Publications by authors named "Elena Gianchecchi"

27 Publications

  • Page 1 of 1

The enemy at home: leishmaniasis in the Mediterranean basin, Italy on the focus.

Expert Rev Anti Infect Ther 2020 06 17;18(6):563-577. Epub 2020 Apr 17.

VisMederi S.r.l, Siena, Italy.

: Leishmaniasis represents one of the most dangerous neglected tropical diseases. The parasite used to show a well-defined geographical distribution; however, during the last decade the parasite has spread into new areas. This change in the worldwide distribution of the parasite and in leishmaniasis epidemiology is the result of man's ill-considered interventions in the environment and of the consequent global warming.: The present review focuses on Leishmaniasis incidence in the Mediterranean basin and underlines the pressing need to raise awareness toward the real burden of the disease in the European region. The research was undertaken using Pubmed and including all studies up to January 2020.: Environmental and climatic transformations have allowed the shifting northward of sand fly European geographical distribution, affecting areas traditionally considered as -free, including Northern Italy, Germany, and even Belgium. The large-scale migration from the Middle East and Africa to Europe, and particularly to Italy for its central position in the Mediterranean basin, represents an additional and critical risk factor for the spread not only of leishmaniasis but also of other potentially life-threatening diseases. These factors highlight how the current epidemiological European scenario could drastically evolve in the next future.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/14787210.2020.1751611DOI Listing
June 2020

Insights on the Effects of Resveratrol and Some of Its Derivatives in Cancer and Autoimmunity: A Molecule with a Dual Activity.

Antioxidants (Basel) 2020 Jan 22;9(2). Epub 2020 Jan 22.

Infectivology and Clinical Trials Research Department, Children's Hospital Bambino Gesù, Viale San Paolo 15, 00146 Rome, Italy.

In recent years, the interest in natural compounds exerting immunoregulatory effects has enormously increased. Among these, the polyphenol resveratrol, found in a variety of foods and beverages, including red grapes and red wine, has been demonstrated to exert both in vitro and in vivo biological activities. More specifically, it has antiaging, cardioprotective, antioxidant, immunomodulatory, anti-inflammatory and chemopreventive activities. Due to its anti-proliferative, pro-apoptotic and immunoregulatory effects, resveratrol has gained substantial attention for the treatment of cancer or autoimmunity, which represent frequently diagnosed diseases with important consequences for the health of the patients affected. The aim of the present review is to focus on the role of resveratrol in the modulation of cancer as well as of several organ-specific or systemic autoimmune diseases, including autoimmune hepatitis, type 1 diabetes mellitus, inflammatory bowel disease, rheumatoid arthritis, systemic lupus erythematosus and multiple sclerosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/antiox9020091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7070243PMC
January 2020

How to assess the effectiveness of nasal influenza vaccines? Role and measurement of sIgA in mucosal secretions.

Influenza Other Respir Viruses 2019 09 21;13(5):429-437. Epub 2019 Jun 21.

VisMederi Srl, Siena, Italy.

Secretory IgAs (sIgA) constitute the principal isotype of antibodies present in nasal and mucosal secretions. They are secreted by plasma cells adjacent to the mucosal epithelial cells, the site where infection occurs, and are the main humoral mediator of mucosal immunity. Mucosally delivered vaccines, such as live attenuated influenza vaccine (LAIV), are able to mimic natural infection without causing disease or virus transmission and mainly elicit a local immune response. The measurement of sIgA concentrations in nasal swab/wash and saliva samples is therefore a valuable tool for evaluating their role in the effectiveness of such vaccines. Here, we describe two standardized assays (enzyme-linked immunosorbent assay and microneutralization) available for the quantification of sIgA and discuss the advantages and limitations of their use.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/irv.12664DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6692539PMC
September 2019

Recent Advances on Microbiota Involvement in the Pathogenesis of Autoimmunity.

Int J Mol Sci 2019 Jan 11;20(2). Epub 2019 Jan 11.

Infectivology and Clinical Trials Research Department, Children's Hospital Bambino Gesù, Viale San Paolo 15, 00146 Rome, Italy.

Autoimmune disorders derive from genetic, stochastic, and environmental factors that all together interact in genetically predisposed individuals. The impact of an imbalanced gut microbiome in the pathogenesis of autoimmunity has been suggested by an increasing amount of experimental evidence, both in animal models and humans. Several physiological mechanisms, including the establishment of immune homeostasis, are influenced by commensal microbiota in the gut. An altered microbiota composition produces effects in the gut immune system, including defective tolerance to food antigens, intestinal inflammation, and enhanced gut permeability. In particular, early findings reported differences in the intestinal microbiome of subjects affected by several autoimmune conditions, including prediabetes or overt disease compared to healthy individuals. The present review focuses on microbiota-host homeostasis, its alterations, factors that influence its composition, and putative involvement in the development of autoimmune disorders. In the light of the existing literature, future studies are necessary to clarify the role played by microbiota modifications in the processes that cause enhanced gut permeability and molecular mechanisms responsible for autoimmunity onset.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms20020283DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6359510PMC
January 2019

Inhibitory Receptors and Pathways of Lymphocytes: The Role of PD-1 in Treg Development and Their Involvement in Autoimmunity Onset and Cancer Progression.

Front Immunol 2018 17;9:2374. Epub 2018 Oct 17.

Infectivology and Clinical Trials Research Department, Children's Hospital Bambino Gesù, Rome, Italy.

