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

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0 Autoimmunity
0 Immunology
0 Immunotherapy
0 Innate Immunity
0 Type 1 Diabetes

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Type 1 Diabetes
Immunotherapy

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Case report
Published: 02 June 2021 in Italian Journal of Pediatrics
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Background Autoimmune polyendocrinopathy-candidiasis-ectodermal-dystrophy (APECED) or autoimmune polyglandular syndrome Type 1 is a rare autosomal recessive syndrome. The disorder is caused by mutations in the AIRE (AutoImmune Regulator) gene. According to the classic criteria, clinical diagnosis requires the presence of at least two of three main components: chronic mucocutaneous candidiasis, hypoparathyroidism and primary adrenal insufficiency. Furthermore, patients are often affected by other endocrine or non-endocrine associated autoimmune conditions. The enrichment of the non-classical triad seems to occur differently in different cohorts. Screenings of the population revealed that homozygous AIRE mutations c.769C > T, c.415C > T and c.254A > G have a founder effect in Finnish, Sardinian and Iranian Jew populations respectively. Case presentation We report here the clinical and genetic characteristics of two new Serbian APECED siblings, one male and one female, actual age of 27 and 24 respectively, born from non-consanguineous parents. Addison’s disease was diagnosed in the male at the age of 3.5 and hypoparathyroidism at the age of 4. The female developed hypoparathyroidism at 4 years of age. She presented diffuse alopecia, madarosis, onychomycosis, teeth enamel dysplasia. She further developed Addison’s disease at the age of 11 and Hashimoto’s thyroiditis at the age of 13.5. She had menarche at the age of 14 but developed autoimmune oophoritis and premature ovarian failure at the age of 16. A treatment with hydrocortisone, fludrocortisone and alfacalcidiol was established for both siblings; L-T4 (levo-thyroxine) for thyroid dysfunction and levonorgestrel and etinilestradiol for POF were also administered to the female. Genetic screening revealed a homozygous c.769C > T (R257X (p.Arg257X)) AIRE mutation. We additionally reviewed the literature on 11 previously published Serbian patients and evaluated the frequency of their main diseases in comparison to Finnish, Sardinian, Turkish, Indian and North/South American cohorts. Conclusion A founder effect was discovered for the R257X genotype detected in the DNA of 10 homozygous and 2 heterozygous patients. Of note, all Serbian APECED patients were affected by adrenal insufficiency and 10 out of 13 patients presented CMC.

ACS Style

Alessandra Fierabracci; MariaFrancesca Lanzillotta; Ivana Vorgučin; Alessia Palma; Dragan Katanić; Corrado Betterle. Report of two siblings with APECED in Serbia: is there a founder effect of c.769C>T AIRE genotype? Italian Journal of Pediatrics 2021, 47, 1 -8.

AMA Style

Alessandra Fierabracci, MariaFrancesca Lanzillotta, Ivana Vorgučin, Alessia Palma, Dragan Katanić, Corrado Betterle. Report of two siblings with APECED in Serbia: is there a founder effect of c.769C>T AIRE genotype? Italian Journal of Pediatrics. 2021; 47 (1):1-8.

Chicago/Turabian Style

Alessandra Fierabracci; MariaFrancesca Lanzillotta; Ivana Vorgučin; Alessia Palma; Dragan Katanić; Corrado Betterle. 2021. "Report of two siblings with APECED in Serbia: is there a founder effect of c.769C>T AIRE genotype?" Italian Journal of Pediatrics 47, no. 1: 1-8.

Review
Published: 28 May 2021 in International Journal of Molecular Sciences
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Siglecs are sialic acid-binding immunoglobulin-like lectins. Most Siglecs function as transmembrane receptors mainly expressed on blood cells in a cell type-specific manner. They recognize and bind sialic acids in specific linkages on glycoproteins and glycolipids. Since Sia is a self-molecule, Siglecs play a role in innate immune responses by distinguishing molecules as self or non-self. Increasing evidence supports the involvement of Siglecs in immune signaling representing immune checkpoints able to regulate immune responses in inflammatory diseases as well as cancer. Although further studies are necessary to fully understand the involvement of Siglecs in pathological conditions as well as their interactions with other immune regulators, the development of therapeutic approaches that exploit these molecules represents a tremendous opportunity for future treatments of several human diseases, as demonstrated by their application in several clinical trials. In the present review, we discuss the involvement of Siglecs in the regulation of immune responses, with particular focus on autoimmunity and cancer and the chance to target the sialic acid-Siglec axis as novel treatment strategy.

ACS Style

Elena Gianchecchi; Andrea Arena; Alessandra Fierabracci. Sialic Acid-Siglec Axis in Human Immune Regulation, Involvement in Autoimmunity and Cancer and Potential Therapeutic Treatments. International Journal of Molecular Sciences 2021, 22, 5774 .

