Publications by authors named "Francesca Wanda Rossi"

35 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10238-021-00693-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8266723PMC
August 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/biomedicines9020132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7911562PMC
February 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-020-77100-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7722869PMC
December 2020

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3892/ijmm.2020.4676DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7447308PMC
October 2020

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms21124430DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352262PMC
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fphys.2020.00347DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7180190PMC
April 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejim.2019.12.033DOI Listing
March 2020

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000500088DOI Listing
September 2019

Immunosuppressive therapy with rituximab in common variable immunodeficiency.

Clin Mol Allergy 2019 6;17. Epub 2019 May 6.

1Department of Translational Medical Sciences and Center for Basic and Clinical Immunology Research (CISI), World Allergy Organization (WAO) Center of Excellence, University of Naples Federico II, Via S. Pansini 5, 80131 Naples, Italy.

Common variable immunodeficiency (CVID) is the most frequent symptomatic primary antibody deficiency in adulthood and is characterized by the marked reduction of IgG and IgA serum levels. Thanks to the successful use of polyvalent immunoglobulin replacement therapy to treat and prevent recurrent infections, non-infectious complications, including autoimmunity, polyclonal lymphoproliferation and malignancies, have progressively become the major cause of morbidity and mortality in CVID patients. The management of these complications is particularly challenging, often requiring multiple lines of immunosuppressive treatments. Over the last 5-10 years, the anti-CD20 monoclonal antibody (i.e., rituximab) has been increasingly used for the treatment of both autoimmune and non-malignant lymphoproliferative manifestations associated with CVID. This review illustrates the evidence on the use of rituximab in CVID. For this purpose, first we discuss the mechanisms proposed for the rituximab mediated B-cell depletion; then, we analyze the literature data regarding the CVID-related complications for which rituximab has been used, focusing on autoimmune cytopenias, granulomatous lymphocytic interstitial lung disease (GLILD) and non-malignant lymphoproliferative syndromes. The cumulative data suggest that in the vast majority of the studies, rituximab has proven to be an effective and relatively safe therapeutic option. However, there are currently no data on the long-term efficacy and side effects of rituximab and other second-line therapeutic options. Further randomized controlled trials are needed to optimize the management strategies of non-infectious complications of CVID.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12948-019-0113-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6501382PMC
May 2019

Mast Cells in Early Rheumatoid Arthritis.

Int J Mol Sci 2019 Apr 25;20(8). Epub 2019 Apr 25.

Department of Translational Medical Sciences (DiSMeT) and Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, 80131 Naples, Italy.

Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease characterized by inflammation of the synovial membrane, with thickening of the synovial layer, cellular hyperplasia, and infiltration of immune cells. Mast cells (MCs) are cells of the innate immunity present in healthy synovia and part of the cellular hyperplasia characterizing RA synovitis. Although their presence in synovia has been well described, the exact functions and the correlation of MCs with disease development and progression have been debated, particularly because of contradictory data obtained in animal models and from patients with longstanding disease. Here, we present a revision of the literature on MCs in RA, including the most recent observations obtained from patients with early RA, indicating MCs as relevant markers of disease severity in early RA.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms20082040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6515166PMC
April 2019

Vascular Leaking, a Pivotal and Early Pathogenetic Event in Systemic Sclerosis: Should the Door Be Closed?

Front Immunol 2018 7;9:2045. Epub 2018 Sep 7.

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

The early phase of systemic sclerosis (SSc) presents edema as one of the main features: this is clinically evident in the digital swelling (puffy fingers) as well as in the edematous skin infiltration of the early active diffuse subset. Other organs could be affected by this same disease process, such as the lung (with the appearance of ground glass opacities) and the heart (with edematous changes on cardiac magnetic resonance imaging). The genesis of tissue edema is tightly linked to pathological changes in the endothelium: various reports demonstrated the effect of transforming growth factor β, vascular endothelial growth factor and hypoxia-reperfusion damage with reactive oxygen species generation in altering vascular permeability and extravasation, in particular in SSc. This condition has an alteration in the glycocalyx thickness, reducing the protection of the vessel wall and causing non-fibrotic interstitial edema, a marker of vascular leak. Moreover, changes in the junctional adhesion molecule family and other adhesion molecules, such as ICAM and VCAM, are associated with an increased myeloid cells' extravasation in the skin and increased myofibroblasts transformation with further vascular leak and cellular migration. This mini-review examines current knowledge on determinants of vascular leak in SSc, shedding light on the role of vascular protection. This could enhance further studies in the light of drug development for early treatment, suggesting that the control of vascular leakage should be considered in the same way that vasodilation and inflammation reduction, as potential therapeutic targets.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2018.02045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6137210PMC
October 2019

Mast cells in early rheumatoid arthritis associate with disease severity and support B cell autoantibody production.

