Publications by authors named "Amato de Paulis"

80 Publications

THE ROLE OF CHEST CT IN DECIPHERING INTERSTITIAL LUNG INVOLVEMENT: SYSTEMIC SCLEROSIS VERSUS COVID-19.

Rheumatology (Oxford) 2021 Jul 28. Epub 2021 Jul 28.

Department of Experimental and Clinical Medicine, University of Florence, and Infectious and TropicalDiseases Unit, AOUC, Florence, Italy.

Objective: To identify the main computed tomography (CT) features that may help distinguishing a progression of interstitial lung disease (ILD) secondary to Systemic sclerosis (SSc) from COVID-19 pneumonia.

Methods: This multicentric study included 22 international readers divided in the radiologist group (RAD) and non-radiologist group (nRAD). A total of 99 patients, 52 with COVID-19 and 47 with SSc-ILD, were included in the study.

Results: Fibrosis inside focal ground glass opacities (GGO) in the upper lobes; fibrosis in the lower lobe GGO; reticulations in lower lobes (especially if bilateral and symmetrical or associated with signs of fibrosis) were the CT features most frequently associated with SSc-ILD. The CT features most frequently associated with COVID- 19 pneumonia were: consolidation (CONS) in the lower lobes, CONS with peripheral (both central/peripheral or patchy distributions), anterior and posterior CONS and rounded-shaped GGOs in the lower lobes. After multivariate analysis, the presence of CONS in the lower lobes (p < 0.0001) and signs of fibrosis in GGO in the lower lobes (p < 0.0001) remained independently associated with COVID-19 pneumonia or SSc-ILD, respectively. A predictive score was created which resulted positively associated with the COVID-19 diagnosis (96.1% sensitivity and 83.3% specificity).

Conclusion: The CT differential diagnosis between COVID-19 pneumonia and SSc-ILD is possible through the combination the proposed score and the radiologic expertise. The presence of consolidation in the lower lobes may suggest a COVID-19 pneumonia while the presence of fibrosis inside GGO may indicate a SSc-ILD.
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http://dx.doi.org/10.1093/rheumatology/keab615DOI Listing
July 2021

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

The N-Formyl Peptide Receptors and Rheumatoid Arthritis: A Dangerous Liaison or Confusing Relationship?

Front Immunol 2021 18;12:685214. Epub 2021 Jun 18.

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

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by a progressive symmetric inflammation of the joints resulting in bone erosion and cartilage destruction with a progressive loss of function and joint deformity. An increased number of findings support the role of innate immunity in RA: many innate immune mechanisms are responsible for producing several cytokines and chemokines involved in RA pathogenesis, such as Tumor Necrosis Factor (TNF)-α, interleukin (IL)-6, and IL-1. Pattern recognition receptors (PRRs) play a crucial role in modulating the activity of the innate arm of the immune response. We focused our attention over the years on the expression and functions of a specific class of PRR, namely formyl peptide receptors (FPRs), which exert a key function in both sustaining and resolving the inflammatory response, depending on the context and/or the agonist. We performed a broad review of the data available in the literature on the role of FPRs and their ligands in RA. Furthermore, we queried a publicly available database collecting data from 90 RA patients with different clinic features to evaluate the possible association between FPRs and clinic-pathologic parameters of RA patients.
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http://dx.doi.org/10.3389/fimmu.2021.685214DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8253054PMC
June 2021

Clinical predictors of psoriatic arthritis and osteoclast differentiation.

Exp Dermatol 2021 Jun 30. Epub 2021 Jun 30.

Department of Advanced Biomedical Sciences University of Naples Federico II, Naples, Italy.

Psoriasis and psoriatic arthritis (PsA) are interrelated inflammatory diseases. Psoriasis usually precedes PsA onset and represents a well-established risk factor for PsA development. Bone erosion is a hallmark of PsA, and the contribution of cutaneous psoriatic inflammation in this process has been demonstrated. However, little is still known on the pathogenetic mechanisms that link psoriatic skin to joint damage. Clinical features of psoriatic disease, including specific body site involvement, seem to be important risk predictors of PsA. The aim of this pilot research study was to investigate if psoriatic cutaneous inflammation, affecting these anatomical predictive sites for PsA, could be linked to osteoclast differentiation and activity. Our results showed that psoriasis skin localizations were positively related to the osteoclastogenic profile in psoriatic patients. These results provide new insights into the fascinating skin-joint axis concept.
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http://dx.doi.org/10.1111/exd.14424DOI Listing
June 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

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

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

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

Allergy 2021 07 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

Immunosuppressive Treatment in Antiphospholipid Syndrome: Is It Worth It?

