Macrophage-polarizing stimuli differentially modulate the inflammatory profile induced by the secreted phospholipase A2 group IA in human lung macrophages.

In this study we investigated the effects of snake venom Group IA secreted phospholipase A2 (svGIA) on the release of inflammatory and angiogenic mediators from human lung macrophages (HLMs). HLMs were incubated with lipopolysaccharide (LPS) or svGIA with or without macrophage-polarizing stimuli (IL-4, IL-10, IFN-γ or the adenosine analogue NECA). M2-polarizing cytokines (IL-4 and IL-10) inhibited TNF-α, IL-6, IL-12, IL-1ß, CXCL8 and CCL1 release induced by both LPS and svGIA. IL-4 inhibited also the release of IL-10. IFN-γ reduced IL-10 and IL-12 and increased CCL1 release by both the LPS and svGIA-stimulated HLMs, conversely IFN-γ reduced IL-1ß only by svGIA-stimulated HLMs. In addition, IFNγ promoted TNF-α and IL-6 release from svGIA-stimulated HLMs to a greater extent than LPS. NECA inhibited TNF-α and IL-12 but promoted IL-10 release from LPS-stimulated HLMs according to the well-known effect of adenosine in down-regulating M1 activation. By contrast NECA reduced TNF-α, IL-10, CCL1 and IL-1ß release from svGIA-activated HLM. IL-10 and NECA increased both LPS- and svGIA-induced vascular endothelial growth factor A (VEGF-A) release. By contrast, IL-10 reduced angiopoietin-1 (ANGPT1) production from activated HLMs. IFN-γ and IL-4 reduced VEGF-A and ANGPT1 release from both LPS- and svGIA-activated HLMs. Moreover, IL-10 inhibited LPS-induced ANGPT2 production. In conclusion, we demonstrated a fine-tuning modulation of svGIA-activated HLMs differentially exerted by the classical macrophage-polarizing cytokines.

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

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.

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

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.

Lipopolysaccharide-Elicited TSLPR Expression Enriches a Functionally Discrete Subset of Human CD14+ CD1c+ Monocytes.

Thymic stromal lymphopoietin (TSLP) is a cytokine produced mainly by epithelial cells in response to inflammatory or microbial stimuli and binds to the TSLP receptor (TSLPR) complex, a heterodimer composed of TSLPR and IL-7 receptor α (CD127). TSLP activates multiple immune cell subsets expressing the TSLPR complex and plays a role in several models of disease. Although human monocytes express TSLPR and CD127 mRNAs in response to the TLR4 agonist LPS, their responsiveness to TSLP is poorly defined. We demonstrate that TSLP enhances human CD14+ monocyte CCL17 production in response to LPS and IL-4. Surprisingly, only a subset of CD14+ CD16- monocytes, TSLPR+ monocytes (TSLPR+ mono), expresses TSLPR complex upon LPS stimulation in an NF-κB- and p38-dependent manner. Phenotypic, functional, and transcriptomic analysis revealed specific features of TSLPR+ mono, including higher CCL17 and IL-10 production and increased expression of genes with important immune functions (i.e., GAS6, ALOX15B, FCGR2B, LAIR1). Strikingly, TSLPR+ mono express higher levels of the dendritic cell marker CD1c. This evidence led us to identify a subset of peripheral blood CD14+ CD1c+ cells that expresses the highest levels of TSLPR upon LPS stimulation. The translational relevance of these findings is highlighted by the higher expression of TSLPR and CD127 mRNAs in monocytes isolated from patients with Gram-negative sepsis compared with healthy control subjects. Our results emphasize a phenotypic and functional heterogeneity in an apparently homogeneous population of human CD14+ CD16- monocytes and prompt further ontogenetic and functional analysis of CD14+ CD1c+ and LPS-activated CD14+ CD1c+ TSLPR+ mono.

Controversial role of mast cells in skin cancers.