AMA Style

Elena Gianchecchi, Andrea Arena, Alessandra Fierabracci. Sialic Acid-Siglec Axis in Human Immune Regulation, Involvement in Autoimmunity and Cancer and Potential Therapeutic Treatments. International Journal of Molecular Sciences. 2021; 22 (11):5774.

Chicago/Turabian Style

Elena Gianchecchi; Andrea Arena; Alessandra Fierabracci. 2021. "Sialic Acid-Siglec Axis in Human Immune Regulation, Involvement in Autoimmunity and Cancer and Potential Therapeutic Treatments." International Journal of Molecular Sciences 22, no. 11: 5774.

Immunology
Published: 19 February 2021 in Frontiers in Immunology
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Autoimmune diseases recognize a multifactorial pathogenesis, although the exact mechanism responsible for their onset remains to be fully elucidated. Over the past few years, the role of natural killer (NK) cells in shaping immune responses has been highlighted even though their involvement is profoundly linked to the subpopulation involved and to the site where such interaction takes place. The aberrant number and functionality of NK cells have been reported in several different autoimmune disorders. In the present review, we report the most recent findings regarding the involvement of NK cells in both systemic and organ-specific autoimmune diseases, including type 1 diabetes (T1D), primary biliary cholangitis (PBC), systemic sclerosis, systemic lupus erythematosus (SLE), primary Sjögren syndrome, rheumatoid arthritis, and multiple sclerosis. In T1D, innate inflammation induces NK cell activation, disrupting the Treg function. In addition, certain genetic variants identified as risk factors for T1D influenced the activation of NK cells promoting their cytotoxic activity. The role of NK cells has also been demonstrated in the pathogenesis of PBC mediating direct or indirect biliary epithelial cell destruction. NK cell frequency and number were enhanced in both the peripheral blood and the liver of patients and associated with increased NK cell cytotoxic activity and perforin expression levels. NK cells were also involved in the perpetuation of disease through autoreactive CD4 T cell activation in the presence of antigen-presenting cells. In systemic sclerosis (SSc), in addition to phenotypic abnormalities, patients presented a reduction in CD56hi NK-cells. Moreover, NK cells presented a deficient killing activity. The influence of the activating and inhibitory killer cell immunoglobulin-like receptors (KIRs) has been investigated in SSc and SLE susceptibility. Furthermore, autoantibodies to KIRs have been identified in different systemic autoimmune conditions. Because of its role in modulating the immune-mediated pathology, NK subpopulation could represent a potential marker for disease activity and target for therapeutic intervention.

ACS Style

Elena Gianchecchi; Domenico V. Delfino; Alessandra Fierabracci. Natural Killer Cells: Potential Biomarkers and Therapeutic Target in Autoimmune Diseases? Frontiers in Immunology 2021, 12, 1 .

AMA Style

Elena Gianchecchi, Domenico V. Delfino, Alessandra Fierabracci. Natural Killer Cells: Potential Biomarkers and Therapeutic Target in Autoimmune Diseases? Frontiers in Immunology. 2021; 12 ():1.

Chicago/Turabian Style

Elena Gianchecchi; Domenico V. Delfino; Alessandra Fierabracci. 2021. "Natural Killer Cells: Potential Biomarkers and Therapeutic Target in Autoimmune Diseases?" Frontiers in Immunology 12, no. : 1.

Review
Published: 07 August 2020 in Journal of Endocrinological Investigation
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Autoimmune polyendocrinopathy-candidiasis-ectodermal-dystrophy (APECED) or autoimmune polyglandular syndrome type 1 (APS-1) is a rare autosomal recessive genetic disease due to mutations in the AIRE (AutoImmune REgulator) gene. The clinical diagnosis is classically based on the presence of at least two of the three main components: chronic mucocutaneous candidiasis, hypoparathyroidism and primary adrenal insufficiency. Patients often suffer from other endocrine or non-endocrine autoimmune conditions throughout life. APECED etiopathogenesis is mediated by T lymphocytes. Autoantibodies against proteins of the affected organs are found in the serum of APECED patients as well as neutralizing antibodies against cytokines. We report here the clinical and genetic characteristics of 45 Indian APECED patients in comparison to Finnish, Sardinian, Turkish and North/South American cohorts from their published results. We also report a new case of APECED of Indian origin, a 2-year old child suffering from chronic mucocutaneous candidiasis since the age of 8 months, with confirmatory AIRE homozygous mutation c.274C > T (p.R92W). With the inherent limitations of a retrospective study, analysis of Indian APECED patients suggested that compared to classic criteria, application of Ferre/Lionakis criteria validated in North/South American patients could help in earlier diagnosis in 3 of 8 (37.5%) patients for whom adequate information for evaluation was available.

ACS Style

A. Fierabracci; A. Arena; F. Toto; N. Gallo; A. Puel; M. Migaud; M. Kumar; K. G. Chengappa; R. Gulati; V. S. Negi; C. Betterle. Autoimmune polyendocrine syndrome type 1 (APECED) in the Indian population: case report and review of a series of 45 patients. Journal of Endocrinological Investigation 2020, 44, 661 -677.

