Publications by authors named "Giuseppe Spadaro"

87 Publications

Common Variable Immunodeficiency and Autoimmune Diseases: A Retrospective Study of 95 Adult Patients in a Single Tertiary Care Center.

Front Immunol 2021 5;12:652487. Epub 2021 Jul 5.

Department of Translational Medical Sciences, University of Naples Federico II, Naples, Italy.

Common variable immunodeficiency (CVID) is the most common clinically significant primary immunodeficiency in adulthood, which presents a broad spectrum of clinical manifestations, often including non-infectious complications in addition to heightened susceptibility to infections. These protean manifestations may significantly complicate the differential diagnosis resulting in diagnostic delay and under-treatment with increased mortality and morbidity. Autoimmunity occurs in up to 30% of CVID patients, and it is an emerging cause of morbidity and mortality in this type of patients. 95 patients (42 males and 53 females) diagnosed with CVID, basing on ESID diagnostic criteria, were enrolled in this retrospective cohort study. Clinical phenotypes were established according to Chapel 2012: i) no other disease-related complications, ii) cytopenias (thrombocytopenia/autoimmune hemolytic anemia/neutropenia), iii) polyclonal lymphoproliferation (granuloma/lymphoid interstitial pneumonitis/persistent unexplained lymphadenopathy), and iv) unexplained persistent enteropathy. Clinical items in the analysis were age, gender, and clinical features. Laboratory data included immunoglobulin (Ig)G, IgM and IgA levels at diagnosis, flow-cytometric analysis of peripheral lymphocytes (CD3+, CD3+CD4+, CD3+CD8+, CD19+, CD4+CD25highCD127low, CD19hiCD21loCD38lo, and follicular T helper cell counts). Comparisons of continuous variables between groups were performed with unpaired t-test, when applicable. 39 patients (41%) showed autoimmune complications. Among them, there were 21 females (53.8%) and 18 males (46.2%). The most prevalent autoimmune manifestations were cytopenias (17.8%), followed by arthritis (11.5%), psoriasis (9.4%), and vitiligo (6.3%). The most common cytopenia was immune thrombocytopenia, reported in 10 out of 95 patients (10.5%), followed by autoimmune hemolytic anemia (n=3, 3.1%) and autoimmune neutropenia (n=3, 3.1%). Other autoimmune complications included thyroiditis, coeliac disease, erythema nodosum, Raynaud's phenomenon, alopecia, recurring oral ulcers, autoimmune gastritis, and primary biliary cholangitis. There were no statistically significant differences comparing immunoglobulin levels between CVID patients with or without autoimmune manifestations. There was no statistical difference in CD3+, CD8+, CD4+CD25highCD127low T, CD19, CD19hiCD21loCD38lo, and follicular T helper cell counts in CVID patients with or without autoimmune disorders. In conclusion, autoimmune manifestations often affect patients with CVID. Early recognition and tailored treatment of these conditions are pivotal to ensure a better quality of life and the reduction of CVID associated complications.
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http://dx.doi.org/10.3389/fimmu.2021.652487DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8287325PMC
July 2021

Real-life evidence of low-dose mepolizumab efficacy in EGPA: a case series.

Respir Res 2021 Jun 23;22(1):185. Epub 2021 Jun 23.

Department of Translational Medical Sciences, University of Naples Ferderico II, Naples, Italy.

Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare, small vessel, necrotizing vasculitis. The disease is mainly characterized by hypereosinophilia and asthma with frequent sinonasal involvement, although multiple organs can be affected, including the heart, lungs, skin, gastrointestinal tract, kidneys, and nervous system. IL-5 production is pathogenetically central for the development of the disease by promoting proliferation, transvascular migration and functional activation of eosinophils. The degree of blood and tissue eosinophilia appears to be associated with disease pathogenesis and eosinophil depletion represents a promising treatment approach for EGPA. We prospectively evaluated the efficacy and safety of a low dose (100 mg q4w), 12-month course of mepolizumab, an anti-IL-5 monoclonal antibody, in eight patients with severe asthma and active EGPA. Patients were recruited by the tertiary care center of Clinical Immunology and Allergy, University of Naples Federico II. The following outcomes were assessed before (T0), and after 6 (T6) and 12 months (T12) of mepolizumab treatment: Birmingham Vasculitis Activity Score (BVAS), prednisone intake, Sino-Nasal Outcome Test (SNOT-22), Total Endoscopic Polyp Score (TENPS), Asthma Control Test (ACT), Forced Expiratory Volume one second (FEV1)%, blood eosinophilia. BVAS score significantly decreased showing a sharp reduction in disease activity score. Clinical improvements in terms of sinonasal scores and asthma symptoms were observed, in parallel with a drastic drop in eosinophil blood count. Prednisone intake was significantly reduced. In two patients, asthma exacerbations led to discontinuation in mepolizumab therapy after 6 and 12 months despite BVAS reduction. Mepolizumab treatment was well tolerated, and no severe adverse drug effects were registered. In conclusion, our 12-month real-life study suggests that mepolizumab may be beneficial and safe in active EGPA patients by improving disease activity score, sinonasal and asthma outcomes while reducing the burden of prednisone intake.
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http://dx.doi.org/10.1186/s12931-021-01775-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8220666PMC
June 2021

Roles of Immune Cells in Hereditary Angioedema.

Clin Rev Allergy Immunol 2021 Jun 29;60(3):369-382. Epub 2021 May 29.

Department of Translational Medical Sciences, University of Naples Federico II, 80131, Naples, Italy.

