vaccine is efficacious; duration of a vaccine; mother- child transmission of antibodies; herd immunity.

Results: 143 children participated in all the phases of the study. The comparison between the scores at the beginning and end of the intervention showed a significant increase in the knowledge about vaccines and immunity. The mean knowledge score arose from 3.52 (SD = 1.67) to 5.97 (SD = 1.81).

Conclusions: This study suggests that the use of games in an elementary school effectively increase the knowledge related to the important topic of vaccination starting at childhood.
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http://dx.doi.org/10.3390/vaccines8020280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7349980PMC
June 2020

The link between varicella and immune system: which children will develop acute cerebellitis?

Ital J Pediatr 2020 May 29;46(1):75. Epub 2020 May 29.

Pediatric and Infectious Diseases Unit, University/hospital Department of Pediatrics, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.

Introduction: Varicella may complicate with cerebellitis in previously healthy children, requiring hospitalization. Aim of our study was to define whether children who experienced varicella cerebellitis have a normal immune system.

Methods: Patients over 3 years of age admitted at Bambino Gesù Children from January 2006 till June 2016 for cerebellitis in varicella were asked to participate to the follow-up study. The immune status was evaluated clinically and by laboratory investigations.

Results: Twenty-five patients were included in the study. At follow up, at least one immunological alteration was detected in 80% of patients. To avoid bias due to possible effects of the recent disease, we separately analyzed patients who had the follow-up control at least 1 year (Group 1) or between 1 month and 1 year (Group 2) after the hospitalization for acute varicella cerebellitis. The results were similar in both groups with immunological alterations detected in 84,6 and 75% of the patients, respectively.

Conclusions: Our preliminary results indicate that sub-clinical immunological defects may correlate to cerebellitis in varicella.
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http://dx.doi.org/10.1186/s13052-020-00840-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7260733PMC
May 2020

The immune system of children: the key to understanding SARS-CoV-2 susceptibility?

Lancet Child Adolesc Health 2020 06 6;4(6):414-416. Epub 2020 May 6.

Department of Haematology and Oncology, Bambino Gesù Children's Hospital, IRCCS, Rome; Department of Paediatrics, Sapienza University of Rome, Rome, Italy.

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http://dx.doi.org/10.1016/S2352-4642(20)30135-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7202830PMC
June 2020

Partial T cell defects and expanded CD56 NK cells in an SCID patient carrying hypomorphic mutation in the IL2RG gene.

J Leukoc Biol 2020 08 11;108(2):739-748. Epub 2020 May 11.

Unit of Immune and Infectious Diseases, Academic Department of Pediatrics, Bambino Gesù Childrens' Hospital-Scientific Institute for Research and Healthcare (IRCCS), Rome, Italy.

X-linked severe combined immunodeficiency (X-SCID) caused by full mutation of the IL2RG gene leads to T B NK phenotype and is usually associated with severe opportunistic infections, diarrhea, and failure to thrive. When IL2RG hypomorphic mutation occurs, diagnosis could be delayed and challenging since only moderate reduction of T and NK cells may be present. Here, we explored phenotypic insights and the impact of the p.R222C hypomorphic mutation (IL2RG ) in distinct cell subsets in an 8-month-old patient with atypical X-SCID. We found reduced CD4 T cell counts, a decreased frequency of naïve CD4 and CD8 T cells, and an expansion of B cells. Ex vivo STAT5 phosphorylation was impaired in CD4 CD45RO T cells, yet compensated by supraphysiological doses of IL-2. Sanger sequencing on purified cell subsets showed a partial reversion of the mutation in total CD3 cells, specifically in recent thymic emigrants (RTE), effector memory (EM), and CD45RA terminally differentiated EM (EMRA) CD4 T cells. Of note, patient's NK cells had a normal frequency compared to age-matched healthy subjects, but displayed an expansion of CD56 cells with higher perforin content and cytotoxic potential, associated with accumulation of NK-cell stimulatory cytokines (IL-2, IL-7, IL-15). Overall, this report highlights an alteration in the NK-cell compartment that, together with the high disease-phenotype variability, should be considered in the suspicion of X-SCID with hypomorphic IL2RG mutation.
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http://dx.doi.org/10.1002/JLB.5MA0220-239RDOI Listing
August 2020

A possible role for B cells in COVID-19? Lesson from patients with agammaglobulinemia.

J Allergy Clin Immunol 2020 07 22;146(1):211-213.e4. Epub 2020 Apr 22.

Pediatrics Clinic and Institute for Molecular Medicine A. Nocivelli, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy; ASST-Spedali Civili di Brescia, Brescia, Italy.

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http://dx.doi.org/10.1016/j.jaci.2020.04.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7175894PMC
July 2020

Effects of Pidotimod on recurrent respiratory infections in children with Down syndrome: a retrospective Italian study.

