Papers by virginia gulino
Caratteristiche Cliniche e DI Funzionalita' Respiratoria DI Un Gruppo DI Pazienti Pediatrici Affetti Da Asma Con Prevalente Interessamento Delle Piccole Vie Aeree
Manifestazioni respiratorie e allergiche in pazienti con difetti congeniti del connettivo
Primary immune deficiencies unravel the molecular basis of immune response
Primary immune deficiencies (PID) represent inborn errors of immunity. Over the years, detailed a... more Primary immune deficiencies (PID) represent inborn errors of immunity. Over the years, detailed analysis of the clinical and laboratory features associated with these unique and rare disorders have shed light on the complex array of signals and processes that govern development and activation of the immune system. While the first examples of PID pertained to severe defects in lymphoid development, more recently a variety of gene defects have been identified in humans that do not compromize the ability to generate lymphocytes, but rather result in profound immune dysregulation. In many cases, identification of the molecular and cellular bases of PID has preceeded development of animal models by gene targeting. Finally, since the very first cases reported in humans, PID have also represented a unique tool to investigate the efficacy of novel therapeutic approaches (from molecular therapy to hematopoietic stem cell transplantation to somatic cells gene therapy), that have been applied ...
International Journal of Environmental Research and Public Health
More and more findings suggest that neurological disorders could have an immunopathological cause... more More and more findings suggest that neurological disorders could have an immunopathological cause. Thus, immune-targeted therapies are increasingly proposed in neurology (even if often controversial), as anakinra, inhibiting IL-1 for febrile inflammatory illnesses, and JAK inhibitors for anti-interferons treatment. Precision medicine in neurology could be fostered by a better understanding of the disease machinery, to develop a rational use of immuno-modulators in clinical trials. In this review, we focus on monogenic disorders with neurological hyper-inflammation/autoimmunity as simplified “models” to correlate immune pathology and targeted treatments. The study of monogenic models yields great advantages for the elucidation of the pathogenic mechanisms that can be reproduced in cellular/animal models, overcoming the limitations of biological samples to study. Moreover, monogenic disorders provide a unique tool to study the mechanisms of neuroinflammatory and autoimmune brain damag...
Hyper IgM syndromes
Current Opinion in Rheumatology, 2003
Hyper IgM syndromes
Current Opinion in Rheumatology, Aug 1, 2003
Tracking gene expression in primary immunodeficiencies
Curr Opin Allergy Clin Immuno, 2003
Epigenetic control of the immune system: a lesson from Kabuki syndrome
Immunologic Research, 2015
5P15.33-31 Deletion and Unilateral Open Lip Schizencephaly: �causal or Casual Association?
Primary immune deficiencies unravel the molecular basis of immune response
Reviews in clinical and experimental hematology, 2003
Primary immune deficiencies (PID) represent inborn errors of immunity. Over the years, detailed a... more Primary immune deficiencies (PID) represent inborn errors of immunity. Over the years, detailed analysis of the clinical and laboratory features associated with these unique and rare disorders have shed light on the complex array of signals and processes that govern development and activation of the immune system. While the first examples of PID pertained to severe defects in lymphoid development, more recently a variety of gene defects have been identified in humans that do not compromize the ability to generate lymphocytes, but rather result in profound immune dysregulation. In many cases, identification of the molecular and cellular bases of PID has preceeded development of animal models by gene targeting. Finally, since the very first cases reported in humans, PID have also represented a unique tool to investigate the efficacy of novel therapeutic approaches (from molecular therapy to hematopoietic stem cell transplantation to somatic cells gene therapy), that have been applied ...
Hyper IgM syndromes
Current Opinion in Rheumatology, 2003
Hyper IgM syndromes
Current Opinion in Rheumatology, 2003
Blood, 2004
word count:198; Total word count: 5715; Figures: 7.
