Simona Ferrari

Policlinico S.Orsola-Malpighi, Bolonia, Emilia-Romagna, Italy

Are you Simona Ferrari?

Claim your profile

Publications (22)128.14 Total impact

  • The Journal of allergy and clinical immunology 07/2013; · 12.05 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Mutations in the gene encoding the cystic fibrosis transmembrane regulator ( CFTR) have been reported to increase the risk of recurrent acute pancreatitis in patients with pancreas divisum. We assessed the CFTR gene in a young male patient with pancreas divisum and recurrent acute pancreatitis. Magnetic resonance cholangiopancreatography and computed tomography revealed that the patient had pancreas divisum, with an enlarged and tortuous pancreatic duct; he also had positive results from the cystic fibrosis sweat test. Genetic analysis did not identify any commonCFTR mutations, but did show that he was homozygous for the 5T allele in intron 8 IVS8 5T-12TG (which affects splicing at intron 8). Endoscopic sphincterotomy and stenting of papilla minor was performed. The IVS8 5T-12TG variant has been associated with abnormal organ development, so it is possible that CFTR has an important role in development of the pancreatic duct. We propose this patient has recurrent acute pancreatitis resulting from a developmental defect associated with a sub-optimal CFTR function.
    Clinical gastroenterology and hepatology: the official clinical practice journal of the American Gastroenterological Association 02/2013; · 5.64 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: BACKGROUND: Chromosome changes in the bone marrow (BM) of patients with persistent cytopenia are often considered diagnostic for a myelodysplastic syndrome (MDS). Comprehensive cytogenetic evaluations may give evidence of the real pathogenetic role of these changes in cases with cytopenia without morphological signs of MDS. RESULTS: Chromosome anomalies were found in the BM of three patients, without any morphological evidence of MDS: 1) an acquired complex rearrangement of chromosome 21 in a boy with severe aplastic anaemia (SAA); the rearrangement caused the loss of exons 2-8 of the RUNX1 gene with subsequent hypoexpression. 2) a constitutional complex rearrangement of chromosome 21 in a girl with congenital thrombocytopenia; the rearrangement led to RUNX1 disruption and hypoexpression. 3) an acquired paracentric inversion of chromosome 1, in which two regions at the breakpoints were shown to be lost, in a boy with aplastic anaemia; the MPL gene, localized in chromosome 1 short arms was not mutated neither disrupted, but its expression was severely reduced: we postulate that the aplastic anaemia was due to position effects acting both in cis and in trans, and causing Congenital Amegakaryocytic Thrombocytopenia (CAMT). CONCLUSIONS: A clonal anomaly in BM does not imply per se a diagnosis of MDS: a subgroup of BM hypoplastic disorders is directly due to chromosome structural anomalies with effects on specific genes, as was the case of RUNX1 and MPL in the patients here reported with diagnosis of SAA, thrombocytopenia, and CAMT. The anomaly may be either acquired or constitutional, and it may act by deletion/disruption of the gene, or by position effects. Full cytogenetic investigations, including a-CGH, should always be part of the diagnostic evaluation of patients with BM aplasia/hypoplasia and peripheral cytopenias.
    Molecular Cytogenetics 10/2012; 5(1):39. · 2.36 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: CD40/CD40 ligand (CD40L) cross-talk plays a key role in B-cell terminal maturation in the germinal centers. Genetic defects affecting CD40 cause a rare form of hyper-immunoglobulin M (IgM) syndrome, a disorder characterized by low or absent serum IgG and IgA, associated with recurrent infections. We previously reported on a few patients with homozygous CD40 mutations resulting in lack or severe reduction of CD40 cell surface expression. Here we characterize the 3 CD40 mutants due to missense mutations or small in-frame deletions, and show that the mutated proteins are synthesized but retained in the endoplasmic reticulum (ER), likely due to protein misfolding. Interestingly, the intracellular behavior and fate differ significantly among the mutants: progressive accumulation of the P2 mutant causes endoplasmic reticulum stress and the activation of an unfolded protein response; the mutant P4 is rather efficiently disposed by the ER-associated degradation pathway, while the P5 mutant partially negotiates transport to the plasma membrane, and is competent for CD40L binding. Interestingly, this latter mutant activates downstream signaling elements when overexpressed in transfected cells. These results give new important insights into the molecular pathogenesis of HIGM disease, and suggest that CD40 deficiency can also be regarded as an ER-storage disease.