Hereditary angioedema (HAE) is a rare genetic disease, characterized by recurrent and unexpected potentially life-threatening mucosal swelling. HAE may be further classified into HAE with C1-inhibitor deficiency (C1-INH-HAE) and HAE with normal C1-INH activity (nlC1-INH-HAE), mostly due to mutations leading to increased vascular permeability. Recent evidence implicates also the innate and adaptive immune responses in several aspects of angioedema pathophysiology. Monocytes/macrophages, granulocytes, lymphocytes, and mast cells contribute directly or indirectly to the pathophysiology of angioedema. Immune cells are a source of vasoactive mediators, including bradykinin, histamine, complement components, or vasoactive mediators, whose concentrations or activities are altered in both attacks and remissions of HAE. In turn, through the expression of various receptors, these cells are also activated by a plethora of molecules. Thereby, activated immune cells are the source of molecules in the context of HAE, and on the other hand, increased levels of certain mediators can, in turn, activate immune cells through the engagement of specific surface receptors and contribute to vascular endothelial processes that lead to hyperpemeability and tissue edema. In this review, we summarize recent developments in the putative involvement of the innate and adaptive immune system of angioedema.
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http://dx.doi.org/10.1007/s12016-021-08842-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8272703PMC
June 2021

Diagnostic issues faced by a rare disease healthcare network during Covid-19 outbreak: data from the Campania Rare Disease Registry.

J Public Health (Oxf) 2021 05 13. Epub 2021 May 13.

Centro di Coordinamento Malattie Rare, Regione Campania Naples 80131, Italy.

Background: The aims of this study were: to investigate the capacity of the rare disease healthcare network in Campania to diagnose patients with rare diseases during the outbreak of Covid-19; and to shed light on problematic diagnoses during this period.

Methods: To describe the impact of the Covid-19 pandemic on the diagnosis of patients with rare diseases, a retrospective analysis of the Campania Region Rare Disease Registry was performed. A tailored questionnaire was sent to rare disease experts to investigate major issues during the emergency period.

Results: Prevalence of new diagnoses of rare disease in March and April 2020 was significantly lower than in 2019 (117 versus 317, P < 0.001 and 37 versus 349, P < 0.001, respectively) and 2018 (117 versus 389, P < 0.001 and 37 versus 282, P < 0.001, respectively). Eighty-two among 98 rare disease experts completed the questionnaire. Diagnostic success (95%), access to diagnosis (80%) and follow-up (72%), lack of Personal Protective Equipment (60%), lack of Covid-19 guidelines (50%) and the need for home therapy (78%) were the most important issues raised during Covid-19 outbreak.

Conclusions: This study describes the effects of the Covid-19 outbreak on the diagnosis of rare disease in a single Italian region and investigates potential issues of diagnosis and management during this period.
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http://dx.doi.org/10.1093/pubmed/fdab137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8194710PMC
May 2021

Editorial: The Complexity of Primary Antibody Deficiencies.

Front Immunol 2021 21;12:635482. Epub 2021 Apr 21.

Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.

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http://dx.doi.org/10.3389/fimmu.2021.635482DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8097173PMC
April 2021

Episodic Angioedema with Hypereosinophilia (Gleich's Syndrome): A Case Report and Extensive Review of the Literature.

J Clin Med 2021 Apr 1;10(7). Epub 2021 Apr 1.

Department of Translational Medical Sciences and Center for Basic and Clinical Immunology Research (CISI), WAO Center of Excellence, University of Naples Federico II, Via S. Pansini 5, 80131 Naples, Italy.

Episodic angioedema with eosinophilia (EAE) (Gleich's syndrome) is a rare disease characterized by hypereosinophilia (up to 95 × 10 cells/L), recurrent episodes of angioedema, urticaria, weight gain, and fever, that occur at periodical intervals (usually every 3-4 weeks). The exact etiology of EAE is still unclear, but both eosinophils and abnormalities of cytokines homeostasis seem to play a pivotal role in the pathogenesis of the disease. In particular, the cyclic elevation of serum interleukin-5 before the increase in eosinophil count has been reported. Herein, we performed a broad literature review and report the case of a thirty-two-year-old woman with a two-year history of cyclic angioedema attacks, urticaria, periodic weight gain, and severe hypereosinophilia, diagnosed with EAE and treated with oral corticosteroids. Describing the most relevant clinical features of EAE reported so far in the literature, we aim to provide physicians with some useful tools to help them deal with this disease. In addition, we aim to raise awareness about this rare condition in which approved diagnostic classification criteria are currently missing.
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http://dx.doi.org/10.3390/jcm10071442DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8037656PMC
April 2021

Mepolizumab improves sino-nasal symptoms and asthma control in severe eosinophilic asthma patients with chronic rhinosinusitis and nasal polyps: a 12-month real-life study.

Ther Adv Respir Dis 2021 Jan-Dec;15:17534666211009398

Department of Translational Medical Sciences, Allergy and Clinical Immunology Center for Basic and Clinical Immunology Research (CISI), University of Naples, Italy.

Background: Severe eosinophilic asthma is frequently associated to chronic rhinosinusitis and nasal polyposis (CRSwNP) that contribute to poor asthma control. Mepolizumab is an anti-IL-5 monoclonal antibody, approved for the treatment of severe eosinophilic asthma. A limited number of studies have assessed the efficacy of mepolizumab on CRSwNP in severe asthmatics. We aim to evaluate the efficacy of mepolizumab on sino-nasal symptoms, polyp growth and asthma control in severe eosinophilic asthma patients with CRSwNP in real life.

Methods: In this study 44 severe eosinophilic asthma patients with CRSwNP were treated with mepolizumab (100 mg q4w) for 1 year. The following outcomes were assessed before (T0), after 6 (T6) and 12 months (T12) of treatment: sino/nasal outcome test (SNOT-22), Total Endoscopic Nasal Polyp Score (TENPS), %FEV1 (FEV1/FEV1 predicted) and Asthma control test (ACT). Blood eosinophil count, exhaled nitric oxide (FENO) and prednisone intake were measured. In a subgroup of patients, nasal cytology was performed before (T0), after 6 (T6) and after 12 months (T12) of treatment with mepolizumab.