AMA Style

A. Fierabracci, A. Arena, F. Toto, N. Gallo, A. Puel, M. Migaud, M. Kumar, K. G. Chengappa, R. Gulati, V. S. Negi, C. Betterle. Autoimmune polyendocrine syndrome type 1 (APECED) in the Indian population: case report and review of a series of 45 patients. Journal of Endocrinological Investigation. 2020; 44 (4):661-677.

Chicago/Turabian Style

A. Fierabracci; A. Arena; F. Toto; N. Gallo; A. Puel; M. Migaud; M. Kumar; K. G. Chengappa; R. Gulati; V. S. Negi; C. Betterle. 2020. "Autoimmune polyendocrine syndrome type 1 (APECED) in the Indian population: case report and review of a series of 45 patients." Journal of Endocrinological Investigation 44, no. 4: 661-677.

Review
Published: 21 July 2020 in International Journal of Molecular Sciences
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Coronavirus 2 (CoV) Severe Acute Respiratory Syndrome (SARS-CoV2) is causing a highly infectious pandemic pneumonia. Coronaviruses are positive sense single-stranded RNA viruses that infect several animal species, causing symptoms that range from those similar to the common cold to severe respiratory syndrome. The Angiotensin Converting Enzyme 2 (ACE2) is the SARS-CoV2 functional receptor. Measures are currently undertaken worldwide to control the infection to avoid disruption of the social and economic equilibrium, especially in countries with poor healthcare resources. In a guarded optimistic view, we hope that the undertaken preventive and treatment measures will at least contribute to contain viral diffusion, attenuate activity, or even eliminate SARS-CoV2. In this review, we discuss emerging perspectives for prevention/treatment of COVID-19 infection. In addition to vaccines under development, passive immunization is an open opportunity since patients develop neutralizing antibodies. A full spectrum of potential drugs for COVID-19 infections could in turn affect virus binding or enzymatic activities involved in viral replication and transcription. Furthermore, clinical trials are currently evaluating the safety and efficacy of anti-inflammatory drugs, such as tocilizumab. Bioinformatics may allow characterization of specific CD8+ and CD4+ T cell responses; thus, CoV2 T cells’ frequency can be correlated with the disease severity and outcome. Combinatorial antibody phage display may be empowered to identify the immune repertoire of CoV2-specific neutralizing antibodies.

ACS Style

Alessandra Fierabracci; Andrea Arena; Paolo Rossi. COVID-19: A Review on Diagnosis, Treatment, and Prophylaxis. International Journal of Molecular Sciences 2020, 21, 5145 .

AMA Style

Alessandra Fierabracci, Andrea Arena, Paolo Rossi. COVID-19: A Review on Diagnosis, Treatment, and Prophylaxis. International Journal of Molecular Sciences. 2020; 21 (14):5145.

Chicago/Turabian Style

Alessandra Fierabracci; Andrea Arena; Paolo Rossi. 2020. "COVID-19: A Review on Diagnosis, Treatment, and Prophylaxis." International Journal of Molecular Sciences 21, no. 14: 5145.

Review
Published: 19 March 2020 in International Journal of Molecular Sciences
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Type 1 diabetes mellitus is a heterogeneous disorder characterized by destruction of pancreatic β cells, culminating in absolute insulin deficiency. The goals of Type 1 diabetes care, established by the Diabetes Control and Complications Trial (DCCT), are to achieve good glycemic control, to prevent hyperglycaemia (which is associated with long-term microvascular and macrovascular complications) and to avoid recurrent episodes of hypoglycaemia (which may have adverse effects on cognitive function). However, despite continuing optimization of insulin therapy regimes, the actual hormonal substitutive administration acts only to treat the symptoms without an effect on disease pathology and etiopathogenesis. In recent decades, a great deal of interest has been focused on prevention approaches in high-risk individuals, based on the hypothesis that a therapeutic intervention, if applied at the early stage of disease, might contribute to maintaining endogenous β cell function by preserving the residual β cell reservoir from autoimmune attack. This manuscript provides an overview of the most important immunotherapeutic interventions established so far for Type 1 diabetes treatment at different stages of disease that have reached an advanced stage of assessment.

ACS Style

Novella Rapini; Riccardo Schiaffini; Alessandra Fierabracci. Immunotherapy Strategies for the Prevention and Treatment of Distinct Stages of Type 1 Diabetes: An Overview. International Journal of Molecular Sciences 2020, 21, 2103 .

AMA Style

Novella Rapini, Riccardo Schiaffini, Alessandra Fierabracci. Immunotherapy Strategies for the Prevention and Treatment of Distinct Stages of Type 1 Diabetes: An Overview. International Journal of Molecular Sciences. 2020; 21 (6):2103.

