28 results on '"Marrapodi R"'
Search Results
2. PB0802 Platelet Features that Identify Early Stages of Liver Disease Progression
- Author
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Lombardi, L., primary, Maiorca, F., additional, Pallucci, D., additional, Marrapodi, R., additional, Sabetta, A., additional, Miglionico, M., additional, Visentini, M., additional, Romiti, G., additional, Corica, B., additional, Sperduti, N., additional, Vano, M., additional, D'amico, T., additional, Fasano, S., additional, Recchia, F., additional, Cangemi, R., additional, Pellicelli, A., additional, Basili, S., additional, and Stefanini, L., additional
- Published
- 2023
- Full Text
- View/download PDF
3. A machine-learning-based bio-psycho-social model for the prediction of non-obstructive and obstructive coronary artery disease
- Author
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Raparelli, V, Proietti, M, Romiti, G. F., Seccia, R, Di Teodoro, G., Tanzilli, G, Marrapodi, R, Flego, D, Corica, B, Cangemi, R, Palagi, L, Basili, S, Stefanini, L, and Eva, Group
- Published
- 2021
4. Hepatitis B virus causes mixed cryoglobulinaemia by driving clonal expansion of innate B-cells producing a VH1-69-encoded antibody
- Author
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Visentini, M., Pascolini, S., Mitrevski, M., Marrapodi, R., Del Padre, M., Todi, L., Camponeschi, A., Axiotis, E., Carlesimo, M., Adriano De Santis, Fiorilli, M., and Casato, M.
- Subjects
Adult ,Aged, 80 and over ,Male ,B-Lymphocytes ,Immunoglobulin Variable Region ,Middle Aged ,Hepatitis B ,Immunity, Innate ,Cryoglobulinemia ,Antibody Formation ,Humans ,Female ,Immunoglobulin Heavy Chains ,Aged - Abstract
To investigate the expression of a VH1-69-encoded idiotype, and the phenotypic and functional features of monoclonal B-cells from patients with type II mixed cryoglobulinaemia (MC) secondary to chronic hepatitis B virus (HBV) infection.B-cell immunophenotype and expression of a VH1-69-encoded idiotype were investigated by flow cytometry. B-cell proliferative responses to stimuli were investigated by the CFSE dilution assay.Two out of five patients with chronic HBV studied had massive monoclonal expansion of VH1-69-expressing B-cells. These cells had the peculiar CD21(low) phenotype and low responsiveness to stimuli typical of the VH1-69-expressing B-cells commonly expanded in MC secondary to hepatitis C virus (HCV) infection. In both patients, anti-HBV therapy led to the regression of MC and of VH1-69+ B-cell expansion.VH1-69-encoded antibodies are known to preferentially recognise a variety of viral proteins including HCV E2, influenza A virus haemagglutinin and HIV gp41/gp120, and may serve as innate first line antiviral defense. Thus, like HCV, HBV may cause MC by protracted antigenic stimulation of VH1-69-expressing B-cells.
5. Rheumatoid factor-producing CD21low anergic clonal B-cells in essential mixed cryoglobulinaemia: a model for autoantigen-driven pathogenesis of infectious and non-infectious cryoglobulinaemias
- Author
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Del Padre, M., Minafò, Y. A., Marrapodi, R., Radicchio, G., Granata, M., alessandro camponeschi, Fiorilli, M., Quartuccio, L., Vita, S., Casato, M., Colantuono, S., and Visentini, M.
- Subjects
B-lymphocyte ,B-Lymphocytes ,Cryoglobulinemia ,Rheumatoid Factor ,cryoglobulinaemia, B-lymphocyte, B-cell receptor, rheumatoid factor, anergy ,B-cell receptor ,Humans ,Hepacivirus ,cryoglobulinaemia ,Autoantigens ,Hepatitis C ,anergy - Abstract
Essential mixed cryoglobulinaemia (EMC) is a disorder of B-cells producing rheumatoid factor (RF), and is clinically and immunologically similar to mixed cryoglobulinaemia (MC) related to hepatitis C virus (HCV-MC). We report here the first comprehensive analysis of B-cell clonality, phenotype and function in EMC.The study population included 16 patients with EMC and 24 patients with HCV-MC. Molecular analysis was done for the detection of circulating clonal B cells and for B cell receptor sequencing. B-cell phenotype, proliferative response, apoptosis and ERK signaling were analysed by flow cytometry.Molecular analysis of immunoglobulin genes rearrangements revealed circulating B-cell clones in about half of patients, on average of smaller size than those found in HCV-MC patients. Sequence analysis showed usage of the same stereotyped RF-encoding B-cell receptors frequently expressed in HCV-MC and in primary Sjögren's syndrome. B-cells with low expression of CD21 (CD21low) and unusual homing and inhibitory receptors were increased in EMC and in HCV-MC, but at a significantly lower extent in the former. The CD21low B-cells of EMC and HCV-MC patients shared functional features of exhaustion and anergy, namely reduced proliferation upon ligation of Toll-like receptor 9, high constitutive expression of phosphorylated ERK, and proneness to spontaneous apoptosis.Our findings suggest a common pathogenetic mechanism in EMC, HCV-MC and primary Sjögren's syndrome, consisting of autoantigen-driven clonal expansion and exhaustion of selected RF-producing B-cells. The more massive clonal expansion in HCV-MC may be due to co-stimulatory signals provided by the virus.
6. The Keratinocyte in the Picture Cutaneous Melanoma Microenvironment.
- Author
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Marrapodi R and Bellei B
- Abstract
Melanoma progression is a multistep evolution from a common melanocytic nevus through a radial superficial growth phase, the invasive vertical growth phase finally leading to metastatic dissemination into distant organs. Melanoma aggressiveness largely depends on the propensity to metastasize, which means the capacity to escape from the physiological microenvironment since tissue damage due to primary melanoma lesions is generally modest. Physiologically, epidermal melanocytes are attached to the basement membrane, and their adhesion/migration is under the control of surrounding keratinocytes. Thus, the epidermal compartment represents the first microenvironment responsible for melanoma spread. This complex process involves cell-cell contact and a broad range of secreted bioactive molecules. Invasion, or at the beginning of the microinvasion, implies the breakdown of the dermo-epidermal basement membrane followed by the migration of neoplastic melanocytic cells in the superficial papillary dermis. Correspondingly, several experimental evidences documented the structural and functional rearrangement of the entire tissue surrounding neoplasm that in some way reflects the atypia of tumor cells. Lastly, the microenvironment must support the proliferation and survival of melanocytes outside the normal epidermal-melanin units. This task presumably is mostly delegated to fibroblasts and ultimately to the self-autonomous capacity of melanoma cells. This review will discuss remodeling that occurs in the epidermis during melanoma formation as well as skin changes that occur independently of melanocytic hyperproliferation having possible pro-tumoral features.