    Blood 12/2010; 116(26):5867-74. · 9.78 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Coding variants in tumor necrosis factor receptor superfamily member 13B (TNFRSF13B) have been implicated in common variable immunodeficiency (CVID), but the functional effects of such mutations in relation to the development of the disease have not been entirely established. To examine the potential contribution of TNFRSF13B variants to CVID, we have applied an evolutionary approach by sequencing its coding region in 451 individuals belonging to 26 worldwide populations, in addition to controls, patients with CVID and selective IgA deficiency (IgAD) from Italy. The low level of geographical structure for the observed genetic diversity and the several neutrality tests performed confirm the absence of recent population-specific selective pressures, suggesting that TNFRSF13B may be involved also in innate immune functions, rather than in adaptive immunity only. A slight excess of rare derived alleles was found in patients with CVID, and thus some of these variants may contribute to the disease, implying that CVID probably fits the rare variants rather than the common disease/common variant paradigm. This also confirms the previous suggestion that TNFRSF13B defects alone do not cause CVID and that such an extremely heterogeneous immunodeficiency might be more likely related to additional, still unknown environmental and genetic factors.
    Genes and immunity 07/2009; 10(6):566-78. · 4.22 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: To describe novel immunological and molecular findings regarding early B cell development arrest resulting in autosomal recessive agammaglobulinemia. Recently two different groups identified mutations in Ig beta, a component of the pre-B cell receptor, responsible for agammaglobulinemia in humans. These are the first two patients ever described with mutations in Ig beta. These novel findings broaden the spectrum of genetic defects underlying this rare condition. This novel cause of agammaglobulinemia not only sheds light into early B cell development in humans but also sets the basis for potential alternative therapeutic approaches such as gene therapy.
    Current Opinion in Allergy and Clinical Immunology 01/2009; 8(6):515-9. · 3.40 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Ikaros is the prototypic member of a Kruppel-like zinc finger transcription factor subfamily that is required for normal hematopoietic cell differentiation and proliferation, particularly in the lymphoid lineages. Alternative splicing can generate multiple Ikaros isoforms that lack different numbers of exons and have different functions. Shorter isoforms, which lack the amino-terminal domain that mediates sequence-specific DNA binding, exert a dominant negative effect and inhibit the ability of longer heterodimer partners to bind DNA. In this study, we developed a high-throughput capillary electrophoresis sizing method to detect and quantify different Ikaros cDNA transcripts. We demonstrated that Philadelphia chromosome-positive acute lymphoblastic leukemia cells expressed high levels of the non-DNA-binding isoform Ik6 that was generated following IKZF1 genomic deletions (19/46 patients, 41%). Furthermore, a recurring 60 bp insertion immediately upstream of exon 5, at the exon 3/exon 5 junction, was frequently detected in the Ik2 and Ik4 isoforms. This insertion occurred either alone or together with an in-frame ten amino acid deletion that was due to a 30 bp loss at the end of exon 7. Both the alterations are due to the selection of alternative cryptic splice sites and have been suggested to cause impaired DNA-binding activity. Non-DNA-binding isoforms were localized in the cytoplasm whereas the DNA-binding isoforms were localized in the nucleus. Our findings demonstrate that both aberrant splicing and genomic deletion leading to different non-DNA-binding Ikaros cDNA transcripts are common features of Philadelphia chromosome-positive acute lymphoblastic leukemia.
    Haematologica 11/2008; 93(12):1814-21. · 5.94 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Agammaglobulinemia is a rare primary immuno-deficiency characterized by an early block of B-cell development in the bone marrow resulting in the absence of peripheral B cells and low/absent immunoglobulin serum levels. Mutations in the Bruton tyrosine kinase and in components of the pre-B-cell receptor (pre-BCR), such as mu heavy chain, surrogate light chain, and Igalpha have been found in 85% to 90% of patients affected by this disease. Here we review the recent advances in the characterization of molecular defects underlying an early block in B-cell development, focusing on the novel finding of the first two patients with agammaglobulinemia caused by mutations in Igbeta, the transmembrane protein that associates with Igalpha as part of the pre-BCR complex. Characterization of novel genetic defects involving components of the pre-BCR is crucial for a better understanding of the biology of early B-cell development and may have therapeutic and prognostic implications.