Biomedicines 2021 Feb 1;9(2). Epub 2021 Feb 1.

Department of Translational Medical Sciences, University of Naples Federico II, Via S. Pansini 5, 80131 Naples, Italy.

The antiphospholipid syndrome (APS) is characterized by the development of venous and/or arterial thrombosis and pregnancy morbidity in patients with persistent antiphospholipid antibodies (aPL). Catastrophic antiphospholipid syndrome (CAPS) is a life-threatening form of APS occurring in about 1% of cases. Lifelong anticoagulation with vitamin K antagonists remains the cornerstone of the therapy for thrombotic APS, but frequently the use of anticoagulation may be problematic due to the increased risk of bleeding, drug interactions, or comorbidities. Immunosuppressant drugs are widely used to treat several autoimmune conditions, in which their safety and effectiveness have been largely demonstrated. Similar evidence in the treatment of primary APS is limited to case reports or case series, and studies on a large scale lack. Immunomodulatory drugs may be an emerging tool in managing such particular situations, like refractory obstetrical complications, CAPS, or so-called APS non-criteria manifestations. In addition, immunomodulatory drugs may be useful in patients experiencing recurrent thromboembolic events despite optimized anticoagulant therapy. We did a comprehensive review of literature analyzing the possible role of immunomodulation in primary APS to provide a broad overview of potentially safe and effective target treatments for managing this devastating disease.
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http://dx.doi.org/10.3390/biomedicines9020132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7911562PMC
February 2021

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

Cells 2021 01 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

Is There a Role for Basophils in Cancer?

Front Immunol 2020 8;11:2103. Epub 2020 Sep 8.

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

Basophils were identified in human peripheral blood by Paul Ehrlich over 140 years ago. Human basophils represent <1% of peripheral blood leukocytes. During the last decades, basophils have been described also in mice, guinea pigs, rabbits, and monkeys. There are many similarities, but also several immunological differences between human and mouse basophils. There are currently several strains of mice with profound constitutive or inducible basophil deficiency useful to prove that these cells have specific roles . However, none of these mice are solely and completely devoid of all basophils. Therefore, the relevance of these findings to humans remains to be established. It has been known for some time that basophils have the propensity to migrate into the site of inflammation. Recent observations indicate that tissue resident basophils contribute to lung development and locally promote M2 polarization of macrophages. Moreover, there is increasing evidence that lung-resident basophils exhibit a specific phenotype, different from circulating basophils. Activated human and mouse basophils synthesize restricted and distinct profiles of cytokines. Human basophils produce several canonical (e.g., VEGFs, angiopoietin 1) and non-canonical (i.e., cysteinyl leukotriene C) angiogenic factors. Activated human and mouse basophils release extracellular DNA traps that may have multiple effects in cancer. Hyperresponsiveness of basophils has been demonstrated in patients with JAK2-positive polycythemia vera. Basophils are present in the immune landscape of human lung adenocarcinoma and pancreatic cancer and can promote inflammation-driven skin tumor growth. The few studies conducted thus far using different models of basophil-deficient mice have provided informative results on the roles of these cells in tumorigenesis. Much more remains to be discovered before we unravel the hitherto mysterious roles of basophils in human and experimental cancers.
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http://dx.doi.org/10.3389/fimmu.2020.02103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7505934PMC
April 2021

Nitrodi thermal water downregulates protein S‑nitrosylation in RKO cells.

Int J Mol Med 2020 Oct 16;46(4):1359-1366. Epub 2020 Jul 16.

Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, I-80131 Naples, Italy.