- Published
- 2024
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7. Breakthrough infections after COVID-19 vaccinations do not elicit platelet hyperactivation and are associated with high platelet-lymphocyte and low platelet-neutrophil aggregates.
- Author
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Maiorca F, Lombardi L, Marrapodi R, Pallucci D, Sabetta A, Zingaropoli MA, Perri V, Flego D, Romiti GF, Corica B, Miglionico M, Russo G, Pasculli P, Ciardi MR, Mastroianni CM, Ruberto F, Pugliese F, Pulcinelli F, Raparelli V, Cangemi R, Visentini M, Basili S, and Stefanini L
- Abstract
Background: Severe COVID-19 is associated with an excessive immunothrombotic response and thromboinflammatory complications. Vaccinations effectively reduce the risk of severe clinical outcomes in patients with COVID-19, but their impact on platelet activation and immunothrombosis during breakthrough infections is not known., Objectives: To investigate how preemptive vaccinations modify the platelet-immune crosstalk during COVID-19 infections., Methods: Cross-sectional flow cytometry study of the phenotype and interactions of platelets circulating in vaccinated ( n = 21) and unvaccinated patients with COVID-19, either admitted to the intensive care unit (ICU, n = 36) or not (non-ICU, n = 38), in comparison to matched SARS-CoV-2-negative patients ( n = 48), was performed., Results: In the circulation of unvaccinated non-ICU patients with COVID-19, we detected hyperactive and hyperresponsive platelets and platelet aggregates with adaptive and innate immune cells. In unvaccinated ICU patients with COVID-19, most of whom had severe acute respiratory distress syndrome, platelets had high P-selectin and phosphatidylserine exposure but low capacity to activate integrin αIIbβ3, dysfunctional mitochondria, and reduced surface glycoproteins. In addition, in the circulation of ICU patients, we detected microthrombi and platelet aggregates with innate, but not with adaptive, immune cells. In vaccinated patients with COVID-19, who had no acute respiratory distress syndrome, platelets had surface receptor levels comparable to those in controls and did not form microthrombi or platelet-granulocyte aggregates but aggregated avidly with adaptive immune cells., Conclusion: Our study provides evidence that vaccinated patients with COVID-19 are not associated with platelet hyperactivation and are characterized by platelet-leukocyte aggregates that foster immune protection but not excessive immunothrombosis. These findings advocate for the importance of vaccination in preventing severe COVID-19., (© 2023 The Author(s).)
- Published
- 2023
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8. A machine-learning based bio-psycho-social model for the prediction of non-obstructive and obstructive coronary artery disease.
- Author
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Raparelli V, Romiti GF, Di Teodoro G, Seccia R, Tanzilli G, Viceconte N, Marrapodi R, Flego D, Corica B, Cangemi R, Pilote L, Basili S, Proietti M, Palagi L, and Stefanini L
- Subjects
- Adult, Humans, Female, Middle Aged, Aged, Male, Artificial Intelligence, Coronary Angiography methods, Machine Learning, Cytokines, Risk Factors, Predictive Value of Tests, Coronary Artery Disease diagnosis, Frailty, Myocardial Ischemia
- Abstract
Background: Mechanisms of myocardial ischemia in obstructive and non-obstructive coronary artery disease (CAD), and the interplay between clinical, functional, biological and psycho-social features, are still far to be fully elucidated., Objectives: To develop a machine-learning (ML) model for the supervised prediction of obstructive versus non-obstructive CAD., Methods: From the EVA study, we analysed adults hospitalized for IHD undergoing conventional coronary angiography (CCA). Non-obstructive CAD was defined by a stenosis < 50% in one or more vessels. Baseline clinical and psycho-socio-cultural characteristics were used for computing a Rockwood and Mitnitski frailty index, and a gender score according to GENESIS-PRAXY methodology. Serum concentration of inflammatory cytokines was measured with a multiplex flow cytometry assay. Through an XGBoost classifier combined with an explainable artificial intelligence tool (SHAP), we identified the most influential features in discriminating obstructive versus non-obstructive CAD., Results: Among the overall EVA cohort (n = 509), 311 individuals (mean age 67 ± 11 years, 38% females; 67% obstructive CAD) with complete data were analysed. The ML-based model (83% accuracy and 87% precision) showed that while obstructive CAD was associated with higher frailty index, older age and a cytokine signature characterized by IL-1β, IL-12p70 and IL-33, non-obstructive CAD was associated with a higher gender score (i.e., social characteristics traditionally ascribed to women) and with a cytokine signature characterized by IL-18, IL-8, IL-23., Conclusions: Integrating clinical, biological, and psycho-social features, we have optimized a sex- and gender-unbiased model that discriminates obstructive and non-obstructive CAD. Further mechanistic studies will shed light on the biological plausibility of these associations., Clinical Trial Registration: NCT02737982., (© 2023. The Author(s).)
- Published
- 2023
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9. Distinct platelet crosstalk with adaptive and innate immune cells after adenoviral and mRNA vaccination against SARS-CoV-2.
- Author
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Lombardi L, Maiorca F, Marrapodi R, Sabetta A, Scafa N, Pallucci D, Miglionico M, Romiti GF, Corica B, Piconese S, Polimeni A, Pulcinelli F, Cangemi R, Visentini M, Basili S, and Stefanini L
- Subjects
- Humans, SARS-CoV-2, BNT162 Vaccine, COVID-19 Vaccines adverse effects, ChAdOx1 nCoV-19, Retrospective Studies, Vaccination, Adenoviridae genetics, Aspirin, Immunity, Innate, Blood Platelets, COVID-19 prevention & control
- Abstract
Background: Genetic-based COVID-19 vaccines have proved to be highly effective in reducing the risk of hospitalization and death. Because they were first distributed in a large-scale population, the adenoviral-based vaccines were linked to a very rare thrombosis with thrombocytopenia syndrome, and the interplay between platelets and vaccinations increasingly gained attention., Objectives: The objective of this article was to study the crosstalk between platelets and the vaccine-induced immune response., Methods: We prospectively enrolled young healthy volunteers who received the mRNA-based vaccine, BNT162b2 (n = 15), or the adenovirus-based vaccine, AZD1222 (n = 25) and studied their short-term platelet and immune response before and after vaccine injections. In a separate cohort, we retrospectively analyzed the effect of aspirin on the antibody response 1 and 5 months after BNT162b2 vaccination., Results: Here, we show that a faster antibody response to either vaccine is associated with the formation of platelet aggregates with marginal zone-like B cells, a subset geared to bridge the temporal gap between innate and adaptive immunities. However, although the mRNA-based vaccine is associated with a more gradual and tolerogenic response that fosters the crosstalk between platelets and adaptive immunity, the adenovirus-based vaccine, the less immunogenic of the 2, evokes an antiviral-like response during which the platelets are cleared and less likely to cooperate with B cells. Moreover, subjects taking aspirin (n = 56) display lower antibody levels after BNT162b2 vaccination compared with matched individuals., Conclusion: Platelets are a component of the innate immune pathways that promote the B-cell response after vaccination. Future studies on the platelet-immune crosstalk post-immunization will improve the safety, efficacy, and strategic administration of next-generation vaccines., Competing Interests: Declaration of competing interests The authors declare no conflicts of interest., (Copyright © 2023 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)
- Published
- 2023
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10. Opposite Effects of mRNA-Based and Adenovirus-Vectored SARS-CoV-2 Vaccines on Regulatory T Cells: A Pilot Study.