Regulatory T (Treg) cells represent a subpopulation of suppressor CD4 T cells critically involved in the establishment of peripheral tolerance through the inhibition of effector T (Teff) cells and the suppression of the immune-mediated tissue destruction toward self-antigens. Treg generation, their suppressive properties and also Treg-Teff cell interactions could be modulated at least in part by programmed cell death-1 (PD-1) expression on their surface and through binding between PD-1 and programmed cell death ligand-1 (PD-L1). Defects involving PD-1 and Tregs can lead to the development of pathological conditions, including autoimmune disorders or promote cancer progression by favoring tumor evasion from the host immune response. At the same time, PD-1 and Tregs could represent attractive targets for treatment, as demonstrated by the therapeutic blockade of PD-L1 applied for the management of different cancer conditions in humans. In the present Review, we focus specifically the role of PD-1/PD-L1 on Treg development and activity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2018.02374DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6199356PMC
October 2019

Type 1 Diabetes and Its Multi-Factorial Pathogenesis: The Putative Role of NK Cells.

Int J Mol Sci 2018 Mar 10;19(3). Epub 2018 Mar 10.

Type 1 Diabetes Centre, Infectivology and Clinical Trials Research Department, Children's Hospital Bambino Gesù, Viale San Paolo 15, 00146 Rome, Italy.

Type 1 diabetes (T1D) affects millions of people worldwide and is the prevalent form of all pediatric diabetes diagnoses. T1D is recognized to have an autoimmune etiology, since failure in specific self-tolerance mechanisms triggers immune reactions towards self-antigens and causes disease onset. Among all the different immunocytes involved in T1D etiopathogenesis, a relevant role of natural killer cells (NKs) is currently emerging. NKs represent the interface between innate and adaptive immunity; they intervene in the defense against infections and present, at the same time, typical features of the adaptive immune cells, such as expansion and generation of memory cells. Several recent studies, performed both in animal models and in human diabetic patients, revealed aberrations in NK cell frequency and functionality in the peripheral blood and in damaged tissues, suggesting their possible redirection towards affected tissues. NKs oscillate from a quiescent to an activated state through a delicate balance of activating and inhibitory signals transduced via surface receptors. Further accurate investigations are needed to elucidate the exact role of NKs in T1D, in order to develop novel immune-based therapies able to reduce the disease risk or delay its onset.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms19030794DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5877655PMC
March 2018

Immunogenicity and Safety of the New Inactivated Quadrivalent Influenza Vaccine Vaxigrip Tetra: Preliminary Results in Children ≥6 Months and Older Adults.

Vaccines (Basel) 2018 Mar 8;6(1). Epub 2018 Mar 8.

VisMederi srl, Strada del Petriccio e Belriguardo, 35, 53100 Siena, Italy.

Since the mid-1980s, two lineages of influenza B viruses have been distinguished. These can co-circulate, limiting the protection provided by inactivated trivalent influenza vaccines (TIVs). This has prompted efforts to formulate quadrivalent influenza vaccines (QIVs), to enhance protection against circulating influenza B viruses. This review describes the results obtained from seven phase III clinical trials evaluating the immunogenicity, safety, and lot-to-lot consistency of a new quadrivalent split-virion influenza vaccine (Vaxigrip Tetra) formulated by adding a second B strain to the already licensed TIV. Since Vaxigrip Tetra was developed by means of a manufacturing process strictly related to that used for TIV, the data on the safety profile of TIV are considered supportive of that of Vaxigrip Tetra. The safety and immunogenicity of Vaxigrip Tetra were similar to those of the corresponding licensed TIV. Moreover, the new vaccine elicits a superior immune response towards the additional strain, without affecting immunogenicity towards the other three strains. Vaxigrip Tetra is well tolerated, has aroused no safety concerns, and is recommended for the active immunization of individuals aged ≥6 months. In addition, preliminary data confirm its immunogenicity and safety even in children aged 6-35 months and its immunogenicity in older subjects (aged 66-80 years).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/vaccines6010014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5874655PMC
March 2018

Influenza vaccines: Evaluation of the safety profile.

Hum Vaccin Immunother 2018 03 30;14(3):657-670. Epub 2018 Jan 30.

a Department of Molecular and Developmental Medicine , University of Siena , Siena , Italy.

The safety of vaccines is a critical factor in maintaining public trust in national vaccination programs. Vaccines are recommended for children, adults and elderly subjects and have to meet higher safety standards, since they are administered to healthy subjects, mainly healthy children. Although vaccines are strictly monitored before authorization, the possibility of adverse events and/or rare adverse events cannot be totally eliminated. Two main types of influenza vaccines are currently available: parenteral inactivated influenza vaccines and intranasal live attenuated vaccines. Both display a good safety profile in adults and children. However, they can cause adverse events and/or rare adverse events, some of which are more prevalent in children, while others with a higher prevalence in adults. The aim of this review is to provide an overview of influenza vaccine safety according to target groups, vaccine types and production methods.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/21645515.2017.1423153DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5861790PMC
March 2018

Identification of GAD65 AA 114-122 reactive 'memory-like' NK cells in newly diagnosed Type 1 diabetic patients by HLA-class I pentamers.

PLoS One 2017 13;12(12):e0189615. Epub 2017 Dec 13.

Type 1 Diabetes Centre, Infectivology and Clinical Trials Research Department, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.