Results: We reported a significant reduction of SNOT-22 [from 51.5 ± 21.2 at baseline (T0) to 31.70 ± 17.36 at T6 and 29.7 ± 21.5 at T12 (T0-T12  < 0.001)] and a decrease of TENPS (from 2.88 ± 3.07 to 1.70 ± 2.37 and 1.77 ± 2.56 at T0, T6 and T12, respectively, T0-T12  = 0.99). A significant improvement of %FEV, ACT and a decrease in blood eosinophils and mean prednisone intake were also reported. No statistically significant decreasing trend was measured for FENO. Nasal cytology findings suggest a significant reduction of eosinophil percentage following mepolizumab treatment (from 16.8 ± 7.2% to 3.6 ± 6.2% and 0.8 ± 2.4% at T0, T6 and T12 respectively, T0 to T12:  < 0.001).

Conclusions: Mepolizumab improves sino-nasal and asthma symptoms and reduces polyp growth in patients with severe eosinophilic asthma and concomitant CRSwNP in real life.
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http://dx.doi.org/10.1177/17534666211009398DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8107661PMC
April 2021

Analysis of Heart-Rate Variability during Angioedema Attacks in Patients with Hereditary C1-Inhibitor Deficiency.

Int J Environ Res Public Health 2021 03 12;18(6). Epub 2021 Mar 12.

Department of Medicine, IRCCS Istituti Clinici Scientifici Maugeri, 20138 Milan, Italy.

C1-inhibitor hereditary angioedema (C1-INH-HAE) is a rare disease characterized by self-limiting edema associated with localized vasodilation due to increased levels of circulating bradykinin. C1-INH-HAE directly influences patients' everyday lives, as attacks are unpredictable in frequency, severity, and the involved anatomical site. The autonomic nervous system could be involved in remission. The cardiac autonomic profile has not yet been evaluated during the attack or prodromal phases. In this study, a multiday continuous electrocardiogram was obtained in four C1-INH-HAE patients until attack occurrence. Power spectral heart rate variability (HRV) indices were computed over the 4 h preceding the attack and during the first 4 h of the attack in three patients. Increased vagal modulation of the sinus node was detected in the prodromal phase. This finding may reflect localized vasodilation mediated by the release of bradykinin. HRV analysis may furnish early markers of an impending angioedema attack, thereby helping to identify patients at higher risk of attack recurrence. In this perspective, it could assist in the timing, titration, and optimization of prophylactic therapy, and thus improve patients' quality of life.
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http://dx.doi.org/10.3390/ijerph18062900DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8002127PMC
March 2021

Granulomatous Lymphocytic Interstitial Lung Disease (GLILD) in Common Variable Immunodeficiency (CVID): A Multicenter Retrospective Study of Patients From Italian PID Referral Centers.

Front Immunol 2021 10;12:627423. Epub 2021 Mar 10.

Department of Molecular Medicine, "Sapienza" University of Rome, Rome, Italy.

Granulomatous and Lymphocytic Interstitial Lung Diseases (GLILD) is a severe non-infectious complication of Common Variable Immunodeficiency (CVID), often associated with extrapulmonary involvement. Due to a poorly understood pathogenesis, GLILD diagnosis and management criteria still lack consensus. Accordingly, it is a relevant cause of long-term loss of respiratory function and is closely associated with a markedly reduced survival. The aim of this study was to describe clinical, immunological, laboratory and functional features of GLILD, whose combination in a predictive model might allow a timely diagnosis. In a multicenter retrospective cross-sectional study we enrolled 73 CVID patients with radiologic features of interstitial lung disease (ILD) associated to CVID (CVID-ILD) and 125 CVID patients without ILD (controls). Of the 73 CVID-ILD patients, 47 received a definite GLILD diagnosis while 26 received a clinical-radiologic diagnosis of CVID related ILD defined as uILD. In GLILD group we found a higher prevalence of splenomegaly (84.8 vs. 39.2%), autoimmune cytopenia (59.6 vs. 6.4%) and bronchiectasis (72.3 vs. 28%), and lower IgA and IgG serum levels at CVID diagnosis. GLILD patients presented lower percentage of switched-memory B cells and marginal zone B cells, and a marked increase in the percentage of circulating CD21lo B cells (14.2 vs. 2.9%). GLILD patients also showed lower total lung capacity (TLC 87.5 vs. 5.0%) and gas transfer (DLCO 61.5 vs. 5.0%) percent of predicted. By univariate logistic regression analysis, we found IgG and IgA levels at CVID diagnosis, presence of splenomegaly and autoimmune cytopenia, CD21lo B cells percentage, TLC and DCLO percent of predicted to be associated to GLILD. The joint analysis of four variables (CD21lo B cells percentage, autoimmune cytopenia, splenomegaly and DLCO percent of predicted), together in a multiple logistic regression model, yielded an area under the ROC curve (AUC) of 0.98 (95% CI: 0.95-1.0). The AUC was only slightly modified when pooling together GLILD and uILD patients (0.92, 95% CI: 0.87-0.97). we propose the combination of two clinical parameters (splenomegaly and autoimmune cytopenia), one lung function index (DLCO%) and one immunologic variable (CD21lo%) as a promising tool for early identification of CVID patients with interstitial lung disease, limiting the use of aggressive diagnostic procedures.
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http://dx.doi.org/10.3389/fimmu.2021.627423DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987811PMC
March 2021

Vascular endothelial growth factors and angiopoietins as new players in mastocytosis.

Clin Exp Med 2021 Aug 9;21(3):415-427. Epub 2021 Mar 9.

Department of Translational Medical Sciences, University of Naples Federico II, 80131, Naples, Italy.