Balneotherapy and spa therapy have been used in the treatment of ailments since time immemorial. Moreover, there is evidence to suggest that the beneficial effects of thermal water continue for months following the completion of treatment. The mechanisms through which thermal water exerts its healing effects remain unknown. Both balneological and hydroponic therapy at 'the oldest spa in the world', namely, the Nitrodi spring on the Island of Ischia (Southern Italy) are effective in a number of diseases and conditions. The aim of the present study was to investigate the molecular basis underlying the therapeutic effects of Nitrodi spring water in low‑grade inflammation and stress‑related conditions. For this purpose, an in vitro model was devised in which RKO colorectal adenocarcinoma cells were treated with phosphate‑buffered saline or phosphate‑buffered saline prepared with Nitrodi water for 4 h daily, 5 days a week for 6 weeks. The RKO cells were then subjected to the following assays: 3‑(4,5‑Dimethylthiazol‑2‑yl)‑2,5‑diphenyl‑2H‑tetrazolium bromide assay, Transwell migration assay, western blot analysis, the fluorimetric detection of protein S‑nitrosothiols and S‑nitrosylation western blot analysis. The results revealed that Nitrodi spring water promoted cell migration and cell viability, and downregulated protein S‑nitrosylation, probably also the nitrosylated active form of the cyclooxygenase (COX)‑2 protein. These results concur with all the previously reported therapeutic properties of Nitrodi spring water, and thus reinforce the concept that this natural resource is an important complementary therapy to traditional medicine.
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http://dx.doi.org/10.3892/ijmm.2020.4676DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7447308PMC
October 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

Persistence of Mast Cell-Positive Synovitis in Early Rheumatoid Arthritis Following Treatment With Conventional Synthetic Disease Modifying Anti-Rheumatic Drugs.

Front Pharmacol 2020 14;11:1051. Epub 2020 Jul 14.

Centre for Experimental Medicine & Rheumatology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.

Mast cells (MCs) are immune cells infiltrating the synovial membrane and implicated in the pathogenesis of Rheumatoid Arthritis (RA). Their infiltration in the synovia of early RA patients has been shown to be associated with systemic inflammation, disease activity and autoantibody positivity. Here, we analyzed their presence in matched synovial samples obtained by ultrasound-guided synovial biopsies pre- and post-treatment with conventional synthetic Disease Modifying Anti-Rheumatic Drugs (csDMARDs) (n=20). Upon IHC staining, patients were classified as MC based on the presence/absence of CD117+ synovial MCs. At baseline, MC patients had significantly higher synovial inflammation, inflammatory markers, disease activity and a higher prevalence of lympho-myeloid aggregates. Synovial biopsies after 6 months of treatment with csDMARDs showed a significant reduction of synovitis scores, but only a partial reduction of MC numbers. Accordingly, 45% of patients (9/20) were MC after treatment, in association with significantly higher degree of synovitis and higher proportion lympho-myeloid aggregates. Finally, significantly lower patients with MC synovitis at 6 months reached Low Disease Activity (LDA), while the association of MCs with disease activity was independent from lymphoid aggregates, after adjustment for BMI and age. Overall, this study confirms the relevance of MCs as part of the inflammatory infiltrate in the synovia of RA patients, warranting further investigations in larger cohorts to clarify their role in disease progression and response to treatment and their relevance as prognostic markers and potential therapeutic targets.
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http://dx.doi.org/10.3389/fphar.2020.01051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7371927PMC
July 2020

Gastrointestinal manifestations of angioedema: a potential area of misdiagnosis.

Eur J Gastroenterol Hepatol 2021 06;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

The Role of Endogenous Eicosapentaenoic Acid and Docosahexaenoic Acid-Derived Resolvins in Systemic Sclerosis.

Front Immunol 2020 19;11:1249. Epub 2020 Jun 19.

Department of Experimental and Clinical Medicine, University of Florence and Department of Geriatric Medicine, Division of Rheumatology AOUC, Florence, Italy.