Chicago/Turabian Style

Novella Rapini; Riccardo Schiaffini; Alessandra Fierabracci. 2020. "Immunotherapy Strategies for the Prevention and Treatment of Distinct Stages of Type 1 Diabetes: An Overview." International Journal of Molecular Sciences 21, no. 6: 2103.

Research article
Published: 29 January 2020 in PLOS ONE
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Various immunotherapies for the treatment of type 1 diabetes are currently under investigation. Some of these aim to rescue the remaining beta cells from autoimmune attack caused by the disease. Among the strategies employed, p53 has been envisaged as a possible target for immunomodulation. We studied the possible effect of p53 activation on Treg subsets and Treg/Teff balance in type 1 diabetes patients' PBMC. Upon p53 activation, we observed an increase in CD8+ Treg and activated CD8+ Teff whilst CD8+ Teff cells significantly decreased in healthy PBMC when stimulated with anti-CD3/CD28. No effect was detected on percentages of CD4+ Treg, while a reduction was seen in CD4+ Teff cells and an increase in activated CD4+ Teff cells. In patients' PBMC, upon p53 activation followed by 6 days of anti-CD3/CD28 stimulation, CD8+ Treg and activated CD8+ Teff were increased while CD8+ Teff were decreased. No differences were detected in the CD4+ counterparts. CD8+ Teff PD1+, CD8+ Teff PD1low were increased upon p53 activation in type 1 diabetics compared to controls while CD8+ Teff PD1high were increased in both groups. The same increased percentages were detected for CD4+ counterparts. CD4+ Treg PD1high cells were decreased in diabetics upon p53 activation at day 6 of anti-CD3/CD28 stimulation. In conclusion, a Teff dysregulation is observed upon p53 activation suggesting that molecules promoting p53 cannot be used for therapy in type 1 diabetics.

ACS Style

Marsha Pellegrino; Gianandrea Traversi; Andrea Arena; Marco Cappa; M. Manuela Rosado; Marco Andreani; Domenico V. Delfino; Fabiola Moretti; Alessandra Fierabracci. Effect of p53 activation through targeting MDM2/MDM4 heterodimer on T regulatory and effector cells in the peripheral blood of Type 1 diabetes patients. PLOS ONE 2020, 15, e0228296 .

AMA Style

Marsha Pellegrino, Gianandrea Traversi, Andrea Arena, Marco Cappa, M. Manuela Rosado, Marco Andreani, Domenico V. Delfino, Fabiola Moretti, Alessandra Fierabracci. Effect of p53 activation through targeting MDM2/MDM4 heterodimer on T regulatory and effector cells in the peripheral blood of Type 1 diabetes patients. PLOS ONE. 2020; 15 (1):e0228296.

Chicago/Turabian Style

Marsha Pellegrino; Gianandrea Traversi; Andrea Arena; Marco Cappa; M. Manuela Rosado; Marco Andreani; Domenico V. Delfino; Fabiola Moretti; Alessandra Fierabracci. 2020. "Effect of p53 activation through targeting MDM2/MDM4 heterodimer on T regulatory and effector cells in the peripheral blood of Type 1 diabetes patients." PLOS ONE 15, no. 1: e0228296.

Review
Published: 22 January 2020 in Antioxidants
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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.

ACS Style

Elena Gianchecchi; Alessandra Fierabracci. Insights on the Effects of Resveratrol and Some of Its Derivatives in Cancer and Autoimmunity: A Molecule with a Dual Activity. Antioxidants 2020, 9, 91 .

AMA Style

Elena Gianchecchi, Alessandra Fierabracci. Insights on the Effects of Resveratrol and Some of Its Derivatives in Cancer and Autoimmunity: A Molecule with a Dual Activity. Antioxidants. 2020; 9 (2):91.

Chicago/Turabian Style

Elena Gianchecchi; Alessandra Fierabracci. 2020. "Insights on the Effects of Resveratrol and Some of Its Derivatives in Cancer and Autoimmunity: A Molecule with a Dual Activity." Antioxidants 9, no. 2: 91.

Review
Published: 18 September 2019 in International Journal of Molecular Sciences
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Diabetic neuropathy is a serious complication of chronic hyperglycemia in diabetes patients. This complication can involve both peripheral sensorimotor and autonomic nervous system. The precise nature of injury to the peripheral nerves mediated by chronic hyperglycemia is unknown; however, several mechanisms have been proposed including polyol pathway activation, enhanced glycation of proteins and lipids, increased oxidative stress, and cytokine release in the site of injury. MicroRNAs (miRNAs) are small non-coding RNAs that mediate RNA interference by post-transcriptionally modulating gene expression and protein synthesis. Therefore, they have been implicated in several developmental, physiological, and pathophysiological processes where they modulate the expression of different proteins. Recently, miRNAs gained an increasing attention also for their role as diagnostic test in many diseases due to their stability in serum and their easy detection. Furthermore, recent studies suggest that miRNAs may be involved in diabetic neuropathy although their role in the onset and the development of this complication is not fully understood. In this review, we discuss the most recent literature providing evidence for miRNAs role in diabetic neuropathy opening new pathways to improve both early diagnosis and treatment of this complication.