Mastocytosis is a disorder characterized by the abnormal proliferation and/or accumulation of mast cells in different organs. More than 90% of patients with systemic mastocytosis have a gain-of-function mutation in codon 816 of the KIT receptor on mast cells (MCs). The symptoms of mastocytosis patients are related to the MC-derived mediators that exert local and distant effects. MCs produce angiogenic and lymphangiogenic factors, including vascular endothelial growth factors (VEGFs) and angiopoietins (ANGPTs). Serum concentrations of VEGF-A, VEGF-C, VEGF-D, ANGPT1 and ANGPT2 were determined in 64 mastocytosis patients and 64 healthy controls. Intracellular concentrations and spontaneous release of these mediators were evaluated in the mast cell lines ROSA and ROSA and in human lung mast cells (HLMCs). VEGF-A, ANGPT1, ANGPT2 and VEGF-C concentrations were higher in mastocytosis patients compared to controls. The VEGF-A, ANGPT2 and VEGF-C concentrations were correlated with the symptom severity. ANGPT1 concentrations were increased in all patients compared to controls. ANGPT2 levels were correlated with severity of clinical variants and with tryptase levels. VEGF-A, ANGPT1 and VEGF-C did not differ between indolent and advanced mastocytosis. ROSA, ROSA and HLMCs contained and spontaneously released VEGFs and ANGPTs. Serum concentrations of VEGFs and ANGPTs are altered in mastocytosis patients.
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http://dx.doi.org/10.1007/s10238-021-00693-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8266723PMC
August 2021

Respiratory Manifestations in Primary Immunodeficiencies: Findings From a Pediatric and Adult Cohort.

Arch Bronconeumol (Engl Ed) 2021 Feb 5. Epub 2021 Feb 5.

Department of Translational Medical Sciences - Section of Pediatrics, University of Naples Federico II, Naples, Italy. Electronic address:

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http://dx.doi.org/10.1016/j.arbres.2021.01.019DOI Listing
February 2021

Therapeutic Effects of Benralizumab Assessed in Patients with Severe Eosinophilic Asthma: Real-Life Evaluation Correlated with Allergic and Non-Allergic Phenotype Expression.

J Asthma Allergy 2021 22;14:163-173. Epub 2021 Feb 22.

Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy.

Background: Benralizumab can be utilized as add-on biological treatment of severe eosinophilic asthma. However, so far only a few real-life studies have been published with regard to the use of this anti-IL-5 receptor humanized monoclonal antibody.

Objective: The primary aim of this multicenter observational investigation has been to assess the therapeutic effects of benralizumab in patients with severe uncontrolled, corticosteroid refractory eosinophilic asthma. The secondary objective was to evaluate the efficacy of benralizumab with regard to positive or negative skin prick test (SPT).

Methods: Clinical, functional, and laboratory parameters were evaluated in order to verify the therapeutic actions of benralizumab in atopic and non atopic subjects with difficult-to-treat eosinophilic asthma. Moreover, a comparative evaluation was carried out in relation to the presence or absence of SPT positivity.

Results: After 6 months of add-on biological therapy with benralizumab, our 111 patients experienced a marked improvement of their severe eosinophilic asthma, expressed by significant changes in asthma exacerbation rate, prednisone intake, daily use of short-acting β-adrenergic agonists (SABA), asthma control test (ACT) score, asthma quality of life questionnaire (AQLQ) score (56 patients), forced expiratory volume in one second (FEV), forced vital capacity (FVC), blood eosinophil count, blood basophil count (59 patients), and fractional exhaled nitric oxide (FeNO) levels (39 patients). In addition, significantly more effective outcomes were detected in patients with positive SPT, when compared to subjects with negative SPT, only in regard to asthma exacerbation number, ACT score, and daily SABA utilization. No significant correlation was found between serum IgE concentrations and each of all measured parameters.

Conclusion And Clinical Relevance: Taken together, the results of this real-world study indicate that in both allergic and non-allergic subjects benralizumab can be used as a valuable pharmacotherapeutic option for add-on biological therapy of severe eosinophilic asthma, regardless of SPT positivity or negativity.
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http://dx.doi.org/10.2147/JAA.S297273DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7910091PMC
February 2021

Orofacial granulomatosis: Clinical and therapeutic features in an Italian cohort and review of the literature.

Allergy 2021 Jul 15;76(7):2189-2200. Epub 2021 May 15.

Department of Translational Medical Sciences, Allergy and Clinical Immunology, Center for Basic and Clinical Immunology Research (CISI), WAO Center of Excellence, University of Naples Federico II, Naples, Italy.

Background: Orofacial granulomatosis (OFG) is characterized by granulomatous inflammation of the soft tissues of maxillofacial region. We explored OFG patients from 10 different Italian centers and summarized the most recent literature data.

Methods: A review of patients with OFG was carried out. An extensive online literature search was performed to identify studies reporting diagnosis and management of OFG.

Results: Thirty-nine patients were recruited between January 2018 and February 2020. Most of them (97.4%) displayed involvement of the lips, and 28.2% suffered from Melkersson-Rosenthal syndrome. Two patients received diagnosis of CD and one patient of sarcoidosis, suggesting secondary OFG. Oral aphthosis and cervical lymphadenopathy were also described. The mean diagnostic delay was 3.4 years. Histological evaluation was performed in 34/39 patients (87.2%); non-caseating granulomas were found in 73.5% of them. Neurological symptoms (28.2%), gastrointestinal symptoms in absence of overt inflammatory bowel disease (IBD) (20.5%), and atopy (35.9%) were also identified. Therapeutic approaches varied among the centers. Steroids (51.3%) were used with good or partial results. Anti-TNF-α and anti-IgE monoclonal antibodies were used in 6 (15.4%) and 1 (2.6%) patients, respectively, with variable results. Surgery was the choice for 2 patients with good response.

Conclusions: OFG is a rare and neglected disease showing multiple clinical phenotypes. While early diagnosis is crucial, management is difficult and highly dependent on the expertise of clinicians due to the lack of international guidelines. There is a need to establish registry databases and address challenges of long-term management.
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http://dx.doi.org/10.1111/all.14799DOI Listing
July 2021

IL-33 and Superantigenic Activation of Human Lung Mast Cells Induce the Release of Angiogenic and Lymphangiogenic Factors.

Cells 2021 Jan 12;10(1). Epub 2021 Jan 12.

Department of Translational Medical Sciences, University of Naples Federico II, 80131 Naples, Italy.