Type 1 diabetes is an autoimmune disease, in which pancreatic β cells are destroyed by autoreactive T cells in genetically predisposed individuals. Serum beta cell autoantibody specificities have represented the mainstay for classifying diabetes as autoimmune-mediated and for stratifying risk in first-degree relatives. In recent years, approaches were attempted to solve the difficult issue of detecting rare antigen-specific autoreactive T cells and their significance to etiopathogenesis such as the use of the MHC multimer technology. This tool allowed the specific detection of increased percentages of GAD65 autoreactive T cells by means of HLA A*02:01 GAD65 AA 114-122 pentamers in newly diagnosed diabetics. Here we provide evidence that GAD65 AA 114-122 pentamers can depict a GAD65 AA114-122 peptide expandable population of functionally and phenotypically skewed, preliminary characterized CD3-CD8dullCD56+ 'memory-like' NK cells in PBMC of newly diagnosed diabetics. Our data suggest that the NK cell subset could bind the HLA class I GAD65 AA 114-122 pentamer through ILT2 inhibitory receptor. CD107a expression revealed increased degranulation of CD3-CD8dullCD56+ NK cells in GAD65 AA 114-122 and FLU peptide expanded peripheral blood mononuclear cells of diabetics following GAD65 AA 114-122 peptide HLA A*02:01 presentation in respect to the unpulsed condition. CD107a expression was enriched in ILT2 positive NK cells. As opposite to basal conditions where similar percentages of CD3-CD56+ILT2+ cells were detected in diabetics and controls, CD3-CD56+CD107a+ and CD3-CD56+ILT2+CD107a+ cells were significantly increased in T1D PBMC either GAD65 AA 114-122 or FLU peptides stimulated after co-culture with GAD65 AA 114-122 pulsed APCs. As control, healthy donor NK cells showed similar degranulation against both GAD65 AA 114-122 pulsed and unpulsed APCs. The pathogenetic significance of the CD3-CD8dullCD56+ 'memory-like NK cell subset' with increased response upon secondary challenge in diabetics remains to be elucidated.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0189615PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5728516PMC
January 2018

NK cells in autoimmune diseases: Linking innate and adaptive immune responses.

Autoimmun Rev 2018 Feb 26;17(2):142-154. Epub 2017 Nov 26.

Type 1 Diabetes Centre, Infectivology and Clinical Trials Research Department, Children's Hospital Bambino Gesù, Rome, Italy. Electronic address:

The pathogenesis of autoimmunity remains to be fully elucidated, although the contribution of genetic and environmental factors is generally recognized. Despite autoimmune conditions are principally due to T and B lymphocytes, NK cells also appear to play a role in the promotion and/or maintenance of altered adaptive immune responses or in peripheral tolerance mechanisms. Although NK cells are components of the innate immune system, they shows characteristics of the adaptive immune system, such as the expansion of pathogen-specific cells, the generation of long-lasting "memory" cells able to persist upon cognate antigen encounter, and the possibility to induce an increased secondary recall response to re-challenge. Human NK cells are generally identified as CD56CD3, conversely CD56CD3 cells represent a mixed population of NK-like T (NK T) cells and antigen-experienced T cells showing the up-regulation of several NK cell markers. CD56 constitute about 90% of NK cells in the peripheral blood, they are mature and involved in cytotoxicity responses; CD56 instead are more immature, mostly involved in cytokine production, having only a limited role in cytolytic responses, keen to leave the blood vessels as the principal population observed in lymph nodes. NK cells have been identified also in non-lymphoid tissues since, in pathologic conditions, they can quickly reach the target organs. A cross-talk between NK with dendritic cells and T cells is established throughout different receptor-ligand bindings. Several studies support the correlation between NK cell number and/or functional alterations, such as a defective cytotoxic activity and several autoimmune conditions. Among the different autoimmune pathologies and even within the same disease, NK cell function is significantly different either promoting or even protecting against the onset of the autoimmune condition. In this Review, we discuss recent literature supporting the role played by NK cells, as a bridge between innate and adaptive immunity, in the onset of autoimmune diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.autrev.2017.11.018DOI Listing
February 2018

An unwanted guest: Neisseria meningitidis - carriage, risk for invasive disease and the impact of vaccination with insight on Italy incidence.

Expert Rev Anti Infect Ther 2017 07 29;15(7):689-701. Epub 2017 May 29.

a VisMederi Srl , Siena , Italy.

Introduction: Invasive Meningococcal Disease (IMD) represents a potentially life-threatening condition caused by Neisseria meningitidis. The disease is characterized by a case fatality rate of 5-10% whereas serious clinical sequelae can develop in survivors within 12-24 h from the first symptoms. However, IMD infection only occurs rarely, in fact, most of the interactions established between N. meningitidis and the host are harmless, and an estimated 10% of the population asymptomatically carries the bacterium in the nasopharynx. Meningococcal carriage represents a critical condition for IMD onset since it represents the first step for disease transmission. Furthermore, high levels of carriage can promote genetic recombination among different N. meningitidis strains potentially leading to the development of new pathogenic variants. Areas covered: The present review discusses N. meningitidis carriage, factors able to influence meningococcal carriage and disease and the effect of vaccinations on both conditions, with a particular focus on Italy. Expert commentary: Data regarding the effect of different meningococcal vaccines on N. meningitidis carriage are available, whereas further studies are needed to investigate the positive impact of the two recently licensed vaccines 4CMenB and rLP2086 on meningococcal carriage.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/14787210.2017.1333422DOI Listing
July 2017

Use of short interfering RNA delivered by cationic liposomes to enable efficient down-regulation of PTPN22 gene in human T lymphocytes.