Resolvins, the member of specialized pro-resolving mediators, are produced from omega-3 polyunsaturated fatty acids as a response to an acute inflammatory process in that termination and resolution of inflammation. In the acute inflammation, these lipid mediators limit polymorphonuclear cells infiltration, proinflammatory cytokine production; promote efferocytosis, and regulate several cell types being important roles in innate and adaptive immunity. Any dysregulation or defect of the resolution phase result in prolonged, persistent inflammation and eventually fibrosis. Resolvins are implicated in the development of various chronic autoimmune diseases. Systemic sclerosis (SSc) is a very complicated, chronic autoimmune disorder proceeding with vasculopathy, inflammation, and fibrosis. Dysregulation of innate and adaptive immunity is another important contributing factor in the pathogenesis of SSc. In this review, we will focus on the different roles of this new family of lipid mediators, characterized by the ability to prevent the spread of inflammation and its chronicity in various ways and how they can control the development of fibrotic diseases like SSc.
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http://dx.doi.org/10.3389/fimmu.2020.01249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7318896PMC
April 2021

Pulmonary Hypertension Phenotypes in Systemic Sclerosis: The Right Diagnosis for the Right Treatment.

Int J Mol Sci 2020 Jun 22;21(12). Epub 2020 Jun 22.

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

Systemic sclerosis is an auto-immune disease characterized by skin involvement that often affects multiple organ systems. Pulmonary hypertension is a common finding that can significantly impact prognosis. Molecular pathophysiological mechanisms underlying pulmonary hypertension in systemic sclerosis can be extremely heterogeneous, leading to distinct clinical phenotypes. In addition, different causes of pulmonary hypertension may overlap within the same patient. Since pulmonary hypertension treatment is very different for each phenotype, it is fundamental to perform an adequate diagnostic work-up to properly and promptly identify the prevalent mechanism underlying pulmonary hypertension in order to start the right therapies. When pulmonary hypertension is caused by a primary vasculopathy of the small pulmonary arteries, treatment with pulmonary vasodilators, often in an initial double-combination regimen, is indicated, aimed at reducing the mortality risk profile. In this review, we describe the different clinical phenotypes of pulmonary hypertension in the scleroderma population and discuss the utility of clinical tools to identify the presence of pulmonary vascular disease. Furthermore, we focus on systemic sclerosis-associated pulmonary arterial hypertension, highlighting the advances in the knowledge of right ventricular dysfunction in this setting and the latest updates in terms of treatment with pulmonary vasodilator drugs.
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http://dx.doi.org/10.3390/ijms21124430DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352262PMC
June 2020

Angiopoietins, Vascular Endothelial Growth Factors and Secretory Phospholipase A in Ischemic and Non-Ischemic Heart Failure.

J Clin Med 2020 Jun 19;9(6). Epub 2020 Jun 19.

Department of Translational Medical Sciences, University of Naples Federico II, 80100 Naples, Italy.

Heart failure (HF) is a growing public health burden, with high prevalence and mortality rates. In contrast to ischemic heart failure (IHF), the diagnosis of non-ischemic heart failure (NIHF) is established in the absence of coronary artery disease. Angiopoietins (ANGPTs), vascular endothelial growth factors (VEGFs) and secretory phospholipases A (sPLAs) are proinflammatory mediators and key regulators of endothelial cells. In the present manuscript, we analyze the plasma concentrations of angiogenic (ANGPT1, ANGPT2, VEGF-A) and lymphangiogenic (VEGF-C, VEGF-D) factors and the plasma activity of sPLA in patients with IHF and NIHF compared to healthy controls. The concentrations of ANGPT1, ANGPT2 and their ratio significantly differed between HF patients and healthy controls. Similarly, plasma levels of VEGF-D and sPLA activity were higher in HF as compared to controls. Concentrations of ANGPT2 and the ANGPT2/ANGPT1 ratio (an index of vascular permeability) were increased in NIHF patients. VEGF-A and VEGF-C concentrations did not differ among the three examined groups. Interestingly, VEGF-D was selectively increased in IFH patients compared to controls. Plasma activity of sPLA was increased in IHF and NIHF patients compared to controls. Our results indicate that several regulators of vascular permeability and smoldering inflammation are specifically altered in IHF and NIHF patients. Studies involving larger cohorts of these patients will be necessary to demonstrate the clinical implications of our findings.
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http://dx.doi.org/10.3390/jcm9061928DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7356305PMC
June 2020

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

Metabolic Checkpoints in Rheumatoid Arthritis.

Front Physiol 2020 17;11:347. Epub 2020 Apr 17.

Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom.