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La Gualana F, Maiorca F, Marrapodi R, Villani F, Miglionico M, Santini SA, Pulcinelli F, Gragnani L, Piconese S, Fiorilli M, Basili S, Casato M, Stefanini L, and Visentini M
- Abstract
New-generation mRNA and adenovirus vectored vaccines against SARS-CoV-2 spike protein are endowed with immunogenic, inflammatory and immunomodulatory properties. Recently, BioNTech developed a noninflammatory tolerogenic mRNA vaccine (MOGm1Ψ) that induces in mice robust expansion of antigen-specific regulatory T (Treg) cells. The Pfizer/BioNTech BNT162b2 mRNA vaccine against SARS-CoV-2 is identical to MOGm1Ψ except for the lipid carrier, which differs for containing lipid nanoparticles rather than lipoplex. Here we report that vaccination with BNT162b2 led to an increase in the frequency and absolute count of CD4
pos CD25high CD127low putative Treg cells; in sharp contrast, vaccination with the adenovirus-vectored ChAdOx1 nCoV-19 vaccine led to a significant decrease of CD4pos CD25high cells. This pilot study is very preliminary, suffers from important limitations and, frustratingly, very hardly can be refined in Italy because of the >90% vaccination coverage. Thus, the provocative perspective that BNT162b2 and MOGm1Ψ may share the capacity to promote expansion of Treg cells deserves confirmatory studies in other settings.- Published
- 2023
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11. Dual stimulation by autoantigen and CpG fosters the proliferation of exhausted rheumatoid factor-specific CD21 low B cells in hepatitis C virus-cured mixed cryoglobulinemia.
- Author
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Del Padre M, Marrapodi R, Minafò YA, Piano Mortari E, Radicchio G, Bocci C, Gragnani L, Camponeschi A, Colantuono S, Stefanini L, Basili S, Carsetti R, Fiorilli M, Casato M, and Visentini M
- Subjects
- Humans, Autoantigens, Cell Proliferation, Hepacivirus, Myeloid Differentiation Factor 88 metabolism, NF-kappa B metabolism, Phosphatidylinositol 3-Kinases metabolism, Proto-Oncogene Proteins c-akt metabolism, Rheumatoid Factor, Toll-Like Receptor 9 metabolism, CpG Islands, Receptors, Complement 3d immunology, B-Lymphocytes immunology, Cryoglobulinemia etiology, Hepatitis C
- Abstract
Introduction: Hepatitis C virus (HCV) causes mixed cryoglobulinemia (MC) by driving clonal expansion of B cells expressing B cell receptors (BCRs), often encoded by the VH1-69 variable gene, endowed with both rheumatoid factor (RF) and anti-HCV specificity. These cells display an atypical CD21low phenotype and functional exhaustion evidenced by unresponsiveness to BCR and Toll-like receptor 9 (TLR9) stimuli. Although antiviral therapy is effective on MC vasculitis, pathogenic B cell clones persist long thereafter and can cause virus-independent disease relapses., Methods: Clonal B cells from patients with HCV-associated type 2 MC or healthy donors were stimulated with CpG or heath-aggregated IgG (as surrogate immune complexes) alone or in combination; proliferation and differentiation were then evaluated by flow cytometry. Phosphorylation of AKT and of the p65 NF-kB subunit were measured by flow cytometry. TLR9 was quantified by qPCR and by intracellular flow cytometry, and MyD88 isoforms were analyzed using RT-PCR., Discussion: We found that dual triggering with autoantigen and CpG restored the capacity of exhausted VH1-69pos B cells to proliferate. The signaling mechanism for this BCR/TLR9 crosstalk remains elusive, since TLR9 mRNA and protein as well as MyD88 mRNA were normally expressed and CpG-induced phosphorylation of p65 NF-kB was intact in MC clonal B cells, whereas BCR-induced p65 NF-kB phosphorylation was impaired and PI3K/Akt signaling was intact. Our findings indicate that autoantigen and CpG of microbial or cellular origin may unite to foster persistence of pathogenic RF B cells in HCV-cured MC patients. BCR/TLR9 crosstalk might represent a more general mechanism enhancing systemic autoimmunity by the rescue of exhausted autoreactive CD21low B cells., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Del Padre, Marrapodi, Minafò, Piano Mortari, Radicchio, Bocci, Gragnani, Camponeschi, Colantuono, Stefanini, Basili, Carsetti, Fiorilli, Casato and Visentini.)
- Published
- 2023
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12. Increased von Willebrand Factor Platelet-Binding Capacity Is Related to Poor Prognosis in COVID-19 Patients.
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Stefanini L, Ruberto F, Curreli M, Chistolini A, Schiera E, Marrapodi R, Visentini M, Ceccarelli G, D'Ettorre G, Santoro C, Gandini O, Moro EF, Zullino V, Pugliese F, and Pulcinelli FM
- Subjects
- Humans, Blood Platelets, Prognosis, COVID-19 diagnosis, von Willebrand Factor
- Abstract
Competing Interests: None declared.
- Published
- 2023
- Full Text
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13. Platelet and immune signature associated with a rapid response to the BNT162b2 mRNA COVID-19 vaccine.