    Current Allergy and Asthma Reports 10/2008; 8(5):404-8. · 2.75 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The receptor TLR9, recognizing unmethylated bacterial DNA (CpG), is expressed by B cells and plays a role in the maintenance of serological memory. Little is known about the response of B cells stimulated with CpG alone, without additional cytokines. In this study, we show for the first time the phenotypic modification, changes in gene expression, and functional events downstream to TLR9 stimulation in human B cell subsets. In addition, we demonstrate that upon CpG stimulation, IgM memory B cells differentiate into plasma cells producing IgM Abs directed against the capsular polysaccharides of Streptococcus pneumoniae. This novel finding proves that IgM memory is the B cell compartment responsible for the defense against encapsulated bacteria. We also show that cord blood transitional B cells, corresponding to new bone marrow emigrants, respond to CpG. Upon TLR9 engagement, they de novo express AID and Blimp-1, genes necessary for hypersomatic mutation, class-switch recombination, and plasma cell differentiation and produce Abs with anti-pneumococcal specificity. Transitional B cells, isolated from cord blood, have not been exposed to pneumococcus in vivo. In addition, it is known that Ag binding through the BCR causes apoptotic cell death at this stage of development. Therefore, the ability of transitional B cells to sense bacterial DNA through TLR9 represents a tool to rapidly build up the repertoire of natural Abs necessary for our first-line defense at birth.
    The Journal of Immunology 02/2008; 180(2):800-8. · 5.52 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Agammaglobulinemia is a rare primary immunodeficiency characterized by an early block of B cell development in the bone marrow, resulting in the absence of peripheral B cells and low/absent immunoglobulin serum levels. So far, mutations in Btk, mu heavy chain, surrogate light chain, Igalpha, and B cell linker have been found in 85-90% of patients with agammaglobulinemia. We report on the first patient with agammaglobulinemia caused by a homozygous nonsense mutation in Igbeta, which is a transmembrane protein that associates with Igalpha as part of the preBCR complex. Transfection experiments using Drosophila melanogaster S2 Schneider cells showed that the mutant Igbeta is no longer able to associate with Igalpha, and that assembly of the BCR complex on the cell surface is abrogated. The essential role of Igbeta for human B cell development was further demonstrated by immunofluorescence analysis of the patient's bone marrow, which showed a complete block of B cell development at the pro-B to preB transition. These results indicate that mutations in Igbeta can cause agammaglobulinemia in man.
    Journal of Experimental Medicine 10/2007; 204(9):2047-51. · 13.21 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Congenital amegakaryocytic thrombocytopenia (CAMT) is a rare, autosomal recessive disorder induced by mutations of the gene coding for thrombopoietin (TPO) receptor (c-MPL). Patients initially present with isolated thrombocytopenia that subsequently progresses into pancytopenia. Although the mechanisms leading to aplasia are unknown, the age of onset has been reported to depend on the severity of the c-MPL functional defect. To improve our knowledge in this field, we studied clinical and biological features of five new patients. We diagnosed five CAMT patients, identified c-MPL mutations, including five novel alterations and investigated relationships between mutations and their clinical-biological consequences. In all cases, platelet c-MPL and bone marrow colonies were reduced, while serum TPO levels were elevated. We also documented that the percentage of bone marrow cells expressing tumor necrosis factor-a and interferon-g was increased during pancytopenia as compared to in controls, suggesting that, as in other bone marrow failure diseases, these inhibitory cytokines contributed to the pancytopenia. Contrary to previously published data, we found no evidence of correlations between different types of mutations and the clinical course. These results suggest that therapies, such as hematopoietic stem cell transplantation, which are potentially curative although associated with a risk of treatment-related mortality, should not be postponed even in those CAMT patients whose c-MPL mutations might predict residual activity of the TPO receptor.
    Haematologica 10/2007; 92(9):1186-93. · 5.94 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Autosomal-recessive agammaglobulinemia is a rare and heterogeneous disorder, characterized by early-onset infections, profound hypogammaglobulinemia of all immunoglobulin isotypes and absence of circulating B lymphocytes. To investigate the molecular basis of the disease, 23 patients with early-onset disease and no mutations in Bruton tyrosine kinase, the gene responsible for X-linked agammaglobulinemia, were selected and analyzed by direct sequencing of candidate genes. Two novel mutations in the mu heavy chain (muHC) gene (IGHM) were identified in three patients belonging to two unrelated families. A fourth patient carries a previously described G>A nucleotide substitution at the -1 position of an alternative splice site in IGHM; here, we demonstrate that this mutation is indeed responsible for aberrant splicing. Comparison of bone marrow cytofluorimetric profiles in two patients carrying different mutations in the IGHM gene suggests a genotype-phenotype correlation with the stage at which B-cell development is blocked. Several new single nucleotide polymorphisms (SNPs) both in the muHC and in the lambda5-like/VpreB-coding genes were identified. Two unrelated patients carry compound heterozygous variations in the VpreB1 gene that may be involved in disease ethiology.