Ital J Pediatr 2020 Mar 13;46(1):31. Epub 2020 Mar 13.

Pediatric and Infectious Disease Unit, Bambino Gesù Children's Hospital, IRCCS, Piazza S. Onofrio 4, 00165, Rome, Italy.

Background: Children with Down syndrome (DS) show a high susceptibility to recurrent infections (RI), caused by immune defects and abnormalities of the airways. Our goal was to investigate the effects of Pidotimod on RI prevention in children with DS, comparing immune and clinical parameters before (T0) and after (T1) the treatment with Pidotimod.

Methods: The study was conducted at the Down syndrome outpatient Center of Bambino Gesù Children's Hospital, in Rome. We reviewed the medical records of all children with a positive history for RI and who received oral prophylaxis of Pidotimod from September 2016 to February 2017.

Results: Thirty-three children met the inclusion criteria (males: 51.5%; average age: 6 years ±SD: 3). We found a significant decrease in the number of children with upper respiratory infections (82% at T0 vs 24% at T1; p = 0,0001) and with lower respiratory infections (36% at T0 vs 9% at T1; p = 0.003) after treatment with Pidotimod. We also demonstrated a significant decrease in the number of children hospitalized for respiratory infections (18% at T0 vs 3% at T1; p = 0.03). We measured T and B cells in the peripheral blood and B cell function in vitro at T0 and T1. We found that the response to CpG improved at T1. A significant increase of B cell frequency (p = 0.0009), B cell proliferation (p = 0.0278) and IgM secretion (p = 0.0478) were observed in children with DS after treatment.

Conclusions: Our results provided evidence that Pidotimod may be able to prevent RI in children with Down syndrome.
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http://dx.doi.org/10.1186/s13052-020-0797-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7068926PMC
March 2020

The Interplay between CD27 and CD27 B Cells Ensures the Flexibility, Stability, and Resilience of Human B Cell Memory.

Cell Rep 2020 03;30(9):2963-2977.e6

Multifactorial Disease and Complex Phenotype Research Area, Bambino Gesù Children's Hospital, IRCSS, 00146 Rome, Italy.

Memory B cells (MBCs) epitomize the adaptation of the immune system to the environment. We identify two MBC subsets in peripheral blood, CD27 and CD27 MBCs, whose frequency changes with age. Heavy chain variable region (VH) usage, somatic mutation frequency replacement-to-silent ratio, and CDR3 property changes, reflecting consecutive selection of highly antigen-specific, low cross-reactive antibody variants, all demonstrate that CD27 and CD27 MBCs represent sequential MBC developmental stages, and stringent antigen-driven pressure selects CD27 into the CD27 MBC pool. Dynamics of human MBCs are exploited in pregnancy, when 50% of maternal MBCs are lost and CD27 MBCs transit to the more differentiated CD27 stage. In the postpartum period, the maternal MBC pool is replenished by the expansion of persistent CD27 clones. Thus, the stability and flexibility of human B cell memory is ensured by CD27 MBCs that expand and differentiate in response to change.
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http://dx.doi.org/10.1016/j.celrep.2020.02.022DOI Listing
March 2020

Lack of Gut Secretory Immunoglobulin A in Memory B-Cell Dysfunction-Associated Disorders: A Possible Gut-Spleen Axis.

Front Immunol 2019 8;10:2937. Epub 2020 Jan 8.

Department of Molecular Medicine, Sapienza University, Rome, Italy.

B-1a B cells and gut secretory IgA (SIgA) are absent in asplenic mice. Human immunoglobulin M (IgM) memory B cells, which are functionally equivalent to mouse B-1a B cells, are reduced after splenectomy. To demonstrate whether IgM memory B cells are necessary for generating IgA-secreting plasma cells in the human gut. We studied intestinal SIgA in two disorders sharing the IgM memory B cell defect, namely asplenia, and common variable immune deficiency (CVID). Splenectomy was associated with reduced circulating IgM memory B cells and disappearance of intestinal IgA-secreting plasma cells. CVID patients with reduced circulating IgM memory B cells had a reduced frequency of gut IgA plasma cells and a disrupted film of SIgA on epithelial cells. Toll-like receptor 9 (TLR9) and transmembrane activator and calcium-modulator and cyclophilin ligand interactor (TACI) induced IgM memory B cell differentiation into IgA plasma cells . In the human gut, TACI-expressing IgM memory B cells were localized under the epithelial cell layer where the TACI ligand a proliferation inducing ligand (APRIL) was extremely abundant. Circulating IgM memory B cell depletion was associated with a defect of intestinal IgA-secreting plasma cells in asplenia and CVID. The observation that IgM memory B cells have a distinctive role in mucosal protection suggests the existence of a functional gut-spleen axis.
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http://dx.doi.org/10.3389/fimmu.2019.02937DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6960143PMC
November 2020
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