Human lung mast cells (HLMCs) express the high-affinity receptor FcεRI for IgE and are strategically located in different compartments of human lung, where they play a role in several inflammatory disorders and cancer. Immunoglobulin superantigens (e.g., protein A of and protein L of ) bind to the variable regions of either the heavy (V3) or light chain (κ) of IgE. IL-33 is a cytokine expressed by epithelial cells that exerts pleiotropic functions in the lung. The present study investigated whether immunoglobulin superantigens protein A and protein L and IL-33 caused the release of inflammatory (histamine), angiogenic (VEGF-A) and lymphangiogenic (VEGF-C) factors from HLMCs. The results show that protein A and protein L induced the rapid (30 min) release of preformed histamine from HLMCs. By contrast, IL-33 did not induce the release of histamine from lung mast cells. Prolonged incubation (12 h) of HLMCs with superantigens and IL-33 induced the release of VEGF-A and VEGF-C. Preincubation with IL-33 potentiated the superantigenic release of histamine, angiogenic and lymphangiogenic factors from HLMCs. Our results suggest that IL-33 might enhance the inflammatory, angiogenic and lymphangiogenic activities of lung mast cells in pulmonary disorders.
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http://dx.doi.org/10.3390/cells10010145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7828291PMC
January 2021

Psychological processes in the experience of hereditary angioedema in adult patients: an observational study.

Orphanet J Rare Dis 2021 01 9;16(1):23. Epub 2021 Jan 9.

Department of Humanities, University "Federico II", Naples, Italy.

Background: Hereditary angioedema associated to C1 inhibitor deficiency (C1-INH-HAE) is a pathological condition characterized by episodes of subcutaneous swelling and it is frequently associated with discomfort and social impairment of the patients, due to the anxiety experienced for an unpreventable manifestation of an attack during daily life. In children increased level of stress and alexithymia have been associated to C1-INH-HAE, and the latter correlated also with the severity of the disease. We hypothesized that the involvement of psychological issues may impact on the severity of C1-INH-HAE in adult patients as well, interfering with their ability to engage with the management of the disease.

Methods: 28 adult patients with C1-INH-HAE were evaluated for clinical (C1-INH-HAE Severity Score) and psychological factors (alexithymia, emotion regulation, stress, patient health engagement, general severity index) by means of validated questionnaires.

Results: Mean age (standard deviation [SD]) was 45 (11) years and time from diagnosis was 20 (12) years. The mean C1-INH-HAE severity score was 6.4. Alexithymia was absent in 22 (78%) patients. Moderate and high stress levels were present in 17 (61%) and 4 (14%) patients, respectively. Moderate-high discomfort was experienced by 9 (36%) patients and a discomfort beyond the clinical attention threshold was shown by 3 (12%) patients. Stress correlated with patient health engagement and with psychological discomfort.

Conclusions: In C1-INH-HAE, patients health engagement and moderate-high psychological discomfort are linked with stress but not with the severity of the disease or alexithymia. A better patient health engagement may be a target for psychological intervention in clinics to ameliorate the stress perceived by C1-INH-HAE patients.
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http://dx.doi.org/10.1186/s13023-020-01643-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7796642PMC
January 2021

Cardiovascular Toxicity of Immune Checkpoint Inhibitors: Clinical Risk Factors.

Curr Oncol Rep 2021 01 7;23(2):13. Epub 2021 Jan 7.

Department of Translational Medical Sciences, Federico II University, Naples, Italy.

Purpose Of Review: Immune checkpoint inhibitors, such as monoclonal antibodies targeting CTLA-4, PD-1, and PD-L1, have improved the outcome of many malignancies, but serious immune-related cardiovascular adverse events have been observed. Patients' risk factors for these toxicities are currently being investigated.

Recent Findings: Interfering with the CTLA-4 and PD-1 axes can bring to several immune-related adverse events, including cardiotoxic events such as autoimmune myocarditis, pericarditis, and vasculitis, suggesting that these molecules play an important role in preventing autoimmunity. Risk factors (such as pre-existing cardiovascular conditions, previous and concomitant cardiotoxic treatments, underlying autoimmune diseases, tumor-related factors, simultaneous immune-related toxic effects, and genetic factors) should be always recognized for the correct management of these toxicities.
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http://dx.doi.org/10.1007/s11912-020-01002-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7790474PMC
January 2021

Psychology and hereditary angioedema: A systematic review.

Allergy Asthma Proc 2021 01;42(1):e1-e7

From the Department of Humanities, University Federico II, Naples, Italy, and.

Hereditary angioedema (HAE) is caused by mutations in the C1 inhibitor (C1-INH) gene Serpin Family G Member 1(), which results in either the decreased synthesis of normal C1-INH (C1-INH-HAE type I) or expression of unfunctional C1-INH (C1-INH-HAE type II). In recent studies, emotional stress was reported by patients as the most common trigger factor for C1-INH-HAE attacks. Moreover, patients reported considerable distress over the significant variability and uncertainty with which the disease manifests, in addition to the impact of physical symptoms on their overall quality of life. We did a systematic review of the literature to shed light on the advancements made in the study of how stress and psychological processes impact C1-INH-HAE. All of the articles on C1-INH-HAE were analyzed up to December 2019. Both medical data bases and psychological data bases were examined. The keywords (KWs) used for searching the medical and psychological data bases were the following: "hereditary angioedema," "psychology," "stress," "anxiety," and "depression." Of a total of 2549 articles on C1-INH-HAE, 113 articles were retrieved from the literature search by using the related KWs. Twenty-one of these articles were retrieved, examined, and classified. Although the literature confirmed that stress may induce various physical diseases, it also warned against making simplistic statements about its incidence that did not take into account the complexity and multicausality of factors that contribute to C1-INH-HAE expression.
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http://dx.doi.org/10.2500/aap.2021.42.200073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7768073PMC
January 2021

Differently expressed microRNA in response to the first Ig replacement therapy in common variable immunodeficiency patients.

Sci Rep 2020 12 8;10(1):21482. Epub 2020 Dec 8.