Ann Rheum Dis 2018 12 20;77(12):1773-1781. Epub 2018 Aug 20.

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

Objectives: Mast cells (MCs) are involved in the pathogenesis of rheumatoid arthritis (RA). However, their contribution remains controversial. To establish their role in RA, we analysed their presence in the synovium of treatment-naïve patients with early RA and their association and functional relationship with histological features of synovitis.

Methods: Synovial tissue was obtained by ultrasound-guided biopsy from treatment-naïve patients with early RA (n=99). Immune cells (CD3/CD20/CD138/CD68) and their relationship with CD117MCs in synovial tissue were analysed by immunohistochemistry (IHC) and immunofluorescence (IF). The functional involvement of MCs in ectopic lymphoid structures (ELS) was investigated , by coculturing MCs with naïve B cells and anticitrullinated protein antibodies (ACPA)-producing B cell clones, and in interleukin-27 receptor alpha (IL27)-deficient and control mice during antigen-induced arthritis (AIA).

Results: High synovial MC counts are associated with local and systemic inflammation, autoantibody positivity and high disease activity. IHC/IF showed that MCs reside at the outer border of lymphoid aggregates. Furthermore, human MCs promote the activation and differentiation of naïve B cells and induce the production of ACPA, mainly via contact-dependent interactions. In AIA, synovial MC numbers increase in IL27 deficient mice, in association with ELS and worse disease activity.

Conclusions: Synovial MCs identify early RA patients with a severe clinical form of synovitis characterised by the presence of ELS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/annrheumdis-2018-213418DOI Listing
December 2018

-Formyl Peptide Receptors Induce Radical Oxygen Production in Fibroblasts Derived From Systemic Sclerosis by Interacting With a Cleaved Form of Urokinase Receptor.

Front Immunol 2018 4;9:574. Epub 2018 Apr 4.

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

Systemic sclerosis (SSc) is a chronic autoimmune disease characterized by fibrosis, alteration in the microvasculature and immunologic abnormalities. It has been hypothesized that an abnormal redox state could regulate the persistent fibrotic phenotype in SSc patients. -Formyl peptide receptors (FPRs) are chemotactic receptors overexpressed in fibroblasts derived from SSc patients. In this study, we demonstrated that stimulation of FPRs promotes the generation of reactive oxygen species (ROS) in skin fibroblasts. In fibroblast cells, ROS production was due to FPRs interaction with the urokinase receptor (uPAR) and to β integrin engagement. FPRs cross-talk with uPAR and integrins led to Rac1 and ERKs activation. FPRs stimulation increased gp91phox and p67phox expression as well as the direct interaction between GTP-Rac1 and p67phox, thus promoting assembly and activation of the NADPH oxidase complex. FPRs functions occur through interaction with a specific domain of uPAR (residues SRSRY) that can be exposed on the cell membrane by protease-mediated receptor cleavage. Immunohistochemistry analysis with a specific anti-SRSRY antibody showed increased expression of uPAR in a cleaved form, which exposes the SRSRY sequence at its N-terminus (DIIDIII-uPAR88-92) in skin biopsies from SSc patients. As expected by the increased expression of both FPRs and DII-DIII-uPAR, fibroblasts derived from SSc patients showed a significantly increase in ROS generation both at a basal level than after FPRs stimulation, as compared to fibroblasts from normal subjects. C37, a small molecule blocking the interaction between FPRs and uPAR, and selumetinib, a clinically approved MAPKK/ERK inhibitor, significantly inhibited FPRs-mediated ROS production in fibroblasts derived from SSc patients. Thus, FPRs, through the interaction with the uPA/uPAR system, can induce ROS generation in fibroblasts by activating the NADPH oxidase, playing a role in the alteration of the redox state observed in SSc.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2018.00574DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5893650PMC
May 2019

Novel Therapeutic Approaches in Rheumatoid Arthritis: Role of Janus Kinases Inhibitors.

