Publications by authors named "Alessandro Plebani"

Article Synopsis
  • Activated phosphoinositide 3-kinase delta (PI3Kδ) syndrome (APDS) is a rare genetic disease that disrupts the immune system, causing various symptoms that usually begin in childhood.
  • In a phase III clinical trial, a drug called leniolisib was shown to effectively reduce lymph node swelling and increase naïve B cell levels in both adolescents and adults with APDS compared to those given a placebo.
  • The study found that leniolisib was well-tolerated across age groups and suggests it could be a promising treatment option for managing APDS by addressing the underlying cause rather than just the symptoms.
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Article Synopsis
  • - The study investigates the relationship between X-linked chronic granulomatous disease (X-CGD), a genetic condition marked by recurrent infections, and regulatory T cells (Tregs) which help manage immune responses.
  • - Researchers found that adult X-CGD patients had increased and activated Tregs in their blood, linked to the activation of conventional CD4+ T cells (Tconvs) that produce higher levels of TNF.
  • - The activation of these T cells resulted in an increase of reactive oxygen species (ROS) not from the NOX2 pathway but from cellular metabolism, suggesting that Treg expansion is a response to overall immune activation in X-CGD patients.
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Article Synopsis
  • Activated phosphoinositide 3-kinase delta (PI3Kδ) syndrome (APDS) is a genetic condition characterized by overactive PI3Kδ, leading to immune issues like recurrent infections and autoimmunity.
  • Leniolisib, a targeted inhibitor of PI3Kδ, showed promise in improving immune function and reducing complications like lymphoproliferation in patients with APDS over a 12-week period.
  • An ongoing study involving 37 patients showed that most experienced mild to moderate side effects, but leniolisib significantly decreased infection rates and improved overall health, with many patients needing less immunoglobulin therapy.
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We report a novel case of SMARCD2 (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily D, member 2) mutation successfully treated with hematopoietic stem cell transplantation. The female patient presented delayed cord separation, chronic diarrhea, skin abscesses, skeletal dysmorphisms, and neutropenia with specific granule deficiency. Analysis of the transcriptomic profile of peripheral blood sorted mature and immature SMARCD2 neutrophils showed defective maturation process that associated with altered expression of genes related to specific, azurophilic, and gelatinase granules, such as LTF, CRISP3, PTX3, and CHI3L1.

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Background: Activated phosphoinositide-3-kinase δ syndrome (APDS) is an inborn error of immunity (IEI) with infection susceptibility and immune dysregulation, clinically overlapping with other conditions. Management depends on disease evolution, but predictors of severe disease are lacking.

Objectives: This study sought to report the extended spectrum of disease manifestations in APDS1 versus APDS2; compare these to CTLA4 deficiency, NFKB1 deficiency, and STAT3 gain-of-function (GOF) disease; and identify predictors of severity in APDS.

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Article Synopsis
  • Activated phosphoinositide 3-kinase delta syndrome (APDS) is an immune disorder that leads to various health issues like infections and autoimmunity due to overactive PI3Kδ signaling.
  • A phase 3 clinical trial tested leniolisib, a specific inhibitor of PI3Kδ, on 31 patients aged 12 and older, comparing its effects against a placebo over 12 weeks.
  • Results showed that leniolisib significantly reduced lymph node size and increased naïve B cells, indicating improved immune function, while also being well-tolerated with fewer adverse events compared to placebo.
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Purpose: Binding of the B cell activating factor (BAFF) to its receptor (BAFFR) activates in mature B cells many essential pro-survival functions. Null mutations in the BAFFR gene result in complete BAFFR deficiency and cause a block in B cell development at the transition from immature to mature B cells leading therefore to B lymphopenia and hypogammaglobulinemia. In addition to complete BAFFR deficiency, single nucleotide variants encoding BAFFR missense mutations were found in patients suffering from common variable immunodeficiency (CVID), autoimmunity, or B cell lymphomas.

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Introduction: Autoimmunity is a common feature in CVID patients. To date the mechanisms leading to the development of such complications are not fully elucidated.

Materials And Methods: Data from 122 CVID patients subdivided in three groups based on the absence of autoimmunity (n-AI) or the presence of hematologic autoimmune phenomena (Cy-AI) or non-hematologic autoimmune phenomena (n-Cy-AI) were evaluated.

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Common variable immunodeficiency (CVID) is the most frequent primary antibody deficiency whereby follicular helper T (Tfh) cells fail to establish productive responses with B cells in germinal centers. Here, we analyzed the frequency, phenotype, transcriptome, and function of circulating Tfh (cTfh) cells in CVID patients displaying autoimmunity as an additional phenotype. A group of patients showed a high frequency of cTfh1 cells and a prominent expression of PD-1 and ICOS as well as a cTfh mRNA signature consistent with highly activated, but exhausted, senescent, and apoptotic cells.

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Background: The pathogenesis of diabetic kidney disease (DKD) is complex and involves both glomerular and tubular dysfunction. A global assessment of kidney function is necessary to stage DKD, a progressive kidney disease that is likely to begin in childhood. The present study evaluated whether kidney injury biomarkers identified as early DKD biomarkers in adults have any prognostic value in the very early stages of childhood diabetes.