- Author
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Flego D, Cesaroni S, Romiti GF, Corica B, Marrapodi R, Scafa N, Maiorca F, Lombardi L, Pallucci D, Pulcinelli F, Raparelli V, Visentini M, Cangemi R, Piconese S, Alvaro D, Polimeni A, Basili S, and Stefanini L
- Subjects
- Adult, Antibodies, Viral blood, Female, Humans, Male, SARS-CoV-2, BNT162 Vaccine immunology, Blood Platelets immunology, COVID-19 prevention & control, Immunity, Humoral, Vaccine Efficacy
- Abstract
Background: A rapid immune response is critical to ensure effective protection against COVID-19. Platelets are first-line sentinels of the vascular system able to rapidly alert and stimulate the immune system. However, their role in the immune response to vaccines is not known., Objective: To identify features of the platelet-immune crosstalk that would provide an early readout of vaccine efficacy in adults who received the mRNA-based COVID-19 vaccine (BNT162b2)., Methods: We prospectively enrolled 11 young healthy volunteers (54% females, median age: 28 years) who received two doses of BNT162b2, 21 days apart, and we studied their platelet and immune response before and after each dose of the vaccine (3 and 10 ± 2 days post-injection), in relation to the kinetics of the humoral response., Results: Participants achieving an effective level of neutralizing antibodies before the second dose of the vaccine (fast responders) had a higher leukocyte count, mounted a rapid cytokine response that incremented further after the second dose, and an elevated platelet turnover that ensured platelet count stability. Their circulating platelets were not more reactive but expressed lower surface levels of the immunoreceptor tyrosine-based inhibitory motif (ITIM)-coupled receptor CD31 (PECAM-1) compared to slow responders, and formed specific platelet-leukocyte aggregates, with B cells, just 3 days after the first dose, and with non-classical monocytes and eosinophils., Conclusion: We identified features of the platelet-immune crosstalk that are associated with the development of a rapid humoral response to an mRNA-based vaccine (BNT162b2) and that could be exploited as early biomarkers of vaccine efficacy., (© 2022 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.)
- Published
- 2022
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14. CD21 low B cells are predictive markers of new digital ulcers in systemic sclerosis.
- Author
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Visentini M, Pellicano C, Leodori G, Marrapodi R, Colantuono S, Gigante A, Casato M, and Rosato E
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- B-Lymphocytes metabolism, Female, Humans, Male, Middle Aged, B-Lymphocytes immunology, Biomarkers metabolism, Receptors, Complement 3d metabolism, Scleroderma, Systemic immunology, Scleroderma, Systemic metabolism, Skin Ulcer immunology, Skin Ulcer metabolism
- Abstract
The objective of this study was to evaluate the predictive role of CD21
low B cells as markers of new digital ulcers in systemic sclerosis patients. Peripheral blood B cell subpopulations and clinical assessments have been evaluated in 74 systemic sclerosis patients at baseline and after a 12-month follow-up. After a 12-month follow-up, 23 (31.1%) systemic sclerosis patients developed new digital ulcers. The median percentage of CD21low B cells was significantly higher in patients with than without new digital ulcers [10.1 (4.3-13.6) versus 4.8 (3.5-7.4); p < 0.01]. The 10% cut-off shows good diagnostic accuracy [area under the curve (AUC) = 0.732, confidence interval (CI) = 0.587-0.878; P = 0.01]. Kaplan-Meier curves show a significantly reduced free survival from new digital ulcers in systemic sclerosis patients with CD21low B cells ≥ 10% (p < 0.0001). In multivariate analysis, CD21low B cells ≥ 10%, modified Rodnan skin score (mRSS) and systolic pulmonary arterial pressure (sPAP) are associated with the development of new digital ulcers. We hypothesize that CD21low B cells are a predictive marker of new digital ulcers in systemic sclerosis patients., (© 2021 The Authors. Clinical & Experimental Immunology published by John Wiley & Sons Ltd on behalf of British Society for Immunology.)- Published
- 2021
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15. Biomarkers of minimal residual disease in rituximab-treated patients with mixed cryoglobulinemia.
- Author
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Basile U, Gulli F, Napodano C, Pocino K, Basile V, Marrapodi R, Colantuono S, Todi L, Marino M, Rapaccini GL, and Visentini M
- Subjects
- Adult, Aged, Aged, 80 and over, Biomarkers blood, Female, Humans, Male, Middle Aged, Cryoglobulinemia blood, Cryoglobulinemia drug therapy, Immunoglobulin M blood, Immunoglobulin kappa-Chains blood, Immunoglobulin lambda-Chains blood, Rituximab administration & dosage, Vascular Endothelial Growth Factor A blood
- Abstract
Hepatitis C virus (HCV) represents the major risk factor for mixed cryoglobulinemia (MC), a small-vessel vasculitis that may evolve into an overt B-cell non-Hodgkin's lymphoma. Here, we aimed to identify a biomarker signature for the early diagnosis of minimal residual disease (MRD). We assessed free light chains (FLCs), IgM k,and IgM λ heavy/light chain (HLC) pairs, and vascular endothelial growth factor (VEGF) in sera from 34 patients with MC vasculitis (32 HCV- and 2 HBV-related), treated with low-dose rituximab (RTX). FLCs and IgM HLCs were measured by turbidimetric assay; VEGF by an enzyme-linked immunosorbent assay. After RTX, the positive (complete + partial) clinical and laboratory responses were of 85.29% and 50%, respectively; in contrast, the mean levels of FLCs, IgM HLCs, and VEGF were substantially unaffected in most patients and still above the normal range. In those achieving a reduction of FLCs and IgM k and λ chains values within the range of normality, we found that post-treatment free λ chains and IgM k values correlated with clinical and laboratory response. Our results suggest that high levels of FLCs, IgM HLCs, and VEGF could represent the signature of "dormant" B cell clones' activity that could be very useful to identify MRD indicative of possible relapse or worsening outcome., (© 2020 International Union of Biochemistry and Molecular Biology, Inc.)
- Published
- 2021
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16. Clinico-immunological outcomes of HCV-cured cryoglobulinemia: Lower relapse rate with interferon-based than interferon-free therapy.