Several studies have highlighted the interplay between metabolism, immunity and inflammation. Both tissue resident and infiltrating immune cells play a major role in the inflammatory process of rheumatoid arthritis (RA) via the production of cytokines, adipo-cytokines and metabolic intermediates. These functions are metabolically demanding and require the most efficient use of bioenergetic pathways. The synovial membrane is the primary site of inflammation in RA and exhibits distinctive histological patterns characterized by different metabolism, prognosis and response to treatment. In the RA synovium, the high energy demand by stromal and infiltrating immune cells, causes the accumulation of metabolites, and adipo-cytokines, which carry out signaling functions, as well as activating transcription factors which act as metabolic sensors. These events drive immune and joint-resident cells to acquire pro-inflammatory effector functions which in turn perpetuate chronic inflammation. Whether metabolic changes are a consequence of the disease or one of the causes of RA pathogenesis is still under investigation. This review covers our current knowledge of cell metabolism in RA. Understanding the intricate interactions between metabolic pathways and the inflammatory and immune responses will provide more awareness of the mechanisms underlying RA pathogenesis and will identify novel therapeutic options to treat this disease.
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http://dx.doi.org/10.3389/fphys.2020.00347DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7180190PMC
April 2020

Systemic sclerosis and the COVID-19 pandemic: World Scleroderma Foundation preliminary advice for patient management.

Ann Rheum Dis 2020 06 29;79(6):724-726. Epub 2020 Apr 29.

Infectious Diseases Unit, Department of Translational and Precision Medicine, Sapienza University of Rome, Roma, Lazio, Italy.

Due to the frequent presence of interstitial lung disease and widespread use of immunosuppressive treatment, systemic sclerosis (SSc) patients may be considered at risk for a more severe disease course and higher mortality when they develop Severe Acute Respiratory Syndrome - Coronavirus - 2 (SARS-CoV-2) virus infection. Therefore, with World Scleroderma Foundation endorsement, experts from different specialties including rheumatology, virology and clinical immunology gathered virtually to answer to the main practical clinical questions regarding SARS-CoV-2 infection coming from both patients and physicians. This preliminary advice is aligned with other national and international recommendations, adapted for SSc patients.
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http://dx.doi.org/10.1136/annrheumdis-2020-217407DOI Listing
June 2020

Early Disease and Low Baseline Damage as Predictors of Response to Belimumab in Patients With Systemic Lupus Erythematosus in a Real-Life Setting.

Arthritis Rheumatol 2020 08 12;72(8):1314-1324. Epub 2020 Jun 12.

Università degli Studi di Genova, Genoa, Italy.

Objective: To investigate predictors of response, remission, low disease activity, damage, and drug discontinuation in patients with systemic lupus erythematosus (SLE) who were treated with belimumab.

Methods: In this retrospective study of a multicenter cohort of SLE patients who received intravenous belimumab, the proportion of patients who achieved remission, low disease activity, and treatment response according to the SLE Responder Index 4 (SRI-4) was determined, and the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI) was used to score disease damage yearly over the follow-up. Predictors of outcomes were analyzed by multivariate logistic regression with the results expressed as odds ratios (ORs) and 95% confidence intervals (95% CIs).

Results: The study included 466 patients with active SLE from 24 Italian centers, with a median follow-up period of 18 months (range 1-60 months). An SRI-4 response was achieved by 49.2%, 61.3%, 69.7%, 69.6%, and 66.7% of patients at 6, 12, 24, 36, and 48 months, respectively. Baseline predictors of response at 6 months included a score of ≥10 on the SLE Disease Activity Index 2000 (SLEDAI-2K) (OR 3.14 [95% CI 2.033-4.860]) and a disease duration of ≤2 years (OR 1.94 [95% CI 1.078-3.473). Baseline predictors of response at 12 months included a score of ≥10 on the SLEDAI-2K (OR 3.48 [95% CI 2.004-6.025]) and an SDI score of 0 (OR 1.74 [95% CI 1.036-2.923]). Baseline predictors of response at 24 months included a score of ≥10 on the SLEDAI-2K (OR 4.25 [95% CI 2.018-8.940]) and a disease duration of ≤2 years (OR 3.79 [95% CI 1.039-13.52]). Baseline predictors of response at 36 months included a score of ≥10 on the SLEDAI-2K (OR 14.59 [95% CI 3.54-59.79) and baseline status of current smoker (OR 0.19 [95% CI 0.039-0.69]). Patients who were in remission for ≥25% of the follow-up period (44.3%) or who had low disease activity for ≥50% of the follow-up period (66.1%) accrued significantly less damage (P = 0.046 and P = 0.007). A baseline SDI score of 0 was an independent predictor of achieving low disease activity in ≥50% of the follow-up period and remission in ≥25% of the follow-up period. Our findings suggest that the lower the baseline damage, the greater the probability of achieving remission over the course of ≥25% of the follow-up. Further, there was a negative association between the number of flares reported prior to belimumab initiation and the frequency of belimumab discontinuation due to inefficacy (P = 0.009).