PLOS One, 2009
WHIM (warts, hypogammaglobulinemia, infections, and myelokatexis) syndrome is a rare immunodefici... more WHIM (warts, hypogammaglobulinemia, infections, and myelokatexis) syndrome is a rare immunodeficiency syndrome linked to heterozygous mutations of the chemokine receptor CXCR4 resulting in truncations of its cytoplasmic tail. Leukocytes from patients with WHIM syndrome display impaired CXCR4 internalization and enhanced chemotaxis in response to its unique ligand SDF-1/CXCL12, which likely contribute to the clinical manifestations. Here, we investigated the biochemical mechanisms underlying CXCR4 deficiency in WHIM syndrome. We report that after ligand activation, WHIMassociated mutant CXCR4 receptors lacking the carboxy-terminal 19 residues internalize and activate Erk 1/2 slower than wild-type (WT) receptors, while utilizing the same trafficking endocytic pathway. Recruitment of b-Arrestin 2, but not b-Arrestin 1, to the active WHIM-mutant receptor is delayed compared to the WT CXCR4 receptor. In addition, while both kinases Grk3 and Grk6 bind to WT CXCR4 and are critical to its trafficking to the lysosomes, Grk6 fails to associate with the WHIM-mutant receptor whereas Grk3 associates normally. Since b-Arrestins and Grks play critical roles in phosphorylation and internalization of agonist-activated G protein-coupled receptors, these results provide a molecular basis for CXCR4 dysfunction in WHIM syndrome. Citation: McCormick PJ, Segarra M, Gasperini P, Gulino AV, Tosato G (2009) Impaired Recruitment of Grk6 and b-Arrestin2 Causes Delayed Internalization and Desensitization of a WHIM Syndrome-Associated CXCR4 Mutant Receptor. PLoS ONE 4(12): e8102.
Current Opinion in Allergy and Clinical Immunology, 2003
Extensive research on molecular genetics in recent decades has provided a wealth of information a... more Extensive research on molecular genetics in recent decades has provided a wealth of information about the mechanisms of primary immunodeficiency diseases. Microarray technology enables the survey of the expression of thousands of genes simultaneously. This review focuses on the commonly used arrays and initial applications in the study of primary immunodeficiency diseases. The application of this technology has been found to accelerate the discovery rate of gene expression disturbances in primary immunodeficiency diseases and provide potential molecular diagnostic tools.
Human Molecular Genetics, 2001
Human malignant infantile osteopetrosis (arOP; MIM 259700) is a genetically heterogenous autosoma... more Human malignant infantile osteopetrosis (arOP; MIM 259700) is a genetically heterogenous autosomal recessive disorder of bone metabolism, which, if untreated, has a fatal outcome. Our group, as well as others, have recently identified mutations in the ATP6i (TCIRG1) gene, encoding the a3 subunit of the vacuolar proton pump, which mediates the acidification of the bone/osteoclast interface, are responsible for a subset of this condition. By sequencing the ATP6i gene in arOP patients from 44 unrelated families with a worldwide distribution we have now established that ATP6i mutations are responsible for ∼50% of patients affected by this disease. The vast majority of these mutations (40 out of 42 alleles, including seven deletions, two insertions, 10 nonsense substitutions and 21 mutations in splice sites) are predicted to cause severe abnormalities in the protein product and are likely to represent null alleles. In addition, we have also analysed nine unrelated arOP patients from Costa Rica, where this disease is apparently much more frequent than elsewhere. All nine Costa Rican patients bore either or both of two missense mutations (G405R and R444L) in amino acid residues which are evolutionarily conserved from yeast to humans. The identification of ATP6i gene mutations in two families allowed us for the first time to perform prenatal diagnosis: both fetuses were predicted not to be affected and two healthy babies were born. This study contributes to the determination of genetic heterogeneity of arOP and allows further delineation of the other genetic defects causing this severe condition.