Curr Med Chem 2019 ;26(16):2823-2843

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

Rheumatoid Arthritis (RA) is a chronic inflammatory disease characterized by synovial inflammation and hyperplasia, autoantibody production, cartilage and bone destruction and several systemic features. Cardiovascular, pulmonary, psychological, and muscle involvement are the main comorbidities of RA and are responsible for the severity of the disease and long-term prognosis. Pharmacological treatment of rheumatic diseases has evolved remarkably over the past years. In addition, the widespread adoption of treat to target and tight control strategies has led to a substantial improvement of outcomes, so that drug-free remission is nowadays a realistic goal in the treatment of RA. However, despite the availability of multiple therapeutic options, up to 40% of patients do not respond to current treatments, including biologics. Small-molecule therapies offer an alternative to biological therapies for the treatment of inflammatory diseases. In the past 5 years, a number of small-molecule compounds targeting Janus Kinases (JAKs) have been developed. Since JAKs are essential for cell signaling in immune cells, in particular controlling the response to many cytokines, their inhibitors quickly became a promising class of oral therapeutics that proved effective in the treatment of RA. Tofacitinib is the first Janus Kinase (JAK) inhibitor approved for the treatment of RA, followed more recently by baricitinib. Several other JAK inhibitors, are currently being tested in phase II and III trials for the treatment of a different autoimmune diseases. Most of these compounds exhibit an overall acceptable safety profile similar to that of biologic agents, with infections being the most frequent adverse event. Apart from tofacitinib, safety data on other JAK inhibitors are still limited. Long-term follow-up and further research are needed to evaluate the general safety profile and the global risk of malignancy of these small molecules, although no clear association with malignancy has been reported to date. Here, we will review the main characteristics of JAK inhibitors, including details on their molecular targets and on the clinical evidences obtained so far in the treatment of RA.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2174/0929867325666180209145243DOI Listing
October 2019

Severe Aortic Valve Regurgitation in Relapsing Polychondritis.

J Clin Rheumatol 2018 Mar;24(2):109-111

Department of Translational Medical Sciences and Center for Basic and Clinical Immunology Research, University of Naples Federico II, Naples, Department of Translational Medical Sciences and Center for Basic and Clinical Immunology Research, University of Naples Federico II, Naples, Italy Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London London United Kingdom Department of Translational Medical Sciences and Center for Basic and Clinical Immunology Research, University of Naples Federico II, Naples, Italy.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/RHU.0000000000000634DOI Listing
March 2018

Severe Hypothyroidism due to the Loss of Therapeutic Efficacy of l-Thyroxine in a Patient with Esophageal Complication Associated with Systemic Sclerosis.

Front Endocrinol (Lausanne) 2017 20;8:241. Epub 2017 Sep 20.

Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy.

Background: Thyroid function abnormalities and thyroid autoantibodies have been frequently described in patients with systemic autoimmune diseases as systemic sclerosis (SSc). Serum TSH levels are higher in SSc patients with more severe skin diseases and a worse modified Rodnan skin score. Asymptomatic esophageal involvement due to SSc has never been described as a cause of severe hypothyroidism due to l-thyroxine (l-T4) malabsorption in patients with Hashimoto's thyroiditis (HT) and SSc.

Case Report: Here, we report a case of a 56-year-old female affected by both SSc and HT who developed severe hypothyroidism due to the loss of therapeutic efficacy of l-T4. Therapeutic failure resulted from the altered l-T4 absorption because of SSc esophageal complications. Clinical findings improved after the administration of oral liquid l-T4. Thyroid function completely normalized with a full clinical recovery, the disappearance of the pericardial effusion and the improvement of the pulmonary pressure.

Conclusion: A recognition of a poor absorption is crucial in patients with hypothyroidism and SSc to reduce the risk of the subsequent adverse events. This case suggests the importance of clinical and laboratory surveillance in patients with SSc and HT because the systemic complications of these dysfunctions may worsen the prognosis of hypothyroid SSc/HT patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fendo.2017.00241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5611405PMC
September 2017

Autoimmune Tautology in a Complex Case of Polyautoimmunity: Systemic Sclerosis, Autoimmune Liver Involvement, Antiphospholipid Syndrome and Hashimoto's Thyroiditis.

Isr Med Assoc J 2017 Mar;19(3):193-195

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

View Article and Find Full Text PDF

Download full-text PDF

Source
March 2017

Mast cells in rheumatoid arthritis: friends or foes?

Autoimmun Rev 2017 Jun 12;16(6):557-563. Epub 2017 Apr 12.

William Harvey Research Institute and Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.