Conclusion: In patients with active SLE and low damage at baseline, treatment with belimumab early in the disease may lead to favorable outcomes in a real-life setting.
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http://dx.doi.org/10.1002/art.41253DOI Listing
August 2020

Anaplastic Thyroid Cancer Cells Induce the Release of Mitochondrial Extracellular DNA Traps by Viable Neutrophils.

J Immunol 2020 03 20;204(5):1362-1372. Epub 2020 Jan 20.

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

Neutrophils are key effector cells that orchestrate inflammatory responses in the tumor microenvironment. Although neutrophil extracellular DNA traps (NETs) entrap and kill pathogens, they also contribute to chronic inflammation and cancer progression. Thyroid cancer (TC) is the most frequently occurring cancer of the endocrine system, accounting for 70% of deaths due to endocrine tumors. Although anaplastic TC (ATC) is rare among TCs, it is highly lethal. We demonstrated in a recent study that tumor-infiltrating neutrophil density correlated with TC size. Moreover, TC-derived soluble mediators modulate the human neutrophil phenotype. Our study aimed to investigate the involvement of NETs in human TC. Highly purified neutrophils from healthy donors were primed in vitro with a papillary TC or ATC cell line conditioned medium (CM) or with a normal thyroid CM as control. NET release was quantified using a High-Content Imaging System. Neutrophil viability was assessed by flow cytometry. Fluorescence microscopy, flow cytometry, and PCR were performed to determine the mitochondrial origin of ATC-induced NETs. ATC CM-primed neutrophils were cocultured with ATC cells to determine the effects exerted by NETs on cell proliferation. ATC CM induce NET release, whereas papillary TC or normal thyroid CM did not. ATC CM-induced NET production occurred in a reactive oxygen species-dependent and cell death-independent manner and was associated with mitochondrial reactive oxygen species production; the NETs contained mitochondrial DNA. ATC CM-primed neutrophils promoted ATC cell proliferation in a NET-dependent manner.
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http://dx.doi.org/10.4049/jimmunol.1900543DOI Listing
March 2020

Speckle tracking echocardiography in patients with systemic lupus erythematosus: A meta-analysis.

Eur J Intern Med 2020 03 3;73:16-22. Epub 2020 Jan 3.

Department of Advanced Biomedical Sciences, Federico II University, Naples, Italy.

Background: Systemic lupus erythematosus (SLE), is characterized by a systemic involvement including myocardial dysfunction. Being standard echocardiography not able at fully detecting subclinical alterations, speckle tracking echocardiography (STE) has recently emerged as a quantitative ultrasound technique to accurately estimate myocardial function.

Methods: We conducted a systematic review with meta-analysis of studies reporting STE parameters in patients with SLE.

Results: A total of 9 studies were included in the analysis. Left ventricle global longitudinal strain (GLS) was significantly lower in SLE patients than in non-SLE controls (MD: -2.331, 95% CI: -3.083, -1.580, p < 0.001). In addition, we found significant differences between SLE patients and non-SLE controls in left ventricle GLS rate (MD: -0.115, 95% CI: -0.177 to 0.063, p < 0.001), left ventricle circumferential strain(MD: -1.841, 95% CI: -3.160 to 0.521, p = 0.006) and left ventricle radial strain(MD: -11.03, 95% CI: -13.819 to 8.241, p < 0.001). Right ventricle strain was significantly lower in SLE patients than in non-SLE controls (MD: -5.814, 95% CI: -7.347, -4.281, p < 0.001). Meta-regression models showed a lower difference in left ventricle GLS between SLE cases and controls for studies with a higher prevalence of female gender and higher prevalence of hypertension.