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Colantuono S, Marrapodi R, Del Padre M, Collalti G, Garzi G, De Santis A, Fiorilli M, Basili S, Visentini M, and Casato M
- Subjects
- Antiviral Agents therapeutic use, Hepacivirus, Humans, Interferons therapeutic use, Recurrence, Retrospective Studies, Cryoglobulinemia drug therapy, Hepatitis C complications, Hepatitis C drug therapy, Hepatitis C, Chronic complications, Hepatitis C, Chronic drug therapy
- Abstract
Sustained virological response (SVR) obtained with interferon (IFN) or with direct-acting antivirals (DAAs) is commonly followed by response of hepatitis C virus (HCV)-associated mixed cryoglobulinemia vasculitis (MCV), but relapse of MCV despite SVR has been reported in several patients after DAAs and rarely after IFN. Since relapses could have been overlooked in studies with IFN, we retrospectively compared the outcomes of MCV in SVR patients treated with DAAs (n = 70) or IFN (n = 39) followed-up, respectively, for 30.5 (range 11-51) or 48 months. Groups were comparable for demographics and clinics and response rates of MCV were similar (92% and 86%); however, DAA-treated patients less efficiently reduced cryoglobulins (P = .006) and circulating B-cell clones (P = .004), and had more frequently relapses of MCV (18% vs 3%, P = .028) and need for rituximab therapy (P = .01). Although largely inferior on an intention-to-treat basis, IFN may be superior to DAAs on clinico-immunological outcomes possibly owing to its antiproliferative activity., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
- Published
- 2021
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17. Correction to: Reduced Lysosomal Acid Lipase Activity in Blood and Platelets Is Associated With Nonalcoholic Fatty Liver Disease.
- Author
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Ferri F, Mischitelli M, Tozzi G, Messina E, Mignini I, Mazzuca S, Pellone M, Parisse S, Marrapodi R, Visentini M, Baratta F, Del Ben M, Pastori D, Perciballi R, Attilia ML, Carbone M, De Santis A, Violi F, Angelico F, and Corradini SG
- Published
- 2020
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18. CD21 low B cells in systemic sclerosis: A possible marker of vascular complications.
- Author
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Marrapodi R, Pellicano C, Radicchio G, Leodori G, Colantuono S, Iacolare A, Gigante A, Visentini M, and Rosato E
- Subjects
- Aged, Female, Heart Diseases etiology, Humans, Kidney Diseases etiology, Lung Diseases etiology, Male, Middle Aged, Receptors, Complement 3d immunology, Scleroderma, Systemic pathology, Vascular Endothelial Growth Factor A blood, B-Lymphocyte Subsets immunology, Scleroderma, Systemic complications, Scleroderma, Systemic immunology, Vascular Diseases etiology
- Abstract
Objectives: To evaluate expansion of CD21
low B cells and their role in B cell homeostasis, apoptosis, clinical manifestations and serum vascular endothelial growth factor (VEGF) in systemic sclerosis (SSc)., Materials and Methods: B-cells subpopulations and apoptosis have been assessed in 74 SSc patients and 20 healthy donors. Renal Doppler ultrasound, echocardiography, pulmonary function test and VEGF were performed., Results: SSc patients with expanded CD21low B cells (SSc-CD21low ) show a distinct B cell profile with increased memory B cells compared to patients without CD21low B cells (SSc-CD21+ ). Renal resistive index, systolic pulmonary arterial pressure and FVC/DLCO ratio were significantly higher in SSc-CD21low group than SSc-CD21+ , DLCO was lower in SSc-CD21low group than SSc-CD21+ . We found a positive linear correlation between CD21low and sPAP, RI and FVC/DLCO ratio whereas a negative correlation was observed between CD21low and DLCO and VEGF levels., Conclusions: CD21low B cells are increased in SSc patients with visceral vascular manifestations., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier Inc. All rights reserved.)- Published
- 2020
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19. Rheumatoid factor-producing CD21low anergic clonal B-cells in essential mixed cryoglobulinaemia: a model for autoantigen-driven pathogenesis of infectious and non-infectious cryoglobulinaemias.
- Author
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Del Padre M, Minafò YA, Marrapodi R, Radicchio G, Granata M, Camponeschi A, Fiorilli M, Quartuccio L, De Vita S, Casato M, Colantuono S, and Visentini M
- Subjects
- B-Lymphocytes pathology, Cryoglobulinemia virology, Hepacivirus, Humans, Autoantigens immunology, B-Lymphocytes immunology, Cryoglobulinemia pathology, Hepatitis C pathology, Rheumatoid Factor
- Abstract
Objectives: Essential mixed cryoglobulinaemia (EMC) is a disorder of B-cells producing rheumatoid factor (RF), and is clinically and immunologically similar to mixed cryoglobulinaemia (MC) related to hepatitis C virus (HCV-MC). We report here the first comprehensive analysis of B-cell clonality, phenotype and function in EMC., Methods: The study population included 16 patients with EMC and 24 patients with HCV-MC. Molecular analysis was done for the detection of circulating clonal B cells and for B cell receptor sequencing. B-cell phenotype, proliferative response, apoptosis and ERK signaling were analysed by flow cytometry., Results: Molecular analysis of immunoglobulin genes rearrangements revealed circulating B-cell clones in about half of patients, on average of smaller size than those found in HCV-MC patients. Sequence analysis showed usage of the same stereotyped RF-encoding B-cell receptors frequently expressed in HCV-MC and in primary Sjögren's syndrome. B-cells with low expression of CD21 (CD21low) and unusual homing and inhibitory receptors were increased in EMC and in HCV-MC, but at a significantly lower extent in the former. The CD21low B-cells of EMC and HCV-MC patients shared functional features of exhaustion and anergy, namely reduced proliferation upon ligation of Toll-like receptor 9, high constitutive expression of phosphorylated ERK, and proneness to spontaneous apoptosis., Conclusions: Our findings suggest a common pathogenetic mechanism in EMC, HCV-MC and primary Sjögren's syndrome, consisting of autoantigen-driven clonal expansion and exhaustion of selected RF-producing B-cells. The more massive clonal expansion in HCV-MC may be due to co-stimulatory signals provided by the virus.