ACS Style

Raffaele Simeoli; Alessandra Fierabracci. Insights into the Role of MicroRNAs in the Onset and Development of Diabetic Neuropathy. International Journal of Molecular Sciences 2019, 20, 4627 .

AMA Style

Raffaele Simeoli, Alessandra Fierabracci. Insights into the Role of MicroRNAs in the Onset and Development of Diabetic Neuropathy. International Journal of Molecular Sciences. 2019; 20 (18):4627.

Chicago/Turabian Style

Raffaele Simeoli; Alessandra Fierabracci. 2019. "Insights into the Role of MicroRNAs in the Onset and Development of Diabetic Neuropathy." International Journal of Molecular Sciences 20, no. 18: 4627.

Review
Published: 17 September 2019 in International Journal of Molecular Sciences
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Mesenchymal stem cells (MSCs) have regenerative, immunoregulatory properties and can be easily isolated and expanded in vitro. Despite being a powerful tool for clinical applications, they present limitations in terms of delivery, safety, and variability of therapeutic response. Interestingly, the MSC secretome composed by cytokines, chemokines, growth factors, proteins, and extracellular vesicles, could represent a valid alternative to their use. It is noteworthy that MSC-derived extracellular vesicles (MSC-EVs) have the same effect and could be advantageous compared to the parental cells because of their specific miRNAs load. MiRNAs could be useful both in diagnostic procedures such as “liquid biopsy” to identify early pathologies and in the therapeutic field. Not only are MSC-EVs’ preservation, transfer, and production easier, but their administration is also safer, hence some clinical trials are ongoing. However, much effort is required to improve the characterization of EVs to avoid artifacts and guarantee reproducibility of the studies.

ACS Style

Sharon Eleuteri; Alessandra Fierabracci. Insights into the Secretome of Mesenchymal Stem Cells and Its Potential Applications. International Journal of Molecular Sciences 2019, 20, 4597 .

AMA Style

Sharon Eleuteri, Alessandra Fierabracci. Insights into the Secretome of Mesenchymal Stem Cells and Its Potential Applications. International Journal of Molecular Sciences. 2019; 20 (18):4597.

Chicago/Turabian Style

Sharon Eleuteri; Alessandra Fierabracci. 2019. "Insights into the Secretome of Mesenchymal Stem Cells and Its Potential Applications." International Journal of Molecular Sciences 20, no. 18: 4597.

Journal article
Published: 29 August 2019 in Toxins
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Cladosporium species are endophytic fungi that grow on organic matter and are considered food contaminants. The anti-microbial and anti-tumor naphthoquinones fusarubin (FUS) and anhydrofusarubin (AFU) were isolated using column chromatography from a Cladosporium species residing inside Rauwolfia leaves. The impact of FUS and AFU on cell growth was assessed in acute myeloid leukemia (OCI-AML3) and other hematologic tumor cell lines (HL-60, U937, and Jurkat). Treatment with FUS or AFU reduced the number of OCI-AML3 cells as evaluated by a hemocytometer. Flow cytometry analyses showed that this effect was accompanied by diverse impairments in cell cycle progression. Specifically, FUS (20 or 10 μg/mL significantly decreased the percentage of cells in S phase and increased the percentage of cells in G2/M phase, whereas AFU increased the percentage of cells in G0/G1 phase (50 and 25 μg/mL) and decreased the percentage of cells in S (50 μg/mL) and G2/M (50 and 25 μg/mL) phases. Both substances significantly increased apoptosis at higher concentrations. The effects of FUS were more potent than those of AFU, with FUS up-regulating p21 expression in a p53-dependent manner, as detected by Western blot analyses, likely the consequence of decreased ERK phosphorylation and increased p38 expression (both of which increase p21 stability). FUS also decreased Akt phosphorylation and resulted in increased Fas ligand production and caspase-8/3-dependent apoptosis. These results suggest that FUS and AFU inhibit proliferation and increase apoptosis in cell lines derived from hematological cancers.

ACS Style

Sabrina Adorisio; Alessandra Fierabracci; Isabella Muscari; Anna Marina Liberati; Lorenza Cannarile; Trinh Thi Thuy; Tran Van Sung; Hossain Sohrab; Choudhury Mahmood Hasan; Emira Ayroldi; Carlo Riccardi; Abdul Mazid; Domenico V. Delfino. Fusarubin and Anhydrofusarubin Isolated from A Cladosporium Species Inhibit Cell Growth in Human Cancer Cell Lines. Toxins 2019, 11, 503 .

AMA Style

Sabrina Adorisio, Alessandra Fierabracci, Isabella Muscari, Anna Marina Liberati, Lorenza Cannarile, Trinh Thi Thuy, Tran Van Sung, Hossain Sohrab, Choudhury Mahmood Hasan, Emira Ayroldi, Carlo Riccardi, Abdul Mazid, Domenico V. Delfino. Fusarubin and Anhydrofusarubin Isolated from A Cladosporium Species Inhibit Cell Growth in Human Cancer Cell Lines. Toxins. 2019; 11 (9):503.