Conclusions: SLE patients have lower STE parameters than controls, thus suggesting the presence of an impaired myocardial function involving both left and right ventricle.
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http://dx.doi.org/10.1016/j.ejim.2019.12.033DOI Listing
March 2020

Lactate: Fueling the fire starter.

Wiley Interdiscip Rev Syst Biol Med 2020 05 16;12(3):e1474. Epub 2019 Dec 16.

Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.

It is becoming increasingly appreciated that intermediates of metabolic pathways, besides their anabolic and catabolic functions, can act as signaling molecules and influence the outcome of immune responses. Although lactate was previously considered as a waste product of glucose metabolism, accumulating evidence has highlighted its pivotal role in regulating diverse biological processes, including immune cell polarization, differentiation and effector functions. In addition, lactate is a key player in modulating tumor immune surveillance. Hence, targeting lactate-induced signaling pathways is a promising tool to reduce inflammation, to prevent autoimmunity and to restore anti-tumor immune response. This article is characterized under: Biological Mechanisms > Metabolism.
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http://dx.doi.org/10.1002/wsbm.1474DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7187281PMC
May 2020

The Renal Resistive Index in systemic sclerosis: Determinants, prognostic implication and proposal for specific age-adjusted cut-offs.

Eur J Intern Med 2019 Dec 17;70:43-49. Epub 2019 Sep 17.

Department of Experimental and Clinical Medicine, Division of Rheumatology, University of Florence, Via Delle Oblate 4, 50134 Florence, Italy; Department of Geriatric Medicine, Division of Rheumatology, Azienda Ospedaliera Universitaria Careggi, Florence, Italy.

Background: Renal Resistive Index (RRI), reflects changes in both renal vascular and tubular-interstitial compartments and in systemic vascular compliance related to age and comorbidities.

Objectives: a) To investigate determinants of RRI in SSc population, b) its association with SSc-related features and c) to test its prognostic impact on organ specific worsening or death.

Methods: 380 SSc patients ≥18 years were enrolled after giving informed consent. Baseline data on RRI, laboratory, instrumental and therapeutic features were retrospectively collected. Age-SSc adjusted cut-offs were created by dividing the population in age quartiles and considering RRI values >75th percentile as pathologic. Clinical follow-up was performed until last available visit or the development/worsening of specific internal organ involvement or death.

Results: RRI was independently predicted by age and systolic pulmonary arterial pressure on Echo. Therefore, we created Age-SSc adjusted pathologic RRI cut-offs, which were significantly associated with various disease related skin and lung fibrotic manifestations, as well as vasculopathic complications. After a mean follow-up of 3.6 ± 2.6 years, RRI was one of the independent predictors (together with modified Rodnan skin score, interstitial lung disease, presence of dyspnoea and late nailfold-videocapillaroscopy pattern) for mortality, with 0.68 as best cut-off (sensitivity 88.5%, specificity 50.9%).

Conclusion: If corroborated, Renal Resistive Index cut-offs might be used to evaluate renal and extrarenal involvement in SSc and could serve as predictors of mortality.
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http://dx.doi.org/10.1016/j.ejim.2019.09.001DOI Listing
December 2019

Future Needs in Mast Cell Biology.

Int J Mol Sci 2019 Sep 6;20(18). Epub 2019 Sep 6.

Departments of Pathology and of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305-5176, USA.