- Published
- 2020
20. Reduced Lysosomal Acid Lipase Activity in Blood and Platelets Is Associated With Nonalcoholic Fatty Liver Disease.
- Author
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Ferri F, Mischitelli M, Tozzi G, Messina E, Mignini I, Mazzuca S, Pellone M, Parisse S, Marrapodi R, Visentini M, Baratta F, Del Ben M, Pastori D, Perciballi R, Attilia ML, Carbone M, De Santis A, Violi F, Angelico F, and Ginanni Corradini S
- Subjects
- Adult, Aged, Biomarkers blood, Biomarkers metabolism, Cross-Sectional Studies, Disease Progression, Female, Humans, Liver pathology, Liver Cirrhosis blood, Male, Middle Aged, Non-alcoholic Fatty Liver Disease blood, Non-alcoholic Fatty Liver Disease epidemiology, Non-alcoholic Fatty Liver Disease pathology, Risk Assessment methods, Severity of Illness Index, Sterol Esterase metabolism, Blood Platelets metabolism, Liver Cirrhosis pathology, Non-alcoholic Fatty Liver Disease diagnosis, Sterol Esterase blood
- Abstract
Objectives: To investigate whether blood total lysosomal acid lipase activity (BT-LAL) levels are uniquely associated with the noncirrhotic and cirrhotic stages of nonalcoholic fatty liver disease (NAFLD) and with protection from NAFLD in metabolically/genetically predisposed subjects and a normal liver. To clarify which enzyme-carrying circulating cells are involved in reduced BT-LAL of NAFLD., Methods: In a cross-sectional study, BT-LAL was measured by a fluorigenic method in patients with NAFLD (n = 118), alcoholic (n = 116), and hepatitis C virus-related disease (n = 49), in 103 controls with normal liver and in 58 liver transplant recipients. Intracellular platelet and leukocyte LAL was measured in 14 controls and 28 patients with NAFLD., Results: Compared with controls, (i) BT-LAL and LAL in platelets, but not in leukocytes, were progressively reduced in noncirrhotic NAFLD and in nonalcoholic steatohepatitis-related cirrhosis; (ii) platelet and leukocyte counts did not differ in patients with noncirrhotic NAFLD; and (iii) BT-LAL did not differ in alcoholic and hepatitis C virus noncirrhotic patients. BT-LAL progressively increased in controls with metabolic syndrome features according to their PNPLA3 rs738409 steatosis-associated variant status (II vs IM vs MM), and their BT-LAL was higher than that of noncirrhotic NAFLD, only when carriers of the PNPLA3 unfavorable alleles were considered. Liver transplant recipients with de novo NAFLD compared with those without de novo NAFLD had lower BT-LAL., Discussion: LAL in blood and platelets is progressively and uniquely reduced in NAFLD according to disease severity. High BT-LAL is associated with protection from NAFLD occurrence in subjects with metabolic and genetic predisposition. Low LAL in platelets and blood could play a pathogenetic role in NAFLD.
- Published
- 2020
- Full Text
- View/download PDF
21. Flow cytometry in formamide treated cells.
- Author
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Radicchio G, Colicchia V, Marrapodi R, and Carbonari M
- Subjects
- Cell Cycle drug effects, Cell Line, DNA chemistry, Dactinomycin analogs & derivatives, Dactinomycin pharmacology, Fixatives chemistry, Formamides pharmacology, Humans, Staining and Labeling, Surface Properties, Cell Tracking methods, Click Chemistry, DNA isolation & purification, Flow Cytometry
- Abstract
The use of formamide for the study in flow cytometry of cell cycle phases, by DNA content measurement in human cancer cell lines, was recently published. In this manuscript, we verify the possibility of extending the procedure to simultaneous analysis of other parameters. The results obtained, here reported, show that the treatment of samples by formamide is compatible with the simultaneous detection of DNA content and surface phenotypes, with quantification of replicating DNA and with measurement of cells with fractional content of DNA. For each of these three applications, we have adapted the procedure to gain simple, reproducible and above all advantageous protocols. Regarding the simultaneous analysis of DNA content and phenotyping the use of formamide achieves optimal DNA stoichiometric staining (C.V. < 3; G2/G1 ratio = 2 ± 0.05) and sufficient maintenance of physical parameters and membrane fluorescence. In the study of duplicating DNA labeled with click chemistry, our procedure eliminates paraformaldehyde (PFA) fixation improving the DNA stoichiometric staining and allows the use of 7-aminoactinomycin D (7-AAD) preserving the Alexa Fluor 488 quantum efficiency. Concerning the detection of cells with fractional content of DNA, permeabilization and fixation by formamide gives the advantage of resolve on linear scale sub-G1 cells from debris and to allow optimal sample recovery (>90%) which is essential in the study of cell necrobiology. Cells treatment by formamide, suitably modified for different applications, can be used to prepare cell samples for flow cytometry analyses that go far beyond stoichiometric staining of DNA., (© 2018 International Society for Advancement of Cytometry.)
- Published
- 2018
- Full Text
- View/download PDF
22. DEC1/STRA13 is a key negative regulator of activation-induced proliferation of human B cells highly expressed in anergic cells.
- Author
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Camponeschi A, Todi L, Cristofoletti C, Lazzeri C, Carbonari M, Mitrevski M, Marrapodi R, Del Padre M, Fiorilli M, Casato M, and Visentini M
- Subjects
- Basic Helix-Loop-Helix Transcription Factors genetics, Cell Cycle, Cell Proliferation, Cells, Cultured, Cryoglobulinemia genetics, Cryoglobulinemia immunology, Cryoglobulinemia pathology, Gene Expression Regulation immunology, Gene Knockdown Techniques, Hepatitis C genetics, Hepatitis C immunology, Hepatitis C pathology, Homeodomain Proteins genetics, Humans, RNA, Small Interfering metabolism, Receptors, Antigen, B-Cell metabolism, Signal Transduction, Toll-Like Receptor 9 metabolism, B-Lymphocytes immunology, Basic Helix-Loop-Helix Transcription Factors metabolism, Clonal Anergy, Homeodomain Proteins metabolism, Lymphocyte Activation
- Abstract
The transcription factor DEC1/STRA13 (also known as BHLHE40 and SHARP2) is involved in a number of processes including inhibition of cell proliferation and delay of cell cycle, and is a negative regulator of B cell activation and development in mice. We show here that, unlike in mice, DEC1/STRA13 expression is induced in human naïve and memory resting B cells by activation through the B-cell receptor (BCR) or Toll-like receptor 9 (TLR9). siRNA silencing of DEC1/STRA13 increases the capacity of activated B cells to perform a high number of divisions after TLR9 ligation. This identifies DEC1/STRA13 as a critical negative regulator of clonal expansion of activated human B cells. We also show that DEC1/STRA13 is upregulated in human anergic CD21
low B cells clonally expanded in patients with HCV-associated mixed cryoglobulinemia, which fail to proliferate in response to BCR or TLR9 ligation. siRNA knockdown of DEC1/STRA13, however, fails to restore responsiveness to stimuli in these cells, although it might improve the proliferative capacity in a subset of anergic cells with less pronounced proliferative defect., (Copyright © 2018 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.)- Published