Dipartimento di Scienze e Tecnologie Ambientali, Biologiche e Farmaceutiche (DISTABIF), Università della Campania "Luigi Vanvitelli", Via Vivaldi 43, 81100, Caserta, Italy.

Common variable immunodeficiency (CVID) is a complex primary immunodeficiency disorder characterized by a high clinical and genetic heterogeneity. The molecular underlying causes of CVID are not still now clear and the delays in diagnosis and treatment worsen the prognosis of the patients. MicroRNAs are non-coding, endogenous small RNAs often deregulated in human diseases, such as autoimmune and other immune-based disorders. In the present study, we aimed to evaluate miRNAs associated with the CVID and, in particular, with the response to the first Ig replacement therapy. To this aim, we compared miRNA profile obtained by serum samples of treatment-naïve CVID patients before and 24 h after the first Ig replacement therapy. For the first time, using a microarray assay followed by an integrated bioinformatics/biostatistics analysis, we identified five microRNAs (hsa-miR-6742, hsa-miR-1825, hsa-miR-4769-3p, hsa-miR-1228-3p, hsa-miR-1972) differently modulated in CVID patients by Ig infusion. All of them were down-regulated, excepted miR-6742 which was up-regulated. The latter may be of particular interest, since its functions are related to pathways involving Class I MHC mediated antigen processing and adaptive as well as innate Immune System. In conclusion, this study shows for the first time the modulation of miRNAs involved in CVID patients after the first Ig replacement therapy. Further studies are needed to assess whether such miRNAs could represent novel potential biomarkers in management and therapy of CVID patients.
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http://dx.doi.org/10.1038/s41598-020-77100-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7722869PMC
December 2020

Macrophage-polarizing stimuli differentially modulate the inflammatory profile induced by the secreted phospholipase A group IA in human lung macrophages.

Cytokine 2021 02 25;138:155378. Epub 2020 Nov 25.

Department of Translational Medical Sciences and Center for Basic and Clinical Immunology Research (CISI), University of Naples "Federico II", Naples, Italy; WAO Center of Excellence, Naples, Italy; Institute of Experimental Endocrinology and Oncology "G. Salvatore", National Research Council, Naples, Italy. Electronic address:

In this study we investigated the effects of snake venom Group IA secreted phospholipase A (svGIA) on the release of inflammatory and angiogenic mediators from human lung macrophages (HLMs). HLMs were incubated with lipopolysaccharide (LPS) or svGIA with or without macrophage-polarizing stimuli (IL-4, IL-10, IFN-γ or the adenosine analogue NECA). M2-polarizing cytokines (IL-4 and IL-10) inhibited TNF-α, IL-6, IL-12, IL-1β, CXCL8 and CCL1 release induced by both LPS and svGIA. IL-4 inhibited also the release of IL-10. IFN-γ reduced IL-10 and IL-12 and increased CCL1 release by both the LPS and svGIA-stimulated HLMs, conversely IFN-γ reduced IL-1β only by svGIA-stimulated HLMs. In addition, IFNγ promoted TNF-α and IL-6 release from svGIA-stimulated HLMs to a greater extent than LPS. NECA inhibited TNF-α and IL-12 but promoted IL-10 release from LPS-stimulated HLMs according to the well-known effect of adenosine in down-regulating M1 activation. By contrast NECA reduced TNF-α, IL-10, CCL1 and IL-1β release from svGIA-activated HLM. IL-10 and NECA increased both LPS- and svGIA-induced vascular endothelial growth factor A (VEGF-A) release. By contrast, IL-10 reduced angiopoietin-1 (ANGPT1) production from activated HLMs. IFN-γ and IL-4 reduced VEGF-A and ANGPT1 release from both LPS- and svGIA-activated HLMs. Moreover, IL-10 inhibited LPS-induced ANGPT2 production. In conclusion, we demonstrated a fine-tuning modulation of svGIA-activated HLMs differentially exerted by the classical macrophage-polarizing cytokines.
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http://dx.doi.org/10.1016/j.cyto.2020.155378DOI Listing
February 2021

Management of the patient with allergic and immunological disorders in the pandemic COVID-19 era.

Clin Mol Allergy 2020 1;18:18. Epub 2020 Oct 1.

Center of Advanced Science and Technology, G. D'Annunzio University, Chieti-Pescara, Italy.

The pandemic COVID-19 abruptly exploded, taking most health professionals around the world unprepared. Italy, the first European country to be hit violently, was forced to activate the lockdown in mid-February 2020. At the time of the spread, a high number of victims were quickly registered, especially in the regions of Northern Italy which have a high rate of highly-polluting production activities. The need to hospitalize the large number of patients with severe forms of COVID-19 led the National Health System to move a large number of specialists from their disciplines to the emergency hospital departments for the treatment of COVID-19. Furthermore, the lockdown itself has limited the possibility for general practitioners and pediatricians to be able to make outpatient visits and/or home care for patients with chronic diseases. Among them, the patient with atopic diseases, such as asthma, rhinitis and atopic dermatitis, is worthy of particular attention as she/he is immersed in a studded negative scenario with the onset of spring, a factor that should not be underestimated for those who suffer from pollen allergy. The Italian Society of Asthma Allergology and Clinical Immunology, to quickly deal with the lack of references and specialist medical procedures, has produced a series of indications for immunologic patient care that are reported in this paper, and can be used as guidelines by specialists of our discipline.
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http://dx.doi.org/10.1186/s12948-020-00134-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7528155PMC
October 2020

Oral CorticoSteroid sparing with biologics in severe asthma: A remark of the ().

World Allergy Organ J 2020 Oct 20;13(10):100464. Epub 2020 Sep 20.

Section of Respiratory Diseases, Medical and Surgical Sciences Department, University of Foggia, Italy.

