Alessandro Plebani - Academia.edu (original) (raw)

Papers by Alessandro Plebani

The Journal of Allergy and Clinical Immunology: In Practice, 2019

Clinical and Experimental Immunology, Jun 1, 1998

In the present study we evaluated in vitro immunoglobulin production from IgAD individuals and he... more In the present study we evaluated in vitro immunoglobulin production from IgAD individuals and healthy controls. Peripheral blood mononuclear cells (PBMC) from IgAD and controls were cultured with anti-CD40 MoAb presented on a CDw32-transfected fibroblast cell line (CD40 system) in the presence of IL-10, IL-2, IL-4, transforming growth factor-beta (TGF-b) alone as well as of IL-10 in combination with each of the other three cytokines. Only IL-10 added alone induced significant changes in baseline immunoglobulin production; marked increases in median supernatant levels of all three isotypes were observed in both groups. The most striking finding of this study was the synergizing effect of IL-4 on IgA production in the IgAD group when added with IL-10; median IgA supernatant level increased to a value superimposable on that found in the normal controls which remained about the same as when stimulated with IL-10 alone. The synergic effect of IL-4 and IL-10 was specific to the IgA isotype.

Blood, 2002

Conflicting results obtained from animal studies suggest that B cells play a role in maintaining ... more Conflicting results obtained from animal studies suggest that B cells play a role in maintaining long-term T-cell memory and in skewing T-cell response toward a T-helper 2 (TH2) phenotype. X-linked agammaglobulinemia (XLA) is a genetic human disease characterized by the lack of circulating B cells due to the mutation of Bruton tyrosine kinase. This disease thus represents a unique model for studying the role of B lymphocytes in regulating T-cell functions in humans. To this aim, we analyzed hepatitis B envelope antigen (HBenvAg)–specific T-cell memory in a series of XLA patients vaccinated against hepatitis B virus (HBV). We found HBenvAg-specific T lymphocytes producing interferon–γ, interleukin-4, or both in the peripheral blood of XLA patients up to at least 24 months after completing the standard anti-HBV immunization protocol. The HBenvAg-specific T-cell frequencies and the percentage of patients with these responses were not significantly different from healthy vaccinated cont...

Journal of Immunology, Jul 1, 2008

BackgroundCommon variable immunodeficiency (CVID) is the most frequent primary antibody deficienc... more BackgroundCommon variable immunodeficiency (CVID) is the most frequent primary antibody deficiency. A significant number of CVID patients are affected by various manifestations of immune dysregulation such as autoimmunity. Follicular T cells cells are thought to support the development of CVID by providing inappropriate signals to B cells during the germinal center (GC) response.ObjectivesWe determined the possible role of follicular helper (Tfh) and follicular regulatory T (Tfr) cells in patients with CVID by phenotypic, molecular, and functional studies.MethodsWe analyzed the frequency, phenotype, transcriptome, and function of circulating Tfh cells in the peripheral blood of 27 CVID patients (11 pediatric and 16 adult) displaying autoimmunity as additional phenotype and compared them to 106 (39 pediatric and 67 adult) age-matched healthy controls. We applied Whole Exome Sequencing (WES) and Sanger sequencing to identify mutations that could account for the development of CVID and...

Encyclopedia of Medical Immunology, 2019

Reduction of all serum immunoglobulin isotypes (IgM, IgG, and IgA) with decreased or absent B cel... more Reduction of all serum immunoglobulin isotypes (IgM, IgG, and IgA) with decreased or absent B cells is an immunodeficiency syndrome that may result from several genetic defects, which might be inherited either X-linked (Bruton's agammaglobulinemia) or autosomal recessive (i.e., absent mu heavy chain, Ig-alpha deficiency, Ig-beta deficiency).

Purpose B cell activating factor (BAFF) binding to BAFF-receptor(BAFFR) activates essential cellu... more Purpose B cell activating factor (BAFF) binding to BAFF-receptor(BAFFR) activates essential cellular functions required forthe survival of mature, human B cells. Thus,deletion ofthe BAFFR gene blocks the development of B cells at the transition from immature to mature B cells resulting in B lymphopenia and hypogammaglobulinemia. In addition to complete BAFFR deficiency, single nucleotide variants changing the primary amino acid sequence of BAFFR gene exist. Some of these variants were foundin patients suffering from immunodeficiency, autoimmunity, or B cell lymphomas. However, it remains unclearto which extent such variants disturb the activity of BAFFR. Methods Since individual differences and genetic/environmental modifiers change the expression and activity of BAFFR, we developed a cellular system that allows the unbiased analysis of BAFFR variants P21R, A52T, G64V, Dup92-95, P146S, and H159Y regarding oligomerization, signaling, and ectodomain shedding.Results Here we show that ...