    Genes and Immunity 06/2007; 8(4):325-33. · 3.68 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The 5T allele of the polyT tract located within intron 8 of the cystic fibrosis transmembrane conductance regulator (CFTR) gene is a variant that in trans with a severe CFTR mutation can result in normal phenotype, congenital bilateral absence of vas deferens (CBAVD), or mild cystic fibrosis. The 5T allele has been associated with the skipping of exon 9, a process that seems to be influenced by an adjacent 9-13TG tandem repeat. The 12- or 13TG repeats are often associated with an abnormal phenotype. We present here a single-step method for direct haplotyping of the TG repeats in 5T carriers. The method is based on a single-step PCR, using a fluorescently labeled forward primer and a reverse allele-specific primer matching the 5T allele. We validated the test in 30 control samples of known 5T-poly(TG) haplotype and then used this method to evaluate 57 clinical samples. The expected TG genotypes were obtained for all 5T control samples, and no nonspecific amplification of either the 7T or 9T alleles was detected. In our 5T-positive collection 9 of 9 (100%) CBAVD patients, 6 of 12 (50.0%) chronic pancreatitis patients, and 12 of 36 (33.3%) individuals undergoing assisted reproduction showed 5T-12TG haplotype. Our method is an accurate, specific, and simple tool to characterize the 5T poly(TG) haplotype. Our results confirm the high frequency of 5T-12TG in CBAVD patients and do not preclude a potential effect also in pancreatitis. This assay can be useful in assessment of the disease risk in 5T carriers.
    Clinical Chemistry 04/2007; 53(3):531-3. · 7.15 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Angelman Syndrome (AS), characterized by mental retardation, absence of speech, seizures and motor dysfunction, is caused by genetic defects leading to loss of expression of the maternal copy of the chromosome 15q11-13 imprinted region. Most cases are sporadic, being caused by de novo deletion of maternal chromosome 15q11-13 (75%) or by paternal uniparental disomy (3-4%). Familial cases can occur, due to mutations in the UBE3A gene or in the imprinting center. We describe the case of a pregnant woman having two nephews with AS caused by a UBE3A mutation; lack of communication within the family led the woman to be completely unaware of the risk of disease recurrence until 15 weeks of gestation. UBE3A genetic testing revealed she carried the familial mutation 892-893delCT. Prenatal diagnosis was performed on amniotic fluid and demonstrated that the fetus had inherited the mutation. The unexpected diagnosis and the subsequent termination of the pregnancy caused the woman to undergo acute psychological distress showing relevant psychopathological symptoms. Nevertheless, at 2-year follow-up, adverse consequences were minimized, and the couple was planning a new pregnancy. Factors affecting the psychological outcome of abortion and the role of psychological support in reducing the risk of long-term unfavorable consequences are discussed.
    Prenatal Diagnosis 01/2007; 26(12):1156-9. · 2.68 Impact Factor
  • Clinical Immunology - CLIN IMMUNOL. 01/2006; 119.
  • [Show abstract] [Hide abstract]
    ABSTRACT: BAFF receptor (BAFF-R/BR3/TNFRSF13C) is a recently identified molecule that specifically binds BLyS, a protein belonging to the tumor necrosis factor (TNF) family, and is involved in survival and maturation of B cells. Recent studies have demonstrated that mice defective in BAFF-R gene exhibit an altered profile of the B cell pool, a phenotype observed in BLyS knockout mice as well. These features suggest that mutations in this gene may result in humoral immunodeficiency. To test this hypothesis, we sequenced the BAFF-R gene in 48 patients with common variable immunodeficiency (CVID) along with 57 healthy controls. We have identified three novel variants present at the heterozygous state leading to amino acid substitutions, and have also confirmed the existence of a previously reported intronic variant. The hereby described novel variants were also present in healthy controls and in the healthy patients' parents. These variants do not affect the expression of BAFF-R neither at the mRNA nor at the protein level, suggesting that these variants represent novel polymorphic variants of the BAFF-R gene.
    Journal of Clinical Immunology 10/2005; 25(5):496-502. · 3.38 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: CD40 is a member of the tumor necrosis factor receptor family, which is expressed by a variety of cells including B cells, macrophages, dendritic cells, and other nonimmune cell types. CD40 activation is critical for B-cell proliferation, immunoglobulin (Ig)-isotype switching, and germinal center formation. In physiological conditions, the activation of CD40 occurs by binding to its natural ligand, CD154, which is expressed on activated T cells. The in vivo critical role of CD40-CD154 interaction on B-cell differentiation and isotype switching is provided by the discovery that mutations in either CD40 or CD154 gene cause the hyper IgM syndrome, termed HIGM3 or HIGM1, respectively, characterized by very low levels of serum IgG, IgA, and IgE, with normal or elevated IgM, associated with a defective germinal center formation. Originally considered humoral primary immunodeficiencies, the clinical features and the defect of T-cell priming, resulting from a defective T-B cell or dendritic cell interaction, is now considered as combined immunodeficiencies. In this article, we present a comprehensive overview of the clinical, genetic, and immunological features of patients with hyper IgM syndrome due to CD40 mutations.