According to the data derived from several national and international registries, including SANI (Severe Asthma Network Italy), and considering the strong impact that frequent or regular use of oral corticosteroid has on quality of life (QoL) of severe asthmatics, as well as on the costs for managing corticosteroid-related diseases, oral corticosteroid sparing up to withdrawal should be considered a primary outcome in the management of severe asthma. New biologics have clearly demonstrated that this effect is possible, with concomitant reduction in the rate of exacerbations and in symptom control. Then, there is no reason for using so frequently oral corticosteroid before having explored all alternatives currently available for a large part of severe asthmatics.
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http://dx.doi.org/10.1016/j.waojou.2020.100464DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7509464PMC
October 2020

Coronavirus disease 2019 in patients with inborn errors of immunity: An international study.

J Allergy Clin Immunol 2021 Feb 24;147(2):520-531. Epub 2020 Sep 24.

Istituto Molecolare "A Nocivelli," Department of Experimental and Clinical Sciences, University of Brescia & Asst Spedali civili, Brescia, Italy.

Background: There is uncertainty about the impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in individuals with rare inborn errors of immunity (IEI), a population at risk of developing severe coronavirus disease 2019. This is relevant not only for these patients but also for the general population, because studies of IEIs can unveil key requirements for host defense.

Objective: We sought to describe the presentation, manifestations, and outcome of SARS-CoV-2 infection in IEI to inform physicians and enhance understanding of host defense against SARS-CoV-2.

Methods: An invitation to participate in a retrospective study was distributed globally to scientific, medical, and patient societies involved in the care and advocacy for patients with IEI.

Results: We gathered information on 94 patients with IEI with SARS-CoV-2 infection. Their median age was 25 to 34 years. Fifty-three patients (56%) suffered from primary antibody deficiency, 9 (9.6%) had immune dysregulation syndrome, 6 (6.4%) a phagocyte defect, 7 (7.4%) an autoinflammatory disorder, 14 (15%) a combined immunodeficiency, 3 (3%) an innate immune defect, and 2 (2%) bone marrow failure. Ten were asymptomatic, 25 were treated as outpatients, 28 required admission without intensive care or ventilation, 13 required noninvasive ventilation or oxygen administration, 18 were admitted to intensive care units, 12 required invasive ventilation, and 3 required extracorporeal membrane oxygenation. Nine patients (7 adults and 2 children) died.

Conclusions: This study demonstrates that (1) more than 30% of patients with IEI had mild coronavirus disease 2019 (COVID-19) and (2) risk factors predisposing to severe disease/mortality in the general population also seemed to affect patients with IEI, including more younger patients. Further studies will identify pathways that are associated with increased risk of severe disease and are nonredundant or redundant for protection against SARS-CoV-2.
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http://dx.doi.org/10.1016/j.jaci.2020.09.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7832563PMC
February 2021

Role of Endothelial G Protein-Coupled Receptor Kinase 2 in Angioedema.

Hypertension 2020 11 8;76(5):1625-1636. Epub 2020 Sep 8.

Department of Medicine and Surgery (M.R., M.O., M.C.), University of Salerno, Italy.

Excessive BK (bradykinin) stimulation is responsible for the exaggerated permeabilization of the endothelium in angioedema. However, the molecular mechanisms underlying these responses have not been investigated. BK receptors are Gq-protein-coupled receptors phosphorylated by GRK2 (G protein-coupled receptor kinase 2) with a hitherto unknown biological and pathophysiological significance. In the present study, we sought to identify the functional role of GRK2 in angioedema through the regulation of BK signaling. We found that the accumulation of cytosolic Ca in endothelial cells induced by BK was sensitive to GRK2 activity, as it was significantly augmented by inhibiting the kinase. Accordingly, permeabilization and NO production induced by BK were enhanced, as well. In vivo, mice with reduced GRK2 levels in the endothelium (Tie2-CRE/GRK2) exhibited an increased response to BK in terms of vascular permeability and extravasation. Finally, patients with reduced GRK2 levels displayed a severe phenotype of angioedema. Taken together, these findings establish GRK2 as a novel pivotal regulator of BK signaling with an essential role in the pathophysiology of vascular permeability and angioedema.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.120.15130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7544666PMC
November 2020

Immunoglobulins G modulate endothelial function and affect insulin sensitivity in humans.

Nutr Metab Cardiovasc Dis 2020 10 10;30(11):2085-2092. Epub 2020 Jul 10.

Department of Translational Medical Sciences, Federico II University School of Medicine, Naples, Italy.

Background And Aims: Data from animals suggest that immunoglobulins G (IgG) play a mechanistic role in atherosclerosis and diabetes through endothelial dysfunction and insulin resistance. Patients with common variable immunodeficiency (CVID), who have low circulating levels of IgG and are treated with intravenous polyclonal IgG (IVIgG), may provide an ideal model to clarify whether circulating IgG modulate endothelial function and affect insulin sensitivity in humans.

Methods And Results: We studied 24 patients with CVID and 17 matched healthy controls (HC). Endothelial function was evaluated as flow mediated dilation (FMD) of the brachial artery at baseline and 1, 7, 14, and 21 days after IVIgG infusion in the CVID patients. We measured also plasma glucose, insulin, and calculated the HOMA-IR index. We also investigated the role of human IgG on the production of Nitric Oxide (NO) in vitro in Human Coronary Artery Endothelial Cells (HCAEC). Compared to HC, FMD of CVID patients was significantly impaired at baseline (9.4 ± 0.9 and 7.6 ± 0.6% respectively, p < 0.05) but rose above normal levels 1 and 7 days after IVIgG infusion to return at baseline at 14 and 21 days. Serum insulin concentration and HOMA-IR index dropped by 50% in CVID patients after IVIgG (p < 0.002 vs. baseline). In vitro IgG stimulated NO production in HCAEC.

Conclusions: Reduced IgG levels are associated with endothelial dysfunction and IVIgG stimulates endothelial function directly while improving insulin sensitivity. The current findings may suggest an anti-atherogenic role of human IgG.
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http://dx.doi.org/10.1016/j.numecd.2020.07.001DOI Listing
October 2020

The Italian Registry for Primary Immunodeficiencies (Italian Primary Immunodeficiency Network; IPINet): Twenty Years of Experience (1999-2019).