PLoS One 2017 24;12(4):e0175784. Epub 2017 Apr 24.

Type 1 Diabetes Centre, Infectivology and Clinical Trials Area, Children's Hospital Bambino Gesù, Rome, Italy.

Type 1 diabetes and thyroid disease are T cell-dependent autoimmune endocrinopathies. The standard substitutive administration of the deficient hormones does not halt the autoimmune process; therefore, development of immunotherapies aiming to preserve the residual hormonal cells, is of crucial importance. PTPN22 C1858T mutation encoding for the R620W lymphoid tyrosine phosphatase variant, plays a potential pathophysiological role in autoimmunity. The PTPN22 encoded protein Lyp is a negative regulator of T cell antigen receptor signaling; R620W variant, leading to a gain of function with paradoxical reduced T cell activation, may represent a valid therapeutic target. We aimed to develop novel wild type PTPN22 short interfering RNA duplexes (siRNA) and optimize their delivery into Jurkat T cells and PBMC by using liposomal carriers. Conformational stability, size and polydispersion of siRNA in lipoplexes was measured by CD spectroscopy and DLS. Lipoplexes internalization and toxicity evaluation was assessed by confocal microscopy and flow cytometry analysis. Their effect on Lyp expression was evaluated by means of Western Blot and confocal microscopy. Functional assays through engagement of TCR signaling were established to evaluate biological consequences of down-modulation. Both Jurkat T cells and PBMC were efficiently transfected by stable custom lipoplexes. Jurkat T cell morphology and proliferation was not affected. Lipoplexes incorporation was visualized in CD3+ but also in CD3- peripheral blood immunotypes without signs of toxicity, damage or apoptosis. Efficacy in affecting Lyp protein expression was demonstrated in both transfected Jurkat T cells and PBMC. Moreover, impairment of Lyp inhibitory activity was revealed by increase of IL-2 secretion in culture supernatants of PBMC following anti-CD3/CD28 T cell receptor-driven stimulation. The results of our study open the pathway to future trials for the treatment of autoimmune diseases based on the selective inhibition of variant PTPN22 allele using lipoplexes of siRNA antisense oligomers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0175784PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5402975PMC
September 2017

Comparative analysis of influenza A(H3N2) virus hemagglutinin specific IgG subclass and IgA responses in children and adults after influenza vaccination.

Vaccine 2017 01 24;35(1):191-198. Epub 2016 Oct 24.

The Influenza Centre, Department of Clinical Science, University of Bergen, Bergen, Norway; K.G. Jebsen Centre for Influenza Vaccines, Department of Clinical Science, University of Bergen, Bergen, Norway; Department of Research & Development, Haukeland University Hospital, Bergen, Norway. Electronic address:

Two different influenza vaccines are generally used in many countries; trivalent live attenuated influenza vaccine (LAIV3) and trivalent inactivated influenza vaccine (IIV3). Studies comparing the antibody response to IIV3 and LAIV3 commonly investigate the seroprotective response by hemagglutination-inhibition (HI) assay. However, there is limited data regarding comparative analysis of IgG subclass and IgA responses induced by LAIV3 and IIV3. Fifteen children <5years received 2 doses of LAIV3 while 14 children aged 10-17years received one dose. In addition, 15 adults were vaccinated with either intranasal LAIV3 or intramuscular IIV3. We analyzed the H3N2 humoral responses by HI assay and the hemagglutinin (HA) specific IgG1, IgG2, IgG3, IgG4 and IgA1 responses by ELISA. Furthermore, we investigated the avidity of induced IgG antibodies. Pre-existing seroprotective HI antibodies were present in adults (73%) previously vaccinated with IIV3. Vaccination resulted in a significant increase in HI titers in all groups, except LAIV3 vaccinated adults. Furthermore, a negative correlation between age and HI titers in LAIV3 vaccinated subjects was observed post-vaccination. LAIV3 in children and IIV3 in adults induced HA-specific IgG1, low IgG3 but no IgG2 or IgG4. Moreover, significant IgA1 responses were only induced in children. Interestingly, IIV3 and LAIV3 induced IgG antibodies with comparable and significantly augmented avidity post-vaccination in children and adults. Our results suggest that age and/or exposure history play a significant role in determining the antibody response. Clinical trial registry: ClinicalTrials.gov NCT01003288 and NCT01866540.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.vaccine.2016.10.024DOI Listing
January 2017

Altered B cell homeostasis and Toll-like receptor 9-driven response in patients affected by autoimmune polyglandular syndrome Type 1: Altered B cell phenotype and dysregulation of the B cell function in APECED patients.

Immunobiology 2017 02 9;222(2):372-383. Epub 2016 Sep 9.

Immuno-Infectivology and Clinical Trials Research Area, Children's Hospital Bambino Gesù, Rome, Italy. Electronic address:

APECED is a T-cell mediated disease with increased frequencies of CD8+ effector and reduction of FoxP3+ T regulatory cells. Antibodies against affected organs and neutralizing to cytokines are found in the peripheral blood. The contribution of B cells to multiorgan autoimmunity in Aire-/- mice was reported opening perspectives on the utility of anti-B cell therapy. We aimed to analyse the B cell phenotype of APECED patients compared to age-matched controls. FACS analysis was conducted on PBMC in basal conditions and following CpG stimulation. Total B and switched memory (SM) B cells were reduced while IgM memory were increased in patients. In those having more than 15 years from the first clinical manifestation the defect included also mature and transitional B cells; total memory B cells were increased, while SM were unaffected. In patients with shorter disease duration, total B cells were unaltered while SM and IgM memory behaved as in the total group. A defective B cell proliferation was detected after 4day-stimulation. In conclusion APECED patients show, in addition to a significant alteration of the B cell phenotype, a dysregulation of the B cell function involving peripheral innate immune mechanisms particularly those with longer disease duration.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.imbio.2016.09.001DOI Listing
February 2017

On the pathogenesis of insulin-dependent diabetes mellitus: the role of microbiota.