- 2018
- Full Text
- View/download PDF
23. Reversion of anergy signatures in clonal CD21 low B cells of mixed cryoglobulinemia after clearance of HCV viremia.
- Author
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Del Padre M, Todi L, Mitrevski M, Marrapodi R, Colantuono S, Fiorilli M, Casato M, and Visentini M
- Subjects
- Cryoglobulinemia etiology, Female, Gene Expression Regulation immunology, Hepatitis C therapy, Humans, Male, B-Lymphocytes immunology, Clonal Anergy, Cryoglobulinemia immunology, Hepacivirus immunology, Hepatitis C immunology, Receptors, Complement 3d immunology, Viremia immunology
- Abstract
Hepatitis C virus (HCV) causes mixed cryoglobulinemia (MC) by driving clonal expansion of IgM
+ CD27+ B cells. These cells display both the features of anergy induced by continual engagement of the B-cell receptor (BCR), such as high expression of phosphorylated extracellular signal-regulated kinase (pERK) and reduced lifespan, and of virus-specific exhaustion, such as CD21low phenotype and a defective response to ligation of BCR and Toll-like receptor 9 (TLR9). MC usually regresses after eradication of HCV with interferon, whose immunomodulatory activity might contribute to this effect. We investigated the phenotypic and functional changes in clonal B cells of MC patients with sustained virologic responses to direct-acting antivirals (DAAs), which lack immunomodulatory properties. We found that high pERK expression and accelerated apoptosis revert within 4 weeks after beginning therapy, whereas clonal B cells unresponsive to TLR9 stimulation persist for at least 24 weeks, although they may partially rescue normal CD21 expression. Thus, similar to mouse models, features of anergy in MC B cells rapidly revert after disengagement from HCV, whereas virus-specific exhaustion imparts a durable inhibitory imprint on cell function. Treatment of HCV+ MC with DAAs provides a valuable tool for untangling the molecular mechanisms of anergy and exhaustion in human B cells., (© 2017 by The American Society of Hematology.)- Published
- 2017
- Full Text
- View/download PDF
24. Hepatitis B virus causes mixed cryoglobulinaemia by driving clonal expansion of innate B-cells producing a VH1-69-encoded antibody.
- Author
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Visentini M, Pascolini S, Mitrevski M, Marrapodi R, Del Padre M, Todi L, Camponeschi A, Axiotis E, Carlesimo M, De Santis A, Fiorilli M, and Casato M
- Subjects
- Adult, Aged, Aged, 80 and over, Antibody Formation, Female, Humans, Immunity, Innate, Male, Middle Aged, B-Lymphocytes immunology, Cryoglobulinemia etiology, Hepatitis B complications, Immunoglobulin Heavy Chains genetics, Immunoglobulin Variable Region genetics
- Abstract
Objectives: To investigate the expression of a VH1-69-encoded idiotype, and the phenotypic and functional features of monoclonal B-cells from patients with type II mixed cryoglobulinaemia (MC) secondary to chronic hepatitis B virus (HBV) infection., Methods: B-cell immunophenotype and expression of a VH1-69-encoded idiotype were investigated by flow cytometry. B-cell proliferative responses to stimuli were investigated by the CFSE dilution assay., Results: Two out of five patients with chronic HBV studied had massive monoclonal expansion of VH1-69-expressing B-cells. These cells had the peculiar CD21(low) phenotype and low responsiveness to stimuli typical of the VH1-69-expressing B-cells commonly expanded in MC secondary to hepatitis C virus (HCV) infection. In both patients, anti-HBV therapy led to the regression of MC and of VH1-69+ B-cell expansion., Conclusions: VH1-69-encoded antibodies are known to preferentially recognise a variety of viral proteins including HCV E2, influenza A virus haemagglutinin and HIV gp41/gp120, and may serve as innate first line antiviral defense. Thus, like HCV, HBV may cause MC by protracted antigenic stimulation of VH1-69-expressing B-cells.
- Published
- 2016
25. Intravenous Immunoglobulin and Immunomodulation of B-Cell - in vitro and in vivo Effects.
- Author
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Mitrevski M, Marrapodi R, Camponeschi A, Cavaliere FM, Lazzeri C, Todi L, and Visentini M
- Abstract
Intravenous immunoglobulin (IVIG) is used as replacement therapy in patients with antibody deficiencies and at higher dosages in immune-mediated disorders. Although different mechanisms have been described in vitro, the in vivo immunomodulatory effects of IVIG are poorly understood. Different studies have suggested that IVIG modulates B-cell functions as activation, proliferation, and apoptosis. Recently, it was shown that IVIG induces in vitro B-cell unresponsiveness similar to anergy. In accord with this, we recently reported that IVIG therapy in patients affected by common variable immunodeficiency (CVID) interferes in vivo with the B-cell receptor (BCR) signaling by increasing constitutive ERK activation and by reducing the phosphorylated ERK increment induced by BCR cross-linking. Moreover, we observed that IVIG induces in CVID patients an increase of circulating CD21(low) B-cells, an unusual population of anergic-like B-cells prone to apoptosis. Therefore, IVIG at replacement dose in vivo could prime B-cells to an anergic, apoptotic program. Here, we discuss these recent findings, which may improve our understanding of the immunomodulatory effects of IVIG, individualizing single involved molecules for more specific treatments.
- Published
- 2015
- Full Text
- View/download PDF
26. Intravenous immunoglobulin replacement therapy in common variable immunodeficiency induces B cell depletion through differentiation into apoptosis-prone CD21(low) B cells.
- Author
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Mitrevski M, Marrapodi R, Camponeschi A, Lazzeri C, Todi L, Quinti I, Fiorilli M, and Visentini M
- Subjects
- Adult, Aged, B-Lymphocytes drug effects, B-Lymphocytes metabolism, Female, Humans, Immunoglobulins, Intravenous pharmacology, Immunophenotyping, Lymphocyte Count, Male, Middle Aged, Phenotype, Receptors, Complement 3d metabolism, Apoptosis drug effects, Apoptosis immunology, B-Lymphocytes immunology, Common Variable Immunodeficiency drug therapy, Common Variable Immunodeficiency immunology, Immunoglobulins, Intravenous therapeutic use, Lymphocyte Depletion
- Abstract
Intravenous immunoglobulin (IVIG), besides its use as replacement therapy in patients with antibody deficiencies, is broadly used as an immunomodulatory agent for the treatment of autoimmune and inflammatory disorders. The mechanisms of action of IVIG include Fc receptor blockade, inhibition of cytokines and growth factors, modulation of macrophages and dendritic cells, enhancement of regulatory T cells, and modulation of B cells through the FcγRIIB receptor and CD22. Recent studies suggest that in vitro exposure of human B cells to IVIG determines functional changes reminiscent of anergy and that IVIG treatment of patients with common variable immunodeficiency (CVID) induces in B cells ERK activation, a feature of anergy. Here, we show that IVIG therapy drives the B cells of patients with CVID to down-regulate CD21 expression and to assume the peculiar phenotype of the anergic-like, apoptosis-prone CD21(low) B cells that are spontaneously expanded in a subset of CVID and in some other immunological disorders. The CD21(low) B cells newly generated after IVIG infusion undergo spontaneous apoptosis upon in vitro culture. Furthermore, IVIG infusion is rapidly followed by a significant, although discrete, decrease in the number of circulating B cells, but not of T cells or of natural killer cells. These findings suggest that IVIG therapy may constrain antibody responses by inducing B cell depletion through differentiation into CD21(low) B cells that undergo accelerated apoptosis.