Cancer development is a multistep process characterized by genetic and epigenetic alterations during tumor initiation and progression. The stromal microenvironment can promote tumor development. Mast cells, widely distributed throughout all tissues, are a stromal component of many solid and haematologic tumors. Mast cells can be found in human and mouse models of skin cancers such as melanoma, basal and squamous cell carcinomas, primary cutaneous lymphomas, haemangiomas and Merkel cell carcinoma. However, human and animal studies addressing potential functions of mast cells and their mediators in skin cancers have provided conflicting results. In several studies, mast cells play a pro-tumorigenic role, whereas in others, they play an anti-tumorigenic role. Other studies have failed to demonstrate a clear role for tumor-associated mast cells. Many unanswered questions need to be addressed before we understand whether tumor-associated mast cells are adversaries, allies or simply innocent bystanders in different types and subtypes of skin cancers.

IL-3 synergises with basophil-derived IL-4 and IL-13 to promote the alternative activation of human monocytes.

Basophil-derived IL-4 is involved in the alternative activation of mouse monocytes, as recently shown in vivo. Whether this applies to human basophils and monocytes has not been established yet. Here, we sought to characterise the interaction between basophils and monocytes and identify the molecular determinants. A basophil-monocyte co-culture model revealed that IL-3 and basophil-derived IL-4 and IL-13 induced monocyte production of CCL17, a marker of alternative activation. Critically, IL-3 and IL-4 acted directly on monocytes to induce CCL17 production through histone H3 acetylation, but did not increase the recruitment of STAT5 or STAT6. Although freshly isolated monocytes did not express the IL-3 receptor α chain (CD123), and did not respond to IL-3 (as assessed by STAT5 phosphorylation), the overnight incubation with IL-4 (especially if associated with IL-3) upregulated CD123 expression. IL-3-activated JAK2-STAT5 pathway inhibitors reduced the CCL17 production in response to IL-3 and IL-4, but not to IL-4 alone. Interestingly, monocytes isolated from allergen-sensitised asthmatic patients exhibited a higher expression of CD123. Taken together, our data show that the JAK2-STAT5 pathway modulates both basophil and monocyte effector responses. The coordinated activation of STAT5 and STAT6 may have a major impact on monocyte alternative activation in vitro and in vivo.

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

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.

Angiogenesis and lymphangiogenesis in inflammatory skin disorders.

Angiogenesis, the growth of new blood vessels from pre-existing vessels, occurs physiologically in wound healing, during inflammatory diseases, and in tumor growth. Lymphangiogenesis can be activated in inflammation and tumor metastasis. The family of vascular endothelial growth factors (VEGFs) and angiopoietins are essential for angiogenesis and lymphangiogenesis. The angiogenic process is tightly regulated by VEGFs, angiopoietins, and endogenous inhibitors. VEGFs and angiopoietins exert their effects by activating specific receptors present on blood and lymphatic endothelial cells. There is now compelling evidence that cells of innate and adaptive immunity (macrophages, mast cells, neutrophils, eosinophils, lymphocytes) are a major source of angiogenic and lymphangiogenic factors. Chronic inflammatory skin diseases such as psoriasis and atopic dermatitis are characterized by altered angiogenesis, lymphangiogenesis, or both. Also such acute inflammatory skin disorders as urticaria, ultraviolet B-induced damage, and angioedema are associated with changes in angiogenic factors. In systemic sclerosis there is a switch from proangiogenic to antiangiogenic factors that play a role in the defective vascular process of this disorder. As yet, there are no clinical trials showing that canonical VEGF/VEGF receptor-targeted strategies can modulate inflammatory skin diseases. Novel strategies targeting other angiogenic/lymphangiogenic pathways should also be investigated.

Worldwide Heterogeneity of Food Allergy: Focus on Peach Allergy in Southern Italy.