Journal of Clinical Immunology, 2021

Patients with ataxia-telangiectasia (A-T) suffer from progressive cerebellar ataxia, immunodefici... more Patients with ataxia-telangiectasia (A-T) suffer from progressive cerebellar ataxia, immunodeficiency, respiratory failure, and cancer susceptibility. From a clinical point of view, A-T patients with IgA deficiency show more symptoms and may have a poorer prognosis. In this study, we analyzed mortality and immunity data of 659 A-T patients with regard to IgA deficiency collected from the European Society for Immunodeficiencies (ESID) registry and from 66 patients with classical A-T who attended at the Frankfurt Goethe-University between 2012 and 2018. We studied peripheral B- and T-cell subsets and T-cell repertoire of the Frankfurt cohort and survival rates of all A-T patients in the ESID registry. Patients with A-T have significant alterations in their lymphocyte phenotypes. All subsets (CD3, CD4, CD8, CD19, CD4/CD45RA, and CD8/CD45RA) were significantly diminished compared to standard values. Patients with IgA deficiency (n = 35) had significantly lower lymphocyte counts compared...

Cell Death & Differentiation, 2021

Ciliogenesis proteins orchestrate vesicular trafficking pathways that regulate immune synapse (IS... more Ciliogenesis proteins orchestrate vesicular trafficking pathways that regulate immune synapse (IS) assembly in the non-ciliated Tcells. 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. We show that CCDC28B participates in IS assembly by regulating polarized T-cell antigen receptor (TCR) recycling. This involves the CCDC28B-dependent, FAM21-mediated recruitment of the actin regulator WASH to retromer at early endosomes to promote actin polymerization. The CVID-associated CCDC28B R25W variant failed to interact with FAM21, leading to impaired synaptic TCR recycling. CVID T cells carrying the ccdc28b 211 C > T allele displayed IS defects mapping to this pathway that were corrected by overexpression of the wild-type allele. These results identify a new disease gene in T-CVID and pinpoint CCDC28B as a new player in IS assembly.

Cell Reports, 2020

Highlights d CD27 dull and CD27 bright MBCs share their VH repertoire but have different function... more Highlights d CD27 dull and CD27 bright MBCs share their VH repertoire but have different functions d CD27 dull MBCs are the long-lived substrate of selected and specific CD27 bright MBCs d The interplay between CD27 dull and CD27 bright MBCs preserves B cell memory d In pregnancy, MBCs decline, but persisting CD27 dull MBCs re-expand after delivery

Frontiers in Immunology, 2019

from 1994 to 1997. It was in that period that we met and started a collaboration that continued i... more from 1994 to 1997. It was in that period that we met and started a collaboration that continued in the years to follow. He immediately involved us in the production of monoclonal antibodies (mAbs) that allowed the identification and fine characterization of novel receptor molecules that were able to activate or inhibit human Natural Killer cell function, including several antibodies specific for Natural Cytotoxicity Receptor (NCR) and Killer-cell Immunoglobulin-like Receptor (KIR) molecules. These reagents, generated in our laboratory in Brescia, contributed to complete the studies aimed to characterize innate lymphoid NK cells, that had been initiated by Alessandro and his brother Lorenzo in Genoa. Soon, we identified an anti-KIR3DL2 that was subsequently shown to be helpful for the diagnosis and treatment of various forms of cutaneous T cell lymphoma. While in Brescia, Alessandro established a partnership with those of us who were working in the Department of Pediatrics; together, in short time we tackled the goal of studying the role of NK cells in patients with primary immunodeficiencies. This collaboration led to novel discoveries that shed light on the critical role played by NK cells in the immune response against virus and tumors in humans, as best exemplified by our characterization of the molecular mechanisms of impaired control of Epstein-Barr Virus (EBV) infection in patients with X-linked lymphoproliferative (XLP) disease. After Alessandro left Brescia to return to Genoa, our collaboration continued with the same enthusiasm, and even from a distance he remained an extraordinary example of an inspirational and generous mentor. This review is a sign of our gratitude to a mentor and a friend whom we deeply miss.