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COVID-19 manifestations range from asymptomatic to life-threatening infections. The outcome in different inborn errors of immunity (IEI) is still a matter of debate. In this retrospective study, we describe the experience of the of the Italian Primary Immunodeficiencies Network (IPINet).

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Dedicator of Cytokinesis 8 (DOCK8) deficiency is a rare form of autosomal recessive combined immunodeficiency. The effect of DOCK8 deficiency on Natural Killer cell biology has not been fully elucidated yet. Thus, we undertook a detailed phenotypic and functional evaluation of NK cells from seven patients with DOCK8 deficiency.

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Ataxia telangiectasia (AT) is a rare neurodegenerative genetic disorder due to bi-allelic mutations in the Ataxia Telangiectasia Mutated (ATM) gene. The aim of this paper is to better define the immunological profile over time, the clinical immune-related manifestations at diagnosis and during follow-up, and to attempt a genotype-phenotype correlation of an Italian cohort of AT patients. Retrospective data of 69 AT patients diagnosed between December 1984 and November 2019 were collected from the database of the Italian Primary Immunodeficiency Network.

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We present an algorithm that may be applied in case of a diagnosis of pediatric nontuberculous mycobacterial disease to identify the patients who may require an immunologic assessment to discover a possible underlying immune system defect predisposing to their nontuberculous mycobacterial infections.

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Purpose: Jacobsen syndrome (JS) is a rare form of genetic disorder that was recently classified as a syndromic immunodeficiency. Available detailed immunological data from JS patients are limited.

Methods: Clinical and immunological presentation of twelve pediatric patients with JS by means of revision of clinical records, flow cytometry, real-time PCR, and lymphocyte functional testing were collected.

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We studied a child with severe viral, bacterial, fungal, and parasitic diseases, who was homozygous for a loss-of-function mutation of REL, encoding c-Rel, which is selectively expressed in lymphoid and myeloid cells. The patient had low frequencies of NK, effector memory cells reexpressing CD45RA (Temra) CD8+ T cells, memory CD4+ T cells, including Th1 and Th1*, Tregs, and memory B cells, whereas the counts and proportions of other leukocyte subsets were normal. Functional deficits of myeloid cells included the abolition of IL-12 and IL-23 production by conventional DC1s (cDC1s) and monocytes, but not cDC2s.

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Background: Human Cytomegalovirus (HCMV) still represents a crucial concern in solid organ transplant recipients (SOTRs) and the use of antiviral therapy are limited by side effects and the selection of viral mutations conferring antiviral drug resistance.

Case Presentation: Here we reported the case of an HCMV seronegative patient with common variable immunodeficiency (CVID), multiple hepatic adenomatosis, hepatopulmonary syndrome and portal hypertension who received a liver transplant from an HCMV seropositive donor. The patient was treated with Valganciclovir (vGCV) and then IV Ganciclovir (GCV) at 5 week post-transplant for uncontrolled HCMV DNAemia.

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Inhibitor of nuclear factor kappa B kinase alpha (IKKα) is critical for p100/NF-κB2 phosphorylation and processing into p52 and activation of the noncanonical NF-κB pathway. A patient with recurrent infections, skeletal abnormalities, absent secondary lymphoid structures, reduced B cell numbers, hypogammaglobulinemia, and lymphocytic infiltration of intestine and liver was found to have a homozygous p.Y580C mutation in the helix-loop-helix domain of IKKα.

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Article Synopsis
  • - Patients with ataxia-telangiectasia (A-T) often experience severe issues, including progressive coordination problems, weakened immune response, and higher cancer risk, with those having IgA deficiency facing even worse outcomes.
  • - A study of 659 A-T patients showed that those with IgA deficiency had significantly lower lymphocyte counts and altered immune cell types compared to those without IgA deficiency, indicating poorer health.
  • - The findings suggest that IgA deficiency serves as a simple indicator of worse prognosis in A-T patients, emphasizing the need for careful monitoring and potential treatment strategies for those affected.
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Ciliogenesis proteins orchestrate vesicular trafficking pathways that regulate immune synapse (IS) assembly in the non-ciliated T-cells. We hypothesized that ciliogenesis-related genes might be disease candidates for common variable immunodeficiency with impaired T-cell function (T-CVID). We identified a heterozygous, predicted pathogenic variant in the ciliogenesis protein CCDC28B present with increased frequency in a large CVID cohort.

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Predominantly antibody deficiencies (PADs) encompass a heterogeneous group of disorders characterized by low immunoglobulin serum levels in the presence or absence of peripheral B cells. Clinical presentation of affected patients may include recurrent respiratory and gastrointestinal infections, invasive infections, autoimmune manifestations, allergic reactions, lymphoproliferation, and increased susceptibility to malignant transformation. In the last decades, several genetic alterations affecting B-cell development/maturation have been identified as causative of several forms of PADs, adding important information on the genetic background of PADs, which in turn should lead to a better understanding of these disorders and precise clinical management of affected patients.

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Granulomatous and Lymphocytic Interstitial Lung Diseases (GLILD) is a severe non-infectious complication of Common Variable Immunodeficiency (CVID), often associated with extrapulmonary involvement. Due to a poorly understood pathogenesis, GLILD diagnosis and management criteria still lack consensus. Accordingly, it is a relevant cause of long-term loss of respiratory function and is closely associated with a markedly reduced survival.

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