Food allergy (FA) has shown an increasing prevalence in the last decades, becoming a major public health problem. However, data on the prevalence of FA across the world are heterogeneous because they are influenced by several factors. Among IgE-mediated FA, an important role is played by FA related to plant-derived food which can result from the sensitization to a single protein (specific FA) or to homologous proteins present in different foods (cross-reactive FA) including non-specific lipid transfer proteins (nsLTPs), profilins, and pathogenesis-related class 10 (PR-10). In addition, the clinical presentation of FA is widely heterogeneous ranging from mild symptoms to severe reactions up to anaphylaxis, most frequently associated with nsLTP-related FA (LTP syndrome). Considering the potential life-threatening nature of nsLTP-related FA, the patient's geographical setting should always be taken into account; thereby, it is highly recommended to build a personalized approach for managing FA across the world in the precision medicine era. For this reason, in this review, we aim to provide an overview of the prevalence of nsLTP-mediated allergies in the Mediterranean area and to point out the potential reasons for the different geographical significance of LTP-driven allergies with a particular focus on the allergenic properties of food allergens and their cross reactivity.

Eosinophilic Patterns in Patients with Seasonal Allergy Affected by Bronchial Asthma and Rhinitis/Rhinosinusitis: Efficacy of Benralizumab in Patients with the Persistent Pattern.

BACKGROUND: Eosinophilia can be influenced by multiple factors. This study aims to set a protocol for monitoring blood absolute eosinophil count (AEC) in patients with seasonal allergy affected by bronchial asthma (BA), allergic rhinitis (AR), or chronic rhinosinusitis with or without nasal polyposis (CRSw/sNP). METHODS: We planned a total of four annual blood samples to measure AEC in- and out-seasonal pollen exposure (i.e., one measurement every three months for one year). RESULTS: We identified two distinct groups of patients (non-eosinophilic and eosinophilic). Patients in the eosinophilic group presented with four different patterns (episodic, transient, floating, and persistent). Most patients with episodic, transient, and floating patterns were affected by mild allergy and the increase in eosinophils was related to allergen exposure. In contrast, patients with the persistent pattern mostly presented with more severe allergy (i.e., severe BA and relapsing CRSwNP) and the eosinophilia was unrelated to allergen exposure. The subgroup of patients with severe BA, relapsing CRSwNP, and persistent eosinophilc pattern were treated with benralizumab, which induced a noteworthy improvement in both severe BA and CRSwNP. CONCLUSIONS: Multiple AEC measurements in patients with seasonal allergy can better reflect patient's eosinophilic status and help define the relationship of AEC enhancement with allergen exposure.

Human macrophages and monocytes express functional Na(+)/Ca (2+) exchangers 1 and 3.

The Na(+)/Ca(2+) exchanger (NCX) is a plasma membrane protein that can switch Na(+) and Ca(2+) in either direction to maintain the homeostasis of intracellular Ca(2+). A family of three genes (NCX1, NCX2, and NCX3) has been identified in neurons and muscle cells. NCX activity has also been reported in certain immune cells (e.g., mast cells). We have examined the expression and function of these NCX isoforms in the human monocytes and lung macrophages. Monocytes were purified from peripheral blood of healthy donors. Macrophages (HLM) were isolated and purified from the lung parenchyma of patients undergoing thoracic surgery. NCX1 and NCX3, but not NCX2, were expressed in HLM and monocytes at both mRNA and protein level. Exposure to Na(+)-free medium induced a significant increase in intracellular calcium concentration ([Ca(2+)](i)) in both cell types, suggesting that NCX isoforms expressed on these cells were functionally active. This response was completely abolished by the NCX inhibitor 5-(N-4-chlorobenzyl)-20,40-dimethylbenzamil (CB-DMB). In addition, incubation of macrophages with Na(+)-free medium induced a marked release of TNF-α. Preincubation of HLM with CB-DMB and RNAi-mediated knockdown of NCX1 blocked TNF-α release. Our results demonstrate that human macrophages and monocytes express NCX1 and NCX3 that operate in a bidirectional manner to restore [Ca(2+)](i) to generate Ca(2+) signals and to induce TNF-α production. We suggest that NCX may modulate Ca(2+) homeostasis and proinflammatory functions in human macrophages and monocytes.