    Immunological Reviews 03/2005; 203:48-66. · 12.16 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Mutations in activation-induced cytidine deaminase can cause an autosomal recessive form of hyper-IgM syndrome. We have examined a Tunisian family composed of six members: two healthy parents, their two healthy daughters and two affected sons. We found a homozygous transversion G to T in the two sons while heterozygosity for the mutation was found in all other family members. This alteration is localised in intron 2 at the +1 position resulting in defective splicing. Use of various intronic cryptic splice-sites led to expression of various aberrant mRNA species. Conclusion: This is a novel mutation found in the gene encoding for activation-induced cytidine deaminase in a Tunisian family with hyper-IgM type 2 syndrome. This alteration leads to the use of two cryptic splicing sites causing the formation of two different mRNA species.
    European Journal of Pediatrics 01/2005; 163(12):704-8. · 1.91 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: We have recently identified 2 patients with a rare autosomal recessive form of hyper IgM disease, known as HIGM3, caused by mutations in the CD40 gene. These patients had opportunistic infections observed on X-linked hyper IgM syndrome (HIGM), suggesting that the CD40-CD40 ligand interaction is important for promoting T-cell-mediated immunity. To evaluate whether innate immunity signals may substitute CD154 for inducing the maturation of dendritic cells (DCs), we analyzed monocyte-derived DCs in these patients. Monocyte-derived DCs of HIGM3 subjects on ex vivo stimulation with tumor necrosis factor-alpha (TNF-alpha) or lipopolysaccharide (LPS) combined with interferon-gamma (IFN-gamma) normally express all the markers of mature DCs, such as CD83 and DC-LAMP. However, cell surface levels of HLA-DR in mature DCs are reduced, as is costimulatory activity of these cells for allogeneic naive T cells. In addition, CD40-deficient DCs secrete lower amounts of interleukin-12 (IL-12) but larger quantities of IL-10 than control subjects. Finally, analysis of circulating plasmacytoid DCs demonstrates a normal percentage of this subset in CD40-deficient cells, but IFN-alpha secretion in response to herpes simplex virus 1 (HSV-1) infection is severely reduced in patients. These observations suggest that the severe impairment of DC maturation may contribute to the defect of T-cell-mediated immunity observed in HIGM3 patients.
    Blood 01/2004; 102(12):4099-106. · 9.78 Impact Factor
  • Simona Ferrari, Alessandro Plebani
    [Show abstract] [Hide abstract]
    ABSTRACT: The purpose of this review is to provide an update of the molecular bases of CD40-mediated signalling and of the human immune defects associated with abnormalities of this activation pathway. Over the last years considerable progress in the identification of intracellular molecules mediating CD40 signalling has been achieved. This review focuses on the recent work on the molecular mechanisms of CD40 signalling mediated by tumor necrosis factor receptor-associated factors, by transcription of the activation-induced cytidine deaminase gene and by activation of nuclear factor kappa B. Furthermore, the importance of CD40/CD40L interaction for the induction of adaptive immunity will be outlined in the context of primary immunodeficiencies due to defects of the genes involved in the CD40 signalling pathway, which are characterized by an immunological phenotype of hyper-IgM syndrome. The critical role of CD40/CD40L interactions in the development of various disease states has been fully appreciated, and further understanding of the molecular events involved in CD40 signalling may allow the identifications of candidate genes for other hyper-IgM syndromes. Molecular diagnosis will help to provide the most appropriate treatment and prognosis.
    Current Opinion in Allergy and Clinical Immunology 01/2003; 2(6):489-94. · 3.40 Impact Factor

Publication Stats

534 Citations
128.14 Total Impact Points

Institutions

  • 2005–2012
    • Policlinico S.Orsola-Malpighi
      Bolonia, Emilia-Romagna, Italy
  • 2009
    • Azienda Ospedaliero Universitaria Policlinico Modena
      Modène, Emilia-Romagna, Italy
  • 2001–2009
    • Università degli Studi di Brescia
      • "Istituto Angelo Nocivelli” Centre for Research into Molecular Medicine
      Brescia, Lombardy, Italy
    • King Faisal Specialist Hospital and Research Centre
      Ar Riyāḑ, Ar Riyāḑ, Saudi Arabia
  • 2007
    • University of Bologna
      Bolonia, Emilia-Romagna, Italy