Immunol Res 2017 02;65(1):242-256

Infectivology and Clinical Trials Area, Bambino Gesù Children's Hospital, IRCCS, Viale S. Paolo 15, 00146, Rome, Italy.

Type 1 diabetes (T1D) is an autoimmune disorder characterized by the selective destruction of insulin-producing β cells as result of a complex interplay between genetic, stochastic and environmental factors in genetically susceptible individuals. An increasing amount of experimental data from animal models and humans has supported the role played by imbalanced gut microbiome in T1D pathogenesis. The commensal intestinal microbiota is fundamental for several physiologic mechanisms, including the establishment of immune homeostasis. Alterations in its composition have been correlated to changes in the gut immune system, including defective tolerance to food antigens, intestinal inflammation and enhanced gut permeability. Early findings reported differences in the intestinal microbiome of subjects affected by prediabetes or overt disease compared to healthy individuals. The present review focuses on microbiota-host homeostasis, its alterations, factors that influence microbiome composition and discusses their putative correlation with T1D development. Further studies are necessary to clarify the role played by microbiota modifications in the processes that cause enhanced permeability and the autoimmune mechanisms responsible for T1D onset.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12026-016-8832-8DOI Listing
February 2017

N. meningitidis and TLR Polymorphisms: A Fascinating Immunomodulatory Network.

Vaccines (Basel) 2016 May 27;4(2). Epub 2016 May 27.

Strada del Petriccio e Belriguardo, 53100 Siena, Italy.

N. meningitidis infections represent a global health problem that can lead to the development of serious permanent sequelae. Although the use of antibiotics and prevention via vaccination have reduced the incidence of meningococcal disease, our understanding regarding N. meningitidis pathogenesis is still limited, especially of those mechanisms responsible for IMD and fulminant or deadly septic shock. These severe clinical presentations occur in a limited number of subjects, whereas about 10% of healthy individuals are estimated to carry the bacteria as a commensal. Since TLR activation is involved in the defense against N. meningitidis, several studies have highlighted the association between host TLR SNPs and a higher susceptibility and severity of N. meningitidis infections. Moreover, TLR SNPs induced variations in immunological responses and in their persistence upon vaccination against meningococcal disease. In the absence of mass vaccination programs, the early identification of risk factors for meningococcal disease would be recommended in order to start immunization strategies and antibiotic treatment in those subjects carrying the risk variants. In addition, it could allow us to identify individuals with a higher risk for severe disease and sequelae in order to develop a personalized healthcare of high-risk subjects based on their genomic profile. In this review, we have illustrated important preliminary correlations between TLR variants and meningococcal susceptibility/severity and with vaccine-induced immune responses.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/vaccines4020020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4931637PMC
May 2016

Fighting Neisseria meningitidis: past and current vaccination strategies.

Expert Rev Vaccines 2016 11 27;15(11):1393-1407. Epub 2016 May 27.

a VisMederi Srl , Siena , Italy.

Introduction: Neisseria meningitidis infections represent a serious health problem that can lead to invasive meningococcal disease (IMD), a life-threatening condition associated with significant morbidity and mortality. IMD could however be preventable via vaccination. During the past five decades, vaccines against N. meningitidis capsular groups A, C, W and Y were introduced into the market. Recently, group B vaccines based on N. meninigitidis recombinant antigens and outer membrane vesicles have been developed and novel vaccine candidates are under evaluation. Areas covered: In this review we discuss the main meningococcal vaccines available, with focus on immunogenicity data, vaccination impact on disease burden and persistence of vaccine-induced immune response. Preliminary results on new vaccine formulations, potentially able to provide multi-group coverage, are also reported. Expert commentary: Continuous surveillance and optimization of national immunization programs are required in order not only to promptly fight future outbreaks but also to identify possible changes in N. meningitidis epidemiology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/14760584.2016.1187068DOI Listing
November 2016

Neisseria meningitidis infection: who, when and where?

Expert Rev Anti Infect Ther 2015 18;13(10):1249-63. Epub 2015 Jul 18.

a 1 VisMederi Srl, via Fiorentina 1, Siena 53100, Italy.

Neisseria meningitidis is a Gram-negative β-proteobacterium responsible for an endemic worldwide infection. The epidemiology and serogroup distribution can change very quickly. The incidence of meningitis infection varies from very rare to more than 1000 cases per 100,000 of the population yearly. The carriage of N. meningitidis, which represents an exclusive human commensal, is asymptomatic, but in rare cases bacteria proliferate in the CNS and rapidly lead to the death of the affected subjects. Host genetic factors, such as single nucleotide polymorphisms, can promote meningococcal disease, being able to influence the individual predisposition to the pathology. Although a reduction in meningococcal disease has been observed in Europe, a continuous surveillance is necessary to control any possible outbreaks of new hypervirulent clones into populations that could modify the epidemiology of meningococcal infections and the clinical spectrum of affected subjects.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1586/14787210.2015.1070096DOI Listing
June 2016

Gene/environment interactions in the pathogenesis of autoimmunity: new insights on the role of Toll-like receptors.