Current Allergy and Asthma Reports, 2005
The study of inherited immunodeficiencies has proven valuable in elucidating molecular signaling ... more The study of inherited immunodeficiencies has proven valuable in elucidating molecular signaling cascades underlying the developmental and functional regulation of the human immune system. The first example of a human immunologic disease caused by mutation of a chemokine receptor was provided by WHIM (warts, hypogammaglobulinemia, infections, and myelokathexis) syndrome, a rare, combined immunodeficiency featuring an unusual form of neutropenia. Subsequent studies following the initial description of mutations in the CXCR4 gene have revealed a striking concordance in the types of mutations observed, suggesting that impaired regulation of receptor signaling by truncation of the cytoplasmic tail domain is an essential aspect in disease pathogenesis. Biochemical studies have provided support for the model that impaired receptor downregulation leads to the characteristic immunologic and hematologic disturbances. Interestingly, these genetic studies have also identified phenocopies with the same clinical features but without mutation of CXCR4, suggesting that mutations in as yet uncharacterized downstream regulators of the receptor may be involved in a proportion of cases.
Current Opinion in Allergy and Clinical Immunology, 2003
Purpose of review WHIM syndrome (the association of warts, hypogammaglobulinemia, recurrent bacte... more Purpose of review WHIM syndrome (the association of warts, hypogammaglobulinemia, recurrent bacterial infections, and 'myelokathexis') is a rare congenital form of neutropenia associated with an unusual immune disorder involving hypogammaglonulinemia and abnormal susceptibility to warts. In this review, we describe the clinical, laboratory and genetic features of WHIM syndrome.
Clinical Immunology, 2006
Common variable immunodeficiency disease (CVID) is a primary immune disorder affecting B cells an... more Common variable immunodeficiency disease (CVID) is a primary immune disorder affecting B cells and characterized by hypogammaglobulinemia and recurrent infections. To elucidate the clinical and immunological heterogeneity of this condition, we have studied B and T cell subsets in 25 CVID patients. In eleven of them, we observed a remarkable relative expansion of a B cell subpopulation (CD19 hi /CD21 lo cells) characterized by the absence of CD23 and the reduced expression of the chemokine receptors CXCR5 and CCR7. Our analyses demonstrated in these patients that the expansion of CD19 hi /CD21 lo cells correlates with a selective decrease of circulating naRve and CD21 hi memory B lymphocytes. The same group of patients displayed a simultaneous severe reduction of naRve CD4+ T cells associated with decreased levels of T cell receptor excision circles. These observations suggest that a combined defect in generation of B and T subpopulations may account for the abnormal immunophenotype characterizing this subgroup of CVID patients. D a v a i l a b l e a t w w w . s c i e n c e d i r e c t . c o m w w w . e l s e v i e r . c o m / l o c a t e / y c l i m
Mediterranean Journal of Hematology and Infectious Diseases, 2009
Although the risk of acquisition of hepatitis B or hepatitis C virus th products has considerably... more Although the risk of acquisition of hepatitis B or hepatitis C virus th products has considerably reduced since the last decade, some infected patients are candidates to stem cell transplantation. Others may have no alternative than an infected donor. In all these cases, recipients of transplant are prone to short evolution of liver tests under chemotherapy before transplant may give useful information to anticipate on the risk of hepatitis reactivation after transplant, both for HBv and HCv. More than sixty percent of the patients who are HBsAg transplant, and 3% develop acute severe liver failure. Because both viral replication and immune reconstitution are the key factors for reactivation, it is crucial to closely follow liver function tests and viral load during the first months of transplant, and to pay a special attention in slowly tapering the immunosuppression in these patients. Lamivudine reduces HBv viremia, but favors the emergence of HBv polymerase gene mutants and should b individually discussed. Both in case of HBv or HCv hepatitis reactivation with ALT concomitantly to an increase in viral load at time of immune reconstitution, steroids should be given. In case there is no alternative than a HBv or HCv positive gen risk of viral hepatitis, including acute liver failure and late complications, should be balanced with the benefit of transplant in a given situation.
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Papers by virginia gulino