Clinical Immunology, 2018

Molecular Medicine, 2000

Background: The diagnosis of X-linked agammaglobulinemia (XLA) is not always clearcut. Not all XL... more Background: The diagnosis of X-linked agammaglobulinemia (XLA) is not always clearcut. Not all XLA conform to the classic phenotype and less than 50% of affected boys have a family history of immunodeficiency. Mutations in the gene for Bruton's tyrosine kinase (BTK) are responsible for the majority of agammaglobulinemia cases. However, a certain proportion of patients may have mutations involving other genes, although they show with an XLA phenotype. We performed BTK gene mutation analysis in 37 males with presumed XLA and analyzed the pattern of X-chromosome inactivation (XCI) in 31 mothers to evaluate the relevance of these approaches to diagnosis and genetic counseling. Materials and Methods: Twenty affected males with a sporadic occurrence and 17 familial cases belonging to nine families were enrolled within the framework of the Italian Multicenter Clinical Study on XLA. We used non-isotopic RNase cleavage assay (NIRCA), followed by cDNA sequence determination to screen for BTK mutations and X-chromosome inactivation analysis for carrier detection. Results: Using the cDNA-based approach, the identification of BTK gene abnormalities confirmed the clinical diagnosis of XLA in 31 of 37 affected infants. Missense was the most frequent mutational event and the kinase domain was mostly involved. In addition, nine novel mutations were identified. In sporadic cases, BTK gene abnormalities were identified in 9 out of 10 patients whose mothers had a nonrandom pattern of XCI and in 5 out of 6 patients whose mother had a random pattern of XCI. With the exception of one family, all patients with a familial occurrence and born to mothers with a nonrandom pattern of XCI had mutations of the BTK gene. Conclusions: Our findings indicate that in sporadic cases BTK gene sequencing is the only reliable tool for a definitive diagnosis of XLA and support XCI as the first diagnostic tool in the mothers of affected males in multiple generations. Furthermore, our molecular analysis confirms that 10-20% of BTK-unaltered patients have disorders caused by defects in other genes.

Nature genetics, Nov 10, 2016

Selective immunoglobulin A deficiency (IgAD) is the most common primary immunodeficiency in Europ... more Selective immunoglobulin A deficiency (IgAD) is the most common primary immunodeficiency in Europeans. Our genome-wide association study (GWAS) meta-analysis of 1,635 patients with IgAD and 4,852 controls identified four new significant (P < 5 × 10(-8)) loci and association with a rare IFIH1 variant (p.Ile923Val). Peak new variants (PVT1, P = 4.3 × 10(-11); ATG13-AMBRA1, P = 6.7 × 10(-10); AHI1, P = 8.4 × 10(-10); CLEC16A, P = 1.4 × 10(-9)) overlapped with autoimmune markers (3/4) and correlated with 21 putative regulatory variants, including expression quantitative trait loci (eQTLs) for AHI1 and DEXI and DNase hypersensitivity sites in FOXP3(+) regulatory T cells. Pathway analysis of the meta-analysis results showed striking association with the KEGG pathway for IgA production (pathway P < 0.0001), with 22 of the 30 annotated pathway genes containing at least one variant with P ≤ 0.05 in the IgAD meta-analysis. These data suggest that a complex network of genetic effects, in...

The Scientific World Journal, 2012

Broad Toll-like receptor 9 (TLR9) signalling defects after CpG in vitro stimulation have been des... more Broad Toll-like receptor 9 (TLR9) signalling defects after CpG in vitro stimulation have been described in common variable immunodeficiency (CVID). CXCL16, a surface receptor, was recently shown to influence cell responses to CpG. We evaluated the expression and function of CXCL16 on B cells from healthy controls and CVID patients. We report that CXCL16 is normally expressed on B cells throughout peripheral maturation. Decreased B cell expression of CXCL16 was observed in a subgroup of CVID patients that correlated with defective in vitro responses to CpG (such as upregulation of CD69, CD86, AICDA, IL-6, and TLR9). Our data suggest that expression levels of a surface receptor, namely, CXCL16, correlate with B cell responses mediated by TLR9 in common variable immunodeficiency.

Nature Immunology, 2012

Users may view, print, copy, download and text and data-mine the content in such documents, for t... more Users may view, print, copy, download and text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

Nature Immunology, 2011

Nature Immunology, 2009

Immunoglobulin D (IgD) is an enigmatic antibody isotype that mature B cells co-express with IgM t... more Immunoglobulin D (IgD) is an enigmatic antibody isotype that mature B cells co-express with IgM through alternative RNA splicing. We found active T cell-dependent and T cell-independent Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

The Journal of Immunology, 2003

Selective IgA deficiency (IgAD) and common variable immunodeficiency (CVID) are the most common p... more Selective IgA deficiency (IgAD) and common variable immunodeficiency (CVID) are the most common primary immunodeficiencies in humans. A high degree of familial clustering, marked differences in the population prevalence among ethnic groups, association of IgAD and CVID in families, and a predominant inheritance pattern in multiple-case pedigrees have suggested a strong, shared genetic predisposition. Previous genetic linkage, case-control, and family-based association studies mapped an IgAD/CVID susceptibility locus, designated IGAD1, to the MHC, but its precise location within the MHC has been controversial. We have analyzed a sample of 101 multiple- and 110 single-case families using 36 markers at the IGAD1 candidate region and mapped homozygous stretches across the MHC shared by affected family members. Haplotype analysis, linkage disequilibrium, and homozygosity mapping indicated that HLA-DQ/DR is the major IGAD1 locus, strongly suggesting the autoimmune pathogenesis of IgAD/CVI...