J Clin Immunol 2020 10 15;40(7):1026-1037. Epub 2020 Aug 15.

Department of Clinical and Molecular Medicine, Sapienza University, Rome, Italy.

Primary immunodeficiencies (PIDs) are heterogeneous disorders, characterized by variable clinical and immunological features. National PID registries offer useful insights on the epidemiology, diagnosis, and natural history of these disorders. In 1999, the Italian network for primary immunodeficiencies (IPINet) was established. We report on data collected from the IPINet registry after 20 years of activity. A total of 3352 pediatric and adult patients affected with PIDs are registered in the database. In Italy, a regional distribution trend of PID diagnosis was observed. Based on the updated IUIS classification of 2019, PID distribution in Italy showed that predominantly antibody deficiencies account for the majority of cases (63%), followed by combined immunodeficiencies with associated or syndromic features (22.5%). The overall age at diagnosis was younger for male patients. The minimal prevalence of PIDs in Italy resulted in 5.1 per 100.000 habitants. Mortality was similar to other European registries (4.2%). Immunoglobulin replacement treatment was prescribed to less than one third of the patient cohort. Collectively, this is the first comprehensive description of the PID epidemiology in Italy.
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http://dx.doi.org/10.1007/s10875-020-00844-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7505879PMC
October 2020

Gastrointestinal manifestations of angioedema: a potential area of misdiagnosis.

Eur J Gastroenterol Hepatol 2021 Jun;33(6):787-793

Department of Translational Medical Sciences and Center for Basic and Clinical Immunology Research (CISI), WAO Center of Excellence.

Abdominal pain is one of the most common conditions leading people to the emergency department. An uncommon but well described cause of abdominal pain is angioedema of the gastrointestinal tract due to recurrent angioedema without wheals. Abdominal involvement is very common in hereditary angioedema (HAE), but it is also described in acquired angioedema and allergic forms. In patients with HAE, the involvement of gastrointestinal tract with resultant abdominal pain occurs in 43-93% of cases. Attacks can involve the entire gastrointestinal tract, such as the oropharynx, small intestine, colon, liver, or pancreas. Pain is the most common gastrointestinal symptom, and it may occur for many years even without cutaneous or respiratory symptoms. The case report we included in this article emphasizes the importance of accurate evaluation of personal and family history in patients with a long history of acute, severe, and unexplained abdominal pain, and it gives an example of how diagnostic delay may be longer if gastroenterological symptoms are the predominant clinical presentation. Furthermore, sometimes the simultaneous presence of concomitant gastrointestinal disorders and HAE may cause difficulties in differential diagnosis. Gastroenterologists and other physicians should add HAE to their list of potential causes of unexplained abdominal pain. The initiation of appropriate prophylaxis and treatment will prevent needless suffering and useless surgical and medical procedures.
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http://dx.doi.org/10.1097/MEG.0000000000001848DOI Listing
June 2021

First Report of De Novo Nivolumab-Induced Oligoarthritis in a Young Man With Relapsing Classic Hodgkin Lymphoma.

J Clin Rheumatol 2020 Jun 6. Epub 2020 Jun 6.

Department of Translational Medical Sciences and Center for Basic and Clinical Immunology Research WAO Center of Excellence University of Naples Federico II Naples, Italy and Institute of Experimental Endocrinology and Oncology "G. Salvatore" National Research Council Naples, Italy Hematology-Oncology and Stem Cell Transplantation Unit Istituto Nazionale Tumori Fondazione "G. Pascale" IRCCS Naples, Italy Rheumatology, Allergology and Clinical Immunology Department of "Medicina dei Sistemi" University of Rome Tor Vergata Rome, Italy Postgraduate Program in Clinical Immunology and Allergy University of Naples Federico II Naples, Italy Hematology-Oncology and Stem Cell Transplantation Unit Istituto Nazionale Tumori Fondazione "G. Pascale" IRCCS Naples, Italy Department of Translational MedicalSciences and Center for Basic and Clinical Immunology Research WAO Center of ExcellenceUniversity of Naples Federico II Naples, Italy.

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http://dx.doi.org/10.1097/RHU.0000000000001459DOI Listing
June 2020

HIV gp120 Induces the Release of Proinflammatory, Angiogenic, and Lymphangiogenic Factors from Human Lung Mast Cells.

Vaccines (Basel) 2020 May 3;8(2). Epub 2020 May 3.

Department of Translational Medical Sciences, University of Naples Federico II, 80138 Naples, Italy.

Human lung mast cells (HLMCs) express the high-affinity receptor FcεRI for IgE and are involved in chronic pulmonary diseases occurring at high frequency among HIV-infected individuals. Immunoglobulin superantigens bind to the variable regions of either the heavy or light chain of immunoglobulins (Igs). Glycoprotein 120 (gp120) of HIV-1 is a typical immunoglobulin superantigen interacting with the heavy chain, variable 3 (V3) region of human Igs. The present study investigated whether immunoglobulin superantigen gp120 caused the release of different classes of proinflammatory and immunoregulatory mediators from HLMCs. The results show that gp120 from different clades induced the rapid (30 min) release of preformed mediators (histamine and tryptase) from HLMCs. gp120 also caused the de novo synthesis of cysteinyl leukotriene C (LTC) and prostaglandin D (PGD) from HLMCs. Incubation (6 h) of HLMC with gp120 induced the release of angiogenic (VEGF-A) and lymphangiogenic (VEGF-C) factors from HLMCs. The activating property of gp120 was mediated through the interaction with IgE V3 bound to FcεRI. Our data indicate that HIV gp120 is a viral superantigen, which induces the release of different proinflammatory, angiogenic, and lymphangiogenic factors from HLMCs. These observations could contribute to understanding, at least in part, the pathophysiology of chronic pulmonary diseases in HIV-infected individuals.
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http://dx.doi.org/10.3390/vaccines8020208DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7349869PMC
May 2020
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