Autoimmun Rev 2015 Nov 13;14(11):971-83. Epub 2015 Jul 13.

Immunology and Pharmacotherapy Area, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy. Electronic address:

Autoimmune disorders are increasing worldwide. Although their pathogenesis has not been elucidated yet, a complex interaction of genetic and environmental factors is involved in their onset. Toll-like receptors (TLRs) represent a family of pattern recognition receptors involved in the recognition and in the defense of the host from invading microorganisms. They sense a wide range of pathogen associated molecular patterns (PAMPs) deriving from metabolic pathways selective of bacterial, viral, fungal and protozoan microorganisms. TLR activation plays a critical role in the activation of the downstream signaling pathway by interacting and recruiting several adaptor molecules. Although TLRs are involved in the protection of the host, several studies suggest that, in certain conditions, they play a critical role in the pathogenesis of autoimmune diseases. We review the most recent advances showing a correlation between some single nucleotide polymorphisms or copy number variations in TLR genes or in adaptor molecules involved in TLR signaling and the onset of several autoimmune conditions, such as Type I diabetes, autoimmune polyendocrinopathy candidiasis-ectodermal dystrophy, rheumatoid arthritis, systemic lupus erythematosus and systemic sclerosis. In light of the foregoing we finally propose that molecules involved in TLR pathway may represent the targets for novel therapeutic treatments in order to stop autoimmune processes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.autrev.2015.07.006DOI Listing
November 2015

Altered B cell homeostasis and toll-like receptor 9-driven response in type 1 diabetes carriers of the C1858T PTPN22 allelic variant: implications in the disease pathogenesis.

PLoS One 2014 21;9(10):e110755. Epub 2014 Oct 21.

Autoimmunity Laboratory, Immunology and Pharmacotherapy Area, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.

Type 1 diabetes is an autoimmune disease caused by the destruction of pancreatic beta cells by autoreactive T cells. Among the genetic variants associated with type 1 diabetes, the C1858T (Lyp) polymorphism of the protein tyrosine phosphatase non-receptor type 22 (PTPN22) gene alters the function of T cells but also of B cells in innate and adaptive immunity. The Lyp variant was shown to diminish interferon production and responses upon Toll-like receptor stimulation in macrophages and dendritic cells, possibly leading to uncontrolled infections as triggers of the diabetogenic process. The aim of this study was to unravel the yet uncharacterized effects that the variant could exert on the immune and autoimmune responses, particularly regarding the B cell phenotype, in the peripheral blood lymphocytes of diabetic patients and healthy controls in basal conditions and after unmethylated bacterial DNA CpG stimulation. The presence of the Lyp variant resulted in a significant increase in the percentage of transitional B cells in C/T carriers patients and controls compared to C/C patients and controls, in C/T carrier patients compared to C/C controls and in C/T carrier patients compared to C/C patients. A significant reduction in the memory B cells was also observed in the presence of the risk variant. After four days of CpG stimulation, there was a significant increase in the abundance of IgM+ memory B cells in C/T carrier diabetics than in C/C subjects and in the groups of C/T carrier individuals than in C/C individuals. IgM- memory B cells tended to differentiate more precociously into plasma cells than IgM+ memory B cells in heterozygous C/T subjects compared to the C/C subjects. The increased Toll-like receptor response that led to expanded T cell-independent IgM+ memory B cells should be further investigated to determine the putative contribution of innate immune responses in the disease pathogenesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0110755PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4205012PMC
December 2015

Recent insights on the putative role of autophagy in autoimmune diseases.

Autoimmun Rev 2014 Mar 1;13(3):231-41. Epub 2013 Nov 1.

Autoimmunity Laboratory, Immunology Area, Bambino Gesù Children's Hospital IRCCS, Rome, Italy. Electronic address:

The incidence of autoimmune pathologies is increasing worldwide. This has stimulated interest on their etiopathogenesis, caused by a complex interaction of genetic and environmental factors. With the advent of genome-wide linkage, candidate gene and genome wide association studies, risk polymorphisms in autophagy-related genes were discovered in several autoimmune conditions suggesting the possible contribution of autophagy to their etiopathogenesis. Autophagy represents the principal catabolic process mediated by lysosomes used by eukaryotic cells and is strictly regulated by proteins belonging to the Atg family. The function of autophagy has been well characterized in various tissues and systems, but its role in the regulation of innate and adaptive immune systems has been only recently discovered. It plays a fundamental role in the modulation of thymocyte selection and in the generation of T lymphocyte repertoire by participating in the intracellular antigen presentation on MHC class-II molecules by thymic epithelial cells. Furthermore, the generation of mice with knockout for specific autophagy-related genes induced several immunological alterations, including defects in B and T cell compartments and in T cell activation. In this review we report recent evidence on the role of autophagy in autoimmunity and discuss its relevance to the pathogenesis of these diseases. We finally highlight that future research may disclose potential new therapeutic targets for the treatment of this category of disorders by modulating the autophagic pathway.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.autrev.2013.10.007DOI Listing
March 2014

The purinergic P2×7 receptor is expressed on monocytes in Behçet's disease and is modulated by TNF-α.

Eur J Immunol 2014 Jan 24;44(1):227-38. Epub 2013 Oct 24.