- Published
- 2014
- Full Text
- View/download PDF
27. Dysregulated extracellular signal-regulated kinase signaling associated with impaired B-cell receptor endocytosis in patients with common variable immunodeficiency.
- Author
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Visentini M, Marrapodi R, Conti V, Mitrevski M, Camponeschi A, Lazzeri C, Carbonari M, Catizone A, Quinti I, and Fiorilli M
- Subjects
- Adult, Aged, Aged, 80 and over, B-Lymphocyte Subsets immunology, B-Lymphocyte Subsets pathology, Case-Control Studies, Common Variable Immunodeficiency genetics, Common Variable Immunodeficiency immunology, Common Variable Immunodeficiency pathology, Endocytosis, Endosomes immunology, Endosomes metabolism, Extracellular Signal-Regulated MAP Kinases genetics, Female, Gene Expression Regulation, Humans, Immunoglobulin M genetics, Immunoglobulin M immunology, Immunoglobulins, Intravenous administration & dosage, Immunologic Memory, Lysosomal Membrane Proteins genetics, Lysosomal Membrane Proteins immunology, Male, Middle Aged, Phosphorylation, Protein Transport, Receptors, Antigen, B-Cell genetics, Receptors, Complement 3d genetics, Receptors, Complement 3d immunology, B-Lymphocyte Subsets metabolism, Common Variable Immunodeficiency metabolism, Extracellular Signal-Regulated MAP Kinases immunology, Receptors, Antigen, B-Cell immunology, Signal Transduction immunology
- Abstract
Background: Common variable immunodeficiency (CVID) is a heterogeneous disorder characterized by B-cell dysfunction and, in a subgroup, by expansion of CD21(low) B cells. The CD21(low) B cells display defects in early B-cell receptor (BCR) signaling resembling those of anergic B cells., Objective: We sought to investigate whether B cells from patients with CVID, like anergic B cells, have defects in extracellular signal-regulated kinase (ERK) phosphorylation and in endocytic trafficking of the BCR., Methods: Using flow cytometry, we evaluated phosphorylated ERK (pERK) expression and internalization of cross-linked BCR in B-cell subsets. The localization of internalized BCR to lysosome-associated membrane protein 1-positive late endosomes was evaluated with confocal microscopy., Results: Constitutive pERK levels were increased in naive and IgM(+) memory B cells of patients with CVID compared with those of healthy donors, whereas the pERK increment induced by BCR cross-linking was relatively reduced. Intravenous immunoglobulin administration enhanced these anomalies, but they appeared to be intrinsic to B cells from patients with CVID. Cross-linking-induced BCR endocytosis was decreased in the IgM(+) memory B cells, especially in those with a CD21(low) phenotype, but not in the naive B cells of patients with CVID with CD21(low) expansion. Internalized BCR localized normally to late endosomes. Pharmacologic inhibition of ERK phosphorylation suppressed BCR endocytosis in B cells of healthy patients and those with CVID., Conclusions: The B cells of patients with CVID with CD21(low) B-cell expansion resemble anergic B cells based on high constitutive pERK expression. The IgM(+) memory B cells of these patients, especially those that are CD21(low), have a defect in BCR endocytosis seemingly caused by dysregulated ERK signaling., (Copyright © 2014 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)
- Published
- 2014
- Full Text
- View/download PDF
28. Clonal expansion and functional exhaustion of monoclonal marginal zone B cells in mixed cryoglobulinemia: the yin and yang of HCV-driven lymphoproliferation and autoimmunity.
- Author
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Visentini M, Conti V, Cristofoletti C, Lazzeri C, Marrapodi R, Russo G, Casato M, and Fiorilli M
- Subjects
- Cryoglobulinemia genetics, Gene Expression Profiling, Gene Expression Regulation, Hepatitis C immunology, Hepatitis C pathology, Humans, Immunoglobulin Heavy Chains genetics, Immunoglobulin Heavy Chains immunology, Immunoglobulin Variable Region genetics, Immunoglobulin Variable Region immunology, Receptors, Complement 3d metabolism, Spleen immunology, Autoimmunity, B-Lymphocytes cytology, B-Lymphocytes immunology, Cryoglobulinemia immunology, Cryoglobulinemia virology, Hepacivirus immunology, Lymphocyte Activation
- Abstract
Monoclonal marginal zone (MZ) B cells expressing a V(H)1-69-encoded idiotype accumulate in HCV-associated mixed cryoglobulinemia (MC). These cells recognize the E2 protein of HCV and their massive clonal expansion reflects the propensity of MZ B cells to proliferate robustly upon antigenic stimulation by microorganisms, a property that makes them prone to neoplastic transformation. V(H)1-69(+) B cells of MC patients are phenotypically heterogeneous and resemble either mature MZ B cells (IgM(+)CD27(+)CD21(high)) or the unusual CD21(low) B cells that accumulate in other immunological disorders such as common variable immunodeficiency (CVID) or HIV infection. The CD21(low) V(H)1-69(+) B cells of MC patients, like those of CVID and HIV patients, are anergic to BCR and TLR9 stimulation and display deregulation of several anergy-related genes; proliferative anergy is also observed in CD21(high) MZ-like V(H)1-69(+) B cells, that over-express the antiproliferative transcriptional repressor Stra13. Upon evolution to splenic marginal zone lymphoma, MZ-like V(H)1-69(+) B cells down-regulate Stra13 and partially recover their capacity to proliferate in response to TLR9 ligation. Like yin and yang, robust clonal expansion and early proliferative anergy may be viewed as the opposite forces balancing the responses of human MZ B cells to chronic microbial stimuli. Disruption of this balance facilitates autoimmunity and lymphoproliferation., (Copyright © 2012 Elsevier B.V. All rights reserved.)
- Published
- 2013
- Full Text
- View/download PDF
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