Mast cells are tissue-resident cells of the innate immunity, implicated in the pathogenesis of many autoimmune diseases, including rheumatoid arthritis (RA). They are present in synovia and their activation has been linked to the potentiation of inflammation in the course of RA. However, recent investigations questioned the role of mast cells in arthritis. In particular, animal models generated conflicting results, so that many of their pro-inflammatory, i.e. pro-arthritogenic functions, even though supported by robust experimental evidence, have been labelled as redundant. At the same time, a growing body of evidence suggests that mast cells can act as tunable immunomodulatory cells. These characteristics, not yet fully understood in the context of RA, could partially explain the inconsistent results obtained with experimental models, which do not account for the pro- and anti-inflammatory functions exerted in more chronic heterogeneous conditions such as RA. Here we present an overview of the current knowledge on mast cell involvement in RA, including the intriguing hypothesis of mast cells acting as subtle immunomodulatory cells and the emerging concept of synovial mast cells as potential biomarkers for patient stratification.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.autrev.2017.04.001DOI Listing
June 2017

The Urokinase/Urokinase Receptor System in Mast Cells: Effects of its Functional Interaction with fMLF Receptors.

Transl Med UniSa 2016 Nov 1;15:34-41. Epub 2016 Nov 1.

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

Mast cell and basophils express the high affinity receptor for IgE (FcɛRI) and are primary effector cells of allergic disorders. The urokinase (uPA)-mediated plasminogen activation system is involved in physiological and pathological events based on cell migration and tissue remodelling, such as inflammation, wound healing, angiogenesis and metastasis. uPA is a serine protease that binds uPAR, a high affinity glycosyl-phosphatidyl-inositol (GPI)-anchored receptor. uPAR focuses uPA activity at the cell surface and activates intracellular signaling through lateral interactions with integrins, receptor tyrosine kinases and the G-protein-coupled family of fMLF chemotaxis receptors (FPRs). We investigated the expression of the uPA-uPAR system and its functional interaction with FPRs in human mast cells (MCs). Differently from basophils, MCs produced uPA that was able to induce their chemotaxis. Indeed, MCs also expressed uPAR, both in the intact and in a cleaved form (DII-DIII-uPAR) that can expose, at the N-terminus, the SRSRY sequence, able to interact with FPRs and to mediate cell chemotaxis. MCs also expressed mRNAs for FPRs that were functionally active; indeed, uPA and a soluble peptide (uPAR), containing the SRSRY chemotactic sequence of uPAR and able to interact with FPRs, were able to induce MCs chemotaxis. Thus, uPA is a potent chemoattractant for MCs acting through the exposure of the chemotactic epitope of uPAR, that is an endogenous ligand for FPRs. The same mechanism could be involved in VEGF-A secretion by human MCs, also induced by uPA and uPAR stimulation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5120748PMC
November 2016

HIV-1 Nef promotes migration and chemokine synthesis of human basophils and mast cells through the interaction with CXCR4.

Clin Mol Allergy 2016 1;14:15. Epub 2016 Nov 1.

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

Background: The Nef protein can be detected in plasma of HIV-1-infected patients and plays a role in the pathogenesis of HIV-1. Nef produced during the early stages of infection is fundamental in creating the ideal environment for viral replication, e.g. by reducing the ability of infected cells to induce an immune response.

Aim: Based on previous experience showing that both Tat and gp41 of HIV-1 are potent chemotactic factors for basophils and mast cells, and gp120 is a powerful stimulus for the release of histamine and cytokines (IL-4 and IL-13) from basophils, in this study we aimed to verify if the HIV Nef protein can exert some effects on basophils and mast cells purified from healthy volunteers through the interaction with the CXCL12 receptor, CXCR4.

Methods: Basophils purified from peripheral blood cells of 30 healthy volunteers and mast cells obtained from lung tissue of ten healthy volunteers were tested by flow cytometric analysis, chemotaxis and chemokine production by ELISA assays.

Results: Nef is a potent chemoattractant for basophils and lung mast cells obtained from healthy, HIV-1 and HIV-2 seronegative individuals. Incubation of basophils and mast cells with Nef induces the release of chemokines (CXCL8/IL-8 and CCL3/MIP-1α). The chemotactic activity of Nef on basophils and mast cells is mediated by the interaction with CXCR4 receptors, being blocked by preincubation of FcεRI cells with an anti-CXCR4 Ab. Stimulation with Nef or CXCL12/SDF-1α, a CXCR4 ligand, desensitizes basophils to a subsequent challenge with an autologous or heterologous stimulus.