Department of Medical Sciences, Surgery and Neurosciences, University of Siena, Siena, Italy.

The P2×7 receptor (P2×7r) is expressed in innate immune cells (e.g. monocyte/macrophages), playing a key role in IL-1β release. Since innate immune activation and IL-1β release seem to be implicated in Behçet's disease (BD), a systemic immune-inflammatory disorder of unknown origin, we hypothesized that P2×7r is involved in the pathogenesis of the disease. Monocytes were isolated from 18 BD patients and 17 healthy matched controls. In BD monocytes, an increased P2×7r expression and Ca(2+) permeability induced by the selective P2×7r agonist 2'-3'-O-(4-benzoylbenzoyl)ATP (BzATP) was observed. Moreover, IL-1β release from LPS-primed monocytes stimulated with BzATP was markedly higher in BD patients than in controls. TNF-α-incubated monocytes from healthy subjects almost reproduced the findings observed in BD patients, as demonstrated by the increase in P2×7r expression and BzATP-induced Ca(2+) intake. Our results provide evidence that in BD monocytes both the expression and function of the P2×7r are increased compared with healthy controls, as the possible result, at least in part, of a positive modulating effect of TNF-α on the receptor. These data indicate P2×7r as a new potential therapeutic target for the control of BD, further supporting the rationale for the use of anti-TNF-α drugs in the treatment of the disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/eji.201343353DOI Listing
January 2014

Recent insights into the role of the PD-1/PD-L1 pathway in immunological tolerance and autoimmunity.

Autoimmun Rev 2013 Sep 20;12(11):1091-100. Epub 2013 Jun 20.

Autoimmunity Laboratory, Immunology Area, Bambino Gesù Children's Hospital IRCCS, Rome, Italy.

Autoimmune diseases represent a heterogeneous group of conditions whose incidence is increasing worldwide. This has stimulated studies on their etiopathogenesis, derived from a complex interaction between genetic and environmental factors, in order to improve prevention and treatment of these disorders. The relevance of T regulatory cells and of the PD-1/PD-L1 pathway in controlling immune responses has been highlighted. Recent studies have in particular elucidated the putative role of the PD-1/PD-L1 pathway in regulating T cell responses and its effects on immunological tolerance and immune-mediated tissue damage. The role of the PD-1/PD-L1 pathway in autoimmunity has been already investigated in vivo in several experimental animal models including insulin-dependent diabetes mellitus, systemic lupus erythematosus, myocarditis, encephalomyelitis, rheumatoid arthritis and inflammatory bowel diseases. With the advent of candidate gene and genome-wide association studies, single nucleotide polymorphisms (SNPs) in PD-1 gene in humans have demonstrated relevant associations with a higher risk of developing autoimmune diseases in certain ethnic groups. In this review we present recent insights into the role of the PD-1/PD-L1 pathway in regulating lymphocyte activation, promotion of T regulatory cell development and function, breakdown of tolerance and development of autoimmunity. We finally speculate on the possible development of novel therapeutic treatments in human autoimmunity by modulating the PD-1/PD-L1 pathway.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.autrev.2013.05.003DOI Listing
September 2013

Analysis of the autoimmune regulator gene in patients with autoimmune non-APECED polyendocrinopathies.

Genomics 2013 Sep 30;102(3):163-8. Epub 2013 Apr 30.

Research Laboratories, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.

The pathogenesis of autoimmunity was derived from a complex interaction of genetic and environmental factors. Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy is a rare autosomal recessive disease caused by mutations in the autoimmune regulator (AIRE) gene. AIRE gene variants and, in particular, heterozygous loss-of-function mutations were also discovered in organ-specific autoimmune disorders, possibly contributing to their etiopathogenesis. It was suggested that even predisposition to develop certain autoimmune conditions may be derived from AIRE gene polymorphisms including S278R and intronic IVS9+6 G>A. In this study we unravel the hypothesis on whether AIRE gene variants may predispose individuals to associated autoimmune conditions in 41 Italian patients affected by non-APECED autoimmune polyendocrinopathies. We could not detect any heterozygous mutations of the AIRE gene. Although a trend of association was observed, heterozygous polymorphisms S278R and IVS9+6 G>A were detected in patients without statistically significant prevalence than in controls. Their putative contribution to autoimmune polyendocrinopathies and their predictive value in clinical strategies of disease development could be unravelled by analysing a larger sample of diseased patients and healthy individuals.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ygeno.2013.04.016DOI Listing
September 2013

The putative role of the C1858T polymorphism of protein tyrosine phosphatase PTPN22 gene in autoimmunity.

Autoimmun Rev 2013 May 20;12(7):717-25. Epub 2012 Dec 20.

Autoimmunity Laboratory, Immunology Area, Bambino Gesù Children's Hospital IRCCS, Rome, Italy.