Immunogenicity and Safety of Anti-SARS-CoV-2 mRNA Vaccines in a Cohort of Patients with Hereditary Angioedema.

Many factors may trigger hereditary angioedema (HAE) attacks. This study aims to gain insights into the benefits and potential risks of COVID-19 vaccination in HAE patients, focusing particularly on the possibility of triggering attacks. We enrolled 31 patients with HAE undergoing two doses of the SARS-CoV-2 mRNA Comirnaty-BioNTech/Pfizer vaccine. To evaluate the possible influence of the vaccine on disease control and attack frequency, we administered the angioedema control test (AECT) 4-week version before (T0), 21 days after the first dose (T1), and between 21 and 28 days after the second dose (T2). Despite 5 patients (16.1%) experiencing attacks within 72 h of the first dose administration, no significant variation in attack frequency was observed before and after vaccination [F(2,60) = 0.123; p = 0.799]. In addition, patients reported higher AECT scores at T1 and T2 compared to T0 [F(2,44) = 6.541; p < 0.05; post hoc p < 0.05)], indicating that the disease was rather more controlled after vaccinations than in the previous period. All patients showed a positive serological response to the vaccine without significant differences from healthy controls (U = 162; p = 0.062). These observations suggest that the vaccine administration is safe and effective in HAE patients.

Production of vascular endothelial growth factors from human lung macrophages induced by group IIA and group X secreted phospholipases A2.

Angiogenesis and lymphangiogenesis mediated by vascular endothelial growth factors (VEGFs) are main features of chronic inflammation and tumors. Secreted phospholipases A(2) (sPLA(2)s) are overexpressed in inflammatory lung diseases and cancer and they activate inflammatory cells by enzymatic and receptor-mediated mechanisms. We investigated the effect of sPLA(2)s on the production of VEGFs from human macrophages purified from the lung tissue of patients undergoing thoracic surgery. Primary macrophages express VEGF-A, VEGF-B, VEGF-C, and VEGF-D at both mRNA and protein level. Two human sPLA(2)s (group IIA and group X) induced the expression and release of VEGF-A and VEGF-C from macrophages. Enzymatically-inactive sPLA(2)s were as effective as the active enzymes in inducing VEGF production. Me-Indoxam and RO092906A, two compounds that block receptor-mediated effects of sPLA(2)s, inhibited group X-induced release of VEGF-A. Inhibition of the MAPK p38 by SB203580 also reduced sPLA(2)-induced release of VEGF-A. Supernatants of group X-activated macrophages induced an angiogenic response in chorioallantoic membranes that was inhibited by Me-Indoxam. Stimulation of macrophages with group X sPLA(2) in the presence of adenosine analogs induced a synergistic increase of VEGF-A release and inhibited TNF-alpha production through a cooperation between A(2A) and A(3) receptors. These results demonstrate that sPLA(2)s induce production of VEGF-A and VEGF-C in human macrophages by a receptor-mediated mechanism independent from sPLA(2) catalytic activity. Thus, sPLA(2)s may play an important role in inflammatory and/or neoplastic angiogenesis and lymphangiogenesis.

Predictive Response to Immunotherapy Score: A Useful Tool for Identifying Eligible Patients for Allergen Immunotherapy.

A specific predictive tool of allergen immunotherapy (AIT) outcome has not been identified yet. This study aims to evaluate the efficacy of a disease score referred to as Predictive Response to Immunotherapy Score (PRIS) to predict the response to AIT and identify eligible patients. A total of 110 patients diagnosed with allergic rhinitis with or without concomitant asthma were enrolled in this study. Before beginning sublingual immunotherapy (SLIT), patients were evaluated by analyzing clinical and laboratory parameters. A specific rating was assigned to each parameter to be combined in a total score named PRIS. At baseline (T0) and follow-up [after 12 (T12) and 24 months (T24) of SLIT], a Visual Analogue Scale (VAS) was used to calculate a mean symptom score (MSS). Finally, the percentage variation between the MSS at T0 and at T12 [ΔMSS-12(%)] and T24 [ΔMSS-24 (%)] was measured. We observed a significant improvement of symptoms at T12 and T24 compared to T0 in all groups undergoing SLIT. PRIS was effective in predicting ΔMSS-24 (%) in patients treated with single-allergen SLIT. In addition, PRIS was effective in predicting ΔMSS-24 (%) in both patients with only rhinitis and with concomitant asthma. PRIS assessment can represent a useful tool to individuate potential responders before SLIT prescription.