Chicago/Turabian Style

Sabrina Adorisio; Alessandra Fierabracci; Isabella Muscari; Anna Marina Liberati; Lorenza Cannarile; Trinh Thi Thuy; Tran Van Sung; Hossain Sohrab; Choudhury Mahmood Hasan; Emira Ayroldi; Carlo Riccardi; Abdul Mazid; Domenico V. Delfino. 2019. "Fusarubin and Anhydrofusarubin Isolated from A Cladosporium Species Inhibit Cell Growth in Human Cancer Cell Lines." Toxins 11, no. 9: 503.

Research article
Published: 16 January 2019 in PLOS ONE
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Type 1 diabetes is an autoimmune disease where autoreactive T lymphocytes destroy pancreatic beta cells. We previously reported a defect in CD4+ Tregs cell proliferation and reduced CD4+ Tregs PD-1 expression in patients. Another ‘memory-like’ regulatory subset, CD8+ Tregs, evaluated as CD8+CD25+FOXP3+, has recently raised interest for their effective suppressive activity. Different CD8+ T cell populations, their proliferation capacity and expression of PD-1 molecule were evaluated by flow-cytometer analysis in newly diagnosed, long-term Type 1 diabetes patients compared to healthy normal donors. Under basal conditions, CD8+ Tregs and CD8+ Teffs were seemingly represented among study groups while there was evidence of diminished expression of PD-1 in Teff subsets of long-term patients. After 3 days of PMA/ionomycin stimulation, patients CD8+ Tregs showed decreased percentage in respect to control group. CD8+ Teffs were instead increased in long-term diabetics versus controls. PD-1+CD8+ Tregs were represented at a much lower percentage in long-term diabetic patients, in respect to controls. Importantly, patients CD8+ Tregs and CD8+ Teffs presented a significant proliferation defect in respect to the control group. In conclusion, our study indicates that a defect of CD8+ Tregs is observed in diabetics. This subset could thus represent a novel target of immunotherapy in patients.

ACS Style

Marsha Pellegrino; Antonino Crinò; Manuela M. Rosado; Alessandra Fierabracci. Identification and functional characterization of CD8+ T regulatory cells in type 1 diabetes patients. PLOS ONE 2019, 14, e0210839 .

AMA Style

Marsha Pellegrino, Antonino Crinò, Manuela M. Rosado, Alessandra Fierabracci. Identification and functional characterization of CD8+ T regulatory cells in type 1 diabetes patients. PLOS ONE. 2019; 14 (1):e0210839.

Chicago/Turabian Style

Marsha Pellegrino; Antonino Crinò; Manuela M. Rosado; Alessandra Fierabracci. 2019. "Identification and functional characterization of CD8+ T regulatory cells in type 1 diabetes patients." PLOS ONE 14, no. 1: e0210839.

Review
Published: 11 January 2019 in International Journal of Molecular Sciences
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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.

ACS Style

Elena Gianchecchi; Alessandra Fierabracci. Recent Advances on Microbiota Involvement in the Pathogenesis of Autoimmunity. International Journal of Molecular Sciences 2019, 20, 283 .

AMA Style

Elena Gianchecchi, Alessandra Fierabracci. Recent Advances on Microbiota Involvement in the Pathogenesis of Autoimmunity. International Journal of Molecular Sciences. 2019; 20 (2):283.

Chicago/Turabian Style

Elena Gianchecchi; Alessandra Fierabracci. 2019. "Recent Advances on Microbiota Involvement in the Pathogenesis of Autoimmunity." International Journal of Molecular Sciences 20, no. 2: 283.

Journal article
Published: 12 November 2018 in Nanomedicine: Nanotechnology, Biology and Medicine
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In autoimmune diseases as Type 1 diabetes, the actual treatment that provides the missing hormones is not able, however, to interrupt the underlining immunological mechanism. Importantly, novel immunotherapies are exploited to protect and rescue the remaining hormone producing cells. Among probable targets of immunotherapy, the C1858T mutation in the PTPN22 gene, which encodes for the lymphoid tyrosine phosphatase (Lyp) variant R620W, reveals an autoimmunity related pathophysiological role. Our scope was to establish new C1858T PTPN22 siRNA duplexes delivered by liposomal carriers (lipoplexes) to patients PBMC. Following lipoplexes treatment, CD3+ and CD3− immunotypes were efficiently transfected; cell integrity and viability were preserved. Specific target mRNA down-modulation was observed. After T cell receptor stimulation, in lipoplexes-treated PBMC Lyp function was restored by increased release of IL-2 in cultures. Results set-up the stage for ultimate trials in the treatment of autoimmunity based on the specific inhibitory targeting of C1858T PTPN22 by lipoplexes.