The pathophysiological roles of mast cells are still not fully understood, over 140 years since their description by Paul Ehrlich in 1878. Initial studies have attempted to identify distinct "subpopulations" of mast cells based on a relatively small number of biochemical characteristics. More recently, "subtypes" of mast cells have been described based on the analysis of transcriptomes of anatomically distinct mouse mast cell populations. Although mast cells can potently alter homeostasis, in certain circumstances, these cells can also contribute to the restoration of homeostasis. Both solid and hematologic tumors are associated with the accumulation of peritumoral and/or intratumoral mast cells, suggesting that these cells can help to promote and/or limit tumorigenesis. We suggest that at least two major subsets of mast cells, MC1 (meaning anti-tumorigenic) and MC2 (meaning pro-tumorigenic), and/or different mast cell mediators derived from otherwise similar cells, could play distinct or even opposite roles in tumorigenesis. Mast cells are also strategically located in the human myocardium, in atherosclerotic plaques, in close proximity to nerves and in the aortic valve. Recent studies have revealed evidence that cardiac mast cells can participate both in physiological and pathological processes in the heart. It seems likely that different subsets of mast cells, like those of cardiac macrophages, can exert distinct, even opposite, effects in different pathophysiological processes in the heart. In this chapter, we have commented on possible future needs of the ongoing efforts to identify the diverse functions of mast cells in health and disease.
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http://dx.doi.org/10.3390/ijms20184397DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6769913PMC
September 2019

The Immune Landscape of Thyroid Cancer in the Context of Immune Checkpoint Inhibition.

Int J Mol Sci 2019 Aug 13;20(16). Epub 2019 Aug 13.

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

Immune cells play critical roles in tumor prevention as well as initiation and progression. However, immune-resistant cancer cells can evade the immune system and proceed to form tumors. The normal microenvironment (immune cells, fibroblasts, blood and lymphatic vessels, and interstitial extracellular matrix (ECM)) maintains tissue homeostasis and prevents tumor initiation. Inflammatory mediators, reactive oxygen species, cytokines, and chemokines from an altered microenvironment promote tumor growth. During the last decade, thyroid cancer, the most frequent cancer of the endocrine system, has emerged as the fifth most incident cancer in the United States (USA), and its incidence is steadily growing. Inflammation has long been associated with thyroid cancer, raising critical questions about the role of immune cells in its pathogenesis. A plethora of immune cells and their mediators are present in the thyroid cancer ecosystem. Monoclonal antibodies (mAbs) targeting immune checkpoints, such as mAbs anti-cytotoxic T lymphocyte antigen 4 (anti-CTLA-4) and anti-programmed cell death protein-1/programmed cell death ligand-1 (anti-PD-1/PD-L1), have revolutionized the treatment of many malignancies, but they induce thyroid dysfunction in up to 10% of patients, presumably by enhancing autoimmunity. Combination strategies involving immune checkpoint inhibitors (ICIs) with tyrosine kinase (TK) or serine/threonine protein kinase B-raf (BRAF) inhibitors are showing considerable promise in the treatment of advanced thyroid cancer. This review illustrates how different immune cells contribute to thyroid cancer development and the rationale for the antitumor effects of ICIs in combination with BRAF/TK inhibitors.
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http://dx.doi.org/10.3390/ijms20163934DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6720642PMC
August 2019

Physiological Roles of Mast Cells: Collegium Internationale Allergologicum Update 2019.

Int Arch Allergy Immunol 2019 28;179(4):247-261. Epub 2019 May 28.

Department of Translational Medical Sciences (DiSMeT), Naples, Italy,

Mast cells are immune cells which have a widespread distribution in nearly all tissues. These cells and their mediators are canonically viewed as primary effector cells in allergic disorders. However, in the last years, mast cells have gained recognition for their involvement in several physiological and pathological conditions. They are highly heterogeneous immune cells displaying a constellation of surface receptors and producing a wide spectrum of inflammatory and immunomodulatory mediators. These features enable the cells to act as sentinels in harmful situations as well as respond to metabolic and immune changes in their microenvironment. Moreover, they communicate with many immune and nonimmune cells implicated in several immunological responses. Although mast cells contribute to host responses in experimental infections, there is no satisfactory model to study how they contribute to infection outcome in humans. Mast cells modulate physiological and pathological angiogenesis and lymphangiogenesis, but their role in tumor initiation and development is still controversial. Cardiac mast cells store and release several mediators that can exert multiple effects in the homeostatic control of different cardiometabolic functions. Although mast cells and their mediators have been simplistically associated with detrimental roles in allergic disorders, there is increasing evidence that they can also have homeostatic or protective roles in several pathophysiological processes. These findings may reflect the functional heterogeneity of different subsets of mast cells.
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http://dx.doi.org/10.1159/000500088DOI Listing
September 2019
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