Conclusions: These results indicate that Nef, a HIV-1-encoded α-chemokine homolog protein, plays a direct role in basophils and mast cell recruitment and activation at sites of HIV-1 replication, by promoting directional migration of human FcεRI cells and the release of chemokines from these cells. Together with our previous results, these data suggest that FcεRI cells contribute to the dysregulation of the immune system in HIV-1 infection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12948-016-0052-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5088669PMC
November 2016

FPRs: linking innate immune system and fibrosis.

Oncotarget 2015 Aug;6(22):18736-7

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

View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4662448PMC
http://dx.doi.org/10.18632/oncotarget.4915DOI Listing
August 2015

Discovery of new small molecules inhibiting 67 kDa laminin receptor interaction with laminin and cancer cell invasion.

Oncotarget 2015 Jul;6(20):18116-33

Department of Pharmacy, Drug Discovery Laboratory, University of Naples Federico II, Naples, Italy.

The 67 kDa laminin receptor (67LR) is a non-integrin receptor for laminin (LM) that derives from a 37 kDa precursor (37LRP). 67LR expression is increased in neoplastic cells and correlates with an enhanced invasive and metastatic potential. We used structure-based virtual screening (SB-VS) to search for 67LR inhibitory small molecules, by focusing on a 37LRP sequence, the peptide G, able to specifically bind LM. Forty-six compounds were identified and tested on HEK-293 cells transfected with 37LRP/67LR (LR-293 cells). One compound, NSC47924, selectively inhibited LR-293 cell adhesion to LM with IC50 and Ki values of 19.35 and 2.45 μmol/L. NSC47924 engaged residues W176 and L173 of peptide G, critical for specific LM binding. Indeed, NSC47924 inhibited in vitro binding of recombinant 37LRP to both LM and its YIGSR fragment. NSC47924 also impaired LR-293 cell migration to LM and cell invasion. A subsequent hierarchical similarity search with NSC47924 led to the identification of additional four compounds inhibiting LR-293 cell binding to LM: NSC47923, NSC48478, NSC48861, and NSC48869, with IC50 values of 1.99, 1.76, 3.4, and 4.0 μmol/L, respectively, and able to block in vitro cancer cell invasion. These compounds are promising scaffolds for future drug design and discovery efforts in cancer progression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4627239PMC
http://dx.doi.org/10.18632/oncotarget.4016DOI Listing
July 2015

Upregulation of the N-formyl Peptide receptors in scleroderma fibroblasts fosters the switch to myofibroblasts.

J Immunol 2015 Jun 27;194(11):5161-73. Epub 2015 Apr 27.

Department of Translational Medical Sciences and Center for Basic and Clinical Immunology Research, University of Naples Federico II, 80131 Naples, Italy;

Systemic sclerosis (SSc) is characterized by chronic inflammation and fibrosis. N-Formyl peptide (fMLF) receptors (FPRs) are chemotactic receptors involved in inflammation. Three FPRs have been identified: FPR1, FPR2, and FPR3. We have examined, by RT-PCR, Western blot and immunohistochemistry, FPRs expression in skin fibroblasts from 10 normal subjects and 10 SSc patients, showing increased expression in SSc fibroblasts. Several functions of FPRs occur through the interaction with a region of the urokinase-type plasminogen activator receptor (uPAR88-92), able to interact with FPRs and to mediate urokinase (uPA) or fMLF-dependent cell migration. Soluble uPAR84-95 peptide can act as a direct ligand of FPRs. Furthermore, uPA or its aminoterminal fragment (ATF) can promote the exposure of the uPAR88-92 region. The WKYMVm peptide is a FPRs pan-agonist. We investigated the functional effects of these agonists on normal and SSc fibroblasts. ATF, uPAR84-95, and WKYMVm regulated adhesion, migration, and proliferation of normal fibroblasts. Despite FPR overexpression, the response of SSc fibroblasts to the same agonists was greatly reduced, except for the proliferative response to ATF. SSc fibroblasts showed increased α-smooth muscle actin expression and improved capability to induce wound closure. Indeed, they overexpressed a cleaved uPAR form, exposing the uPAR88-92 region, and vitronectin, both involved in fibrosis and in the fibroblast-to-myofibroblast transition. FPR stimulation promoted α-smooth muscle actin expression in normal fibroblasts as well as motility, matrix deposition, αvβ5 integrin expression, and radical oxygen species generation in normal and SSc fibroblasts. This study provides evidence that FPRs may play a role in fibrosis and in the fibroblast-to-myofibroblast transition.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4049/jimmunol.1402819DOI Listing
June 2015
-->