ACS Style

Marsha Pellegrino; Francesca Ceccacci; Stefania Petrini; Anita Scipioni; Serena De Santis; Marco Cappa; Giovanna Mancini; Alessandra Fierabracci. Exploiting novel tailored immunotherapies of type 1 diabetes: Short interfering RNA delivered by cationic liposomes enables efficient down-regulation of variant PTPN22 gene in T lymphocytes. Nanomedicine: Nanotechnology, Biology and Medicine 2018, 18, 371 -379.

AMA Style

Marsha Pellegrino, Francesca Ceccacci, Stefania Petrini, Anita Scipioni, Serena De Santis, Marco Cappa, Giovanna Mancini, Alessandra Fierabracci. Exploiting novel tailored immunotherapies of type 1 diabetes: Short interfering RNA delivered by cationic liposomes enables efficient down-regulation of variant PTPN22 gene in T lymphocytes. Nanomedicine: Nanotechnology, Biology and Medicine. 2018; 18 ():371-379.

Chicago/Turabian Style

Marsha Pellegrino; Francesca Ceccacci; Stefania Petrini; Anita Scipioni; Serena De Santis; Marco Cappa; Giovanna Mancini; Alessandra Fierabracci. 2018. "Exploiting novel tailored immunotherapies of type 1 diabetes: Short interfering RNA delivered by cationic liposomes enables efficient down-regulation of variant PTPN22 gene in T lymphocytes." Nanomedicine: Nanotechnology, Biology and Medicine 18, no. : 371-379.

Review article
Published: 17 October 2018 in Frontiers in Immunology
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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.

ACS Style

Elena Gianchecchi; Alessandra Fierabracci. Inhibitory Receptors and Pathways of Lymphocytes: The Role of PD-1 in Treg Development and Their Involvement in Autoimmunity Onset and Cancer Progression. Frontiers in Immunology 2018, 9, 2374 .

AMA Style

Elena Gianchecchi, Alessandra Fierabracci. Inhibitory Receptors and Pathways of Lymphocytes: The Role of PD-1 in Treg Development and Their Involvement in Autoimmunity Onset and Cancer Progression. Frontiers in Immunology. 2018; 9 ():2374.

Chicago/Turabian Style

Elena Gianchecchi; Alessandra Fierabracci. 2018. "Inhibitory Receptors and Pathways of Lymphocytes: The Role of PD-1 in Treg Development and Their Involvement in Autoimmunity Onset and Cancer Progression." Frontiers in Immunology 9, no. : 2374.

Review
Published: 13 August 2018 in Frontiers in Immunology
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Autoimmune-poly-endocrinopathy-candidiasis–ectodermal-dystrophy syndrome (APECED) is a rare monogenic recessive disorder caused by mutations in the autoimmune regulator (AIRE) gene. Criteria for the diagnosis of APECED are the presence of two of the following disorders: chronic mucocutaneous candidiasis (CMC), chronic hypoparathyroidism (CHP), and Addison’s disease. APECED develops at high incidence in Finns, Sardinians, and Iranian Jews and presents with a wide range of clinical phenotypes and genotypes. In this manuscript, we report the clinical, endocrinological, and molecular features of a 16-year-old female patient from Pakistan living in Italy and presenting the major APECED clinical manifestations CMC, CHP, and primary adrenal insufficiency. Premature ovarian failure, chronic bronchopneumopathy, vitiligo, Hashimoto’s thyroiditis emerged as associated diseases. In our patient, AIRE gene screening revealed the novel c.396G>C (p.Arg132Ser; p.R132S) mutation in homozygosity thus confirming APECED diagnosis. This is the first reported mutation within the nuclear localization signal (NLS) that is associated with APECED. The NLS mutation affects the nuclear import of classical transcription factors through nuclear pore by recognition of nuclear import receptors, the importin α molecules. By displaying crystal structures of the peptide containing the KRK basic residue cluster bound to α importins, we show that p.R132S replacement in 131-KRK-133 does not reproduce these interactions. Thus, we propose that the novel mutation exerts its pathogenetic effect by impairing the nuclear import of the Aire protein. The present case report is added to a limited series of Pakistani APECED patients who we reviewed from the scientific literature, mostly diagnosed on clinical findings.

ACS Style

Marsha Pellegrino; Emanuele Bellacchio; Rudina Dhamo; Federica Frasca; Corrado Betterle; Alessandra Fierabracci. A Novel Homozygous Mutation of the AIRE Gene in an APECED Patient From Pakistan: Case Report and Review of the Literature. Frontiers in Immunology 2018, 9, 1835 .

AMA Style

Marsha Pellegrino, Emanuele Bellacchio, Rudina Dhamo, Federica Frasca, Corrado Betterle, Alessandra Fierabracci. A Novel Homozygous Mutation of the AIRE Gene in an APECED Patient From Pakistan: Case Report and Review of the Literature. Frontiers in Immunology. 2018; 9 ():1835.