Autoimmune diseases represent a heterogeneous group of conditions whose incidence is increasing worldwide. This has stimulated studies on their etiopathogenesis, derived from a complex interaction between genetic and environmental factors, in order to improve prevention and treatment of these diseases. An increasing amount of epidemiologic investigations has associated the presence of the C1858T polymorphism in the protein tyrosine phosphatase non-receptor type 22 (PTPN22) gene to the onset of several autoimmune diseases including insulin-dependent diabetes mellitus (Type 1 diabetes). PTPN22 encodes for the lymphoid tyrosine phosphatase Lyp. This belongs to non-receptor-type protein tyrosine phosphatases involved in lymphocyte activation and differentiation. In humans, Lyp may have a role in the negative regulation of T cell receptor signaling. The single nucleotide polymorphism C1858T encodes for a more active phosphatase Lyp R620W. This has the ability to induce a higher negative regulation of T cell receptor signaling. Thus, C1858T could play an important role at the level of thymocyte polarization and escape of autoreactive T lymphocytes, through the positive selection of otherwise negatively selected autoimmune T cells. In this review we discuss the physiological role exerted by the PTPN22 gene and its encoded Lyp product in lymphocyte processes. We highlight the pathogenic significance of the C1858T PTPN22 polymorphism in human autoimmunity with special reference to Type 1 diabetes. Recently the genetic variation in PTPN22 was shown to induce altered function of T and B-lymphocytes. In particular BCR signaling defects and alterations in the B cell compartment were reported in T1D patients. We finally speculate on the possible development of novel therapeutic treatments in human autoimmunity aiming to selectively target the variant Lyp protein in autoreactive T and B lymphocytes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.autrev.2012.12.003DOI Listing
May 2013

Synthetic cannabinoid ajulemic acid exerts potent antifibrotic effects in experimental models of systemic sclerosis.

Ann Rheum Dis 2012 Sep 4;71(9):1545-51. Epub 2012 Apr 4.

Correspondence to Estrella Garcia Gonzalez, Rheumatology Unit, Department of Clinical Medicine and Immunological Sciences, Siena 53100, Italy.

Background: Cannabinoids modulate fibrogenesis in scleroderma. Ajulemic acid (AjA) is a non-psychoactive synthetic analogue of tetrahydrocannabinol that can bind the peroxisome proliferator-activated receptor-γ (PPAR-γ). Recent evidence suggests a key role for PPAR-γ in fibrogenesis.

Objective: To determine whether AjA can modulate fibrogenesis in murine models of scleroderma.

Material And Methods: Bleomycin-induced experimental fibrosis was used to assess the antifibrotic effects of AjA in vivo. In addition, the efficacy of AjA in pre-established fibrosis was analysed in a modified model of bleomycin-induced dermal fibrosis and in mice overexpressing a constitutively active transforming growth factor β (TGFβ) receptor I. Skin fibrosis was evaluated by quantification of skin thickness and hydroxyproline content. As a marker of fibroblast activation, α-smooth muscle actin was examined. To study the direct effect of AjA in collagen neosynthesis, skin fibroblasts from patients with scleroderma were treated with increasing concentrations of AjA. Protein expression of PPAR-γ, and its endogenous ligand 15d-PGJ2, and TGFβ were assessed before and after AjA treatment.

Results: AjA significantly prevented experimental bleomycin-induced dermal fibrosis and modestly reduced its progression when started 3 weeks into the disease. AjA strongly reduced collagen neosynthesis by scleroderma fibroblasts in vitro, an action which was reversed completely by co-treatment with a selective PPAR-γ antagonist.

Conclusions: AjA prevents progression of fibrosis in vivo and inhibits fibrogenesis in vitro by stimulating PPAR-γ signalling. Since therapeutic doses of AjA are well tolerated in humans, it is suggested that AjA as an interesting molecule targeting fibrosis in patients with scleroderma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/annrheumdis-2011-200314DOI Listing
September 2012

Adenosine A2A receptor activation stimulates collagen production in sclerodermic dermal fibroblasts either directly and through a cross-talk with the cannabinoid system.

J Mol Med (Berl) 2012 Mar 28;90(3):331-42. Epub 2011 Oct 28.

Department of Clinical Medicine and Immunological Sciences, Division of Clinical Immunology, University of Siena, Siena, Italy.

Systemic sclerosis (SSc) is a connective tissue disease characterised by exaggerated collagen deposition in the skin and visceral organs. Adenosine A2A receptor stimulation (A2Ar) promotes dermal fibrosis, while the cannabinoid system modulates fibrogenesis in vitro and in animal models of SSc. Moreover, evidence in central nervous system suggests that A2A and cannabinoid (CB1) receptors may physically and functionally interact. On this basis, we investigated A2Ar expression and function in modulating collagen biosynthesis from SSc dermal fibroblasts and analysed the cross-talk with cannabinoid receptors. In sclerodermic cells, A2Ar expression (RT-PCR, Western blotting) was evaluated together with the effects of A2A agonists and/or antagonists on collagen biosynthesis (EIA, Western blotting). Putative physical and functional interactions between the A2A and cannabinoid receptors were respectively assessed by co-immuno-precipitation and co-incubating the cells with the unselective cannabinoid agonist WIN55,212-2, and the selective A2A antagonist ZM-241385. In SSc fibroblasts, (1) the A2Ar is overexpressed and its occupancy with the selective agonist CGS-21680 increases collagen production, myofibroblast trans-differentiation, and ERK-1/2 phosphorylation; (2) the A2Ar forms an heteromer with the cannabinoid CB1 receptor; and (3) unselective cannabinoid receptor stimulation with a per se ineffective dose of WIN55,212-2, results in a marked anti-fibrotic effect after A2Ar blockage. In conclusion, A2Ar stimulation induces a pro-fibrotic phenotype in SSc dermal fibroblasts, either directly, and indirectly, by activating the CB1 cannabinoid receptor. These findings increase our knowledge of the pathophysiology of sclerodermic fibrosis also further suggesting a new therapeutic approach to the disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00109-011-0824-5DOI Listing
March 2012