Chicago/Turabian Style

Marsha Pellegrino; Emanuele Bellacchio; Rudina Dhamo; Federica Frasca; Corrado Betterle; Alessandra Fierabracci. 2018. "A Novel Homozygous Mutation of the AIRE Gene in an APECED Patient From Pakistan: Case Report and Review of the Literature." Frontiers in Immunology 9, no. : 1835.

Short communication
Published: 03 July 2018 in Clinical Immunology
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APECED is a rare monogenic recessive disorder caused by mutations in the AIRE gene. In this manuscript, we report a male Turkish patient with APECED syndrome who presented with chronic mucocutaneous candidiasis associated with other autoimmune manifestations developed over the years. The presence of the homozygous R257X mutation of the AIRE gene confirmed the diagnosis of APECED syndrome. We further performed literature review in 23 published Turkish APECED patients and noted that Finnish major mutation R257X is common in Turks. In particular, we assessed retrospectively how often the Ferre/Lionakis criteria would have resulted in earlier diagnosis in Finns, Sardinians and Turks in respect to the classic criteria. Since an earlier diagnosis could have been possible in 18.8% of Turkish, in 23.8% of Sardinian and 38.55% of Finnish patients we reviewed from literature, Ferre/Lionakis criteria could indeed allow in future earlier initiation of immunomodulatory treatments, if found effective in future studies.

ACS Style

Alessandra Fierabracci; Marsha Pellegrino; Federica Frasca; Sara Sebnem Kilic; Corrado Betterle. APECED in Turkey: A case report and insights on genetic and phenotypic variability. Clinical Immunology 2018, 194, 60 -66.

AMA Style

Alessandra Fierabracci, Marsha Pellegrino, Federica Frasca, Sara Sebnem Kilic, Corrado Betterle. APECED in Turkey: A case report and insights on genetic and phenotypic variability. Clinical Immunology. 2018; 194 ():60-66.

Chicago/Turabian Style

Alessandra Fierabracci; Marsha Pellegrino; Federica Frasca; Sara Sebnem Kilic; Corrado Betterle. 2018. "APECED in Turkey: A case report and insights on genetic and phenotypic variability." Clinical Immunology 194, no. : 60-66.

Review
Published: 10 March 2018 in International Journal of Molecular Sciences
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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.

ACS Style

Valeria La Marca; Elena Gianchecchi; Alessandra Fierabracci. Type 1 Diabetes and Its Multi-Factorial Pathogenesis: The Putative Role of NK Cells. International Journal of Molecular Sciences 2018, 19, 794 .

AMA Style

Valeria La Marca, Elena Gianchecchi, Alessandra Fierabracci. Type 1 Diabetes and Its Multi-Factorial Pathogenesis: The Putative Role of NK Cells. International Journal of Molecular Sciences. 2018; 19 (3):794.

Chicago/Turabian Style

Valeria La Marca; Elena Gianchecchi; Alessandra Fierabracci. 2018. "Type 1 Diabetes and Its Multi-Factorial Pathogenesis: The Putative Role of NK Cells." International Journal of Molecular Sciences 19, no. 3: 794.

Review
Published: 01 February 2018 in Autoimmunity Reviews
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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 CD56+CD3-, conversely CD56+CD3+ 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. CD56dim constitute about 90% of NK cells in the peripheral blood, they are mature and involved in cytotoxicity responses; CD56bright 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.

ACS Style

Elena Gianchecchi; Domenico Vittorio Delfino; Alessandra Fierabracci. NK cells in autoimmune diseases: Linking innate and adaptive immune responses. Autoimmunity Reviews 2018, 17, 142 -154.

AMA Style

Elena Gianchecchi, Domenico Vittorio Delfino, Alessandra Fierabracci. NK cells in autoimmune diseases: Linking innate and adaptive immune responses. Autoimmunity Reviews. 2018; 17 (2):142-154.

Chicago/Turabian Style

Elena Gianchecchi; Domenico Vittorio Delfino; Alessandra Fierabracci. 2018. "NK cells in autoimmune diseases: Linking innate and adaptive immune responses." Autoimmunity Reviews 17, no. 2: 142-154.

Research article
Published: 13 December 2017 in PLOS ONE
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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.

ACS Style

Valentina Perri; Elena Gianchecchi; Loredana Cifaldi; Marsha Pellegrino; Ezio Giorda; Marco Andreani; Marco Cappa; Alessandra Fierabracci. 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, 12, e0189615 .

AMA Style

Valentina Perri, Elena Gianchecchi, Loredana Cifaldi, Marsha Pellegrino, Ezio Giorda, Marco Andreani, Marco Cappa, Alessandra Fierabracci. 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; 12 (12):e0189615.

Chicago/Turabian Style

Valentina Perri; Elena Gianchecchi; Loredana Cifaldi; Marsha Pellegrino; Ezio Giorda; Marco Andreani; Marco Cappa; Alessandra Fierabracci. 2017. "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 12, no. 12: e0189615.