Immunogenicity and Safety of mRNA Anti-SARS-CoV-2 Vaccines in Patients with Systemic Lupus Erythematosus.

Vaccination is the most effective preventive measure to control the spread of COVID-19 and reduce associated complications. This study aims to evaluate the efficacy and safety of mRNA COVID-19 vaccines in patients with systemic lupus erythematosus (SLE). A total of 41 adult SLE patients receiving two doses of the SARS-CoV-2 mRNA Comirnaty-BioNTech/Pfizer vaccine were enrolled. The quantitative determination of anti-trimeric spike protein-specific IgG antibodies to SARS-CoV-2 was assessed before (T0), 21 days after the administration of the first dose of the vaccine (T1), and between 21 and 28 days after the second dose (T2). They were compared with the same determinations from a cohort of 29 patients with C1-esterase inhibitor deficiency hereditary angioedema (C1-INH-HAE) as controls. All the SLE patients and controls demonstrated a positive serological response after a single dose of the vaccine (T1), which significantly increased after the second dose (T2). No significant difference was found between SLE patients and controls at T1 [t(52.81) = -0.68; p = 0.49] and at T2 [t(67.74) = -0.22; p = 0.825]. Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) analysis showed that the vaccine did not influence SLE activity or caused disease flare in our cohort. In conclusion, COVID-19 vaccines produced a satisfactory response in SLE patients without variation in the disease activity.

Radiological patterns and pulmonary function values of lung involvement in primary Sjögren's syndrome: A pilot analysis.

Background: Lung involvement in primary Sjögren's syndrome (pSS) may vary from 9 to 90%. Interstitial lung disease and tracheobronchial alterations are the most typical findings. The evidence of primarily emphysematous changes at computed tomography of the chest of pSS patients has occasionally been described but poorly characterized. This study aims to assess pulmonary involvement and the impact on respiratory function in a cohort of pSS patients. Materials and methods: A total of 22 consecutive patients diagnosed with pSS underwent pulmonary function tests to investigate the presence of ventilatory impairment and evaluate the exchanges of alveolar gases. All patients underwent a chest high-resolution computed tomography (HRTC). Results: Dynamic volumes were within the normal range in 21 patients (95.4%). A reduction in the diffusing capacity of the lung for carbon monoxide (DLCO) was observed in 18 patients (81.8%). Ten (45.5%) patients showed a mild degree deficit, while 8 patients (36%) showed a moderate degree deficit. Analysis of DLCO revealed a significant difference between pSS patients and controls [t(30.98) = -10.77; p < 0.001], showing a higher DLCO value for the healthy controls (mean ± SE; 101.27 ± 6.08) compared to pSS patients (mean ± SE; 65.95 ± 12.78). Emphysema was found in 21 (94.5%) patients and was the most widespread pulmonary injury. Tracheal thickness was reduced in 15 (67%) patients. Micronodules were observed in 10 (45%) patients in all the pulmonary fields. Bronchial wall thickening and bronchiectasis were observed in 8 (36%) patients, mainly in the lower lobes. Ground glass was found in 5 (22.5%) patients in lower and higher lobes. Cysts were observed in two patients (9%). Conclusion: The reduction of the DLCO could be related to early emphysematous alterations in the absence of spirometric alterations and relevant respiratory symptoms. In conclusion, emphysema might be seen as an early pulmonary involvement mark in patients suffering from pSS.

Functional Modulation of Human Macrophages by Secreted Phospholipases A2: Implications in Cancer.

Cancer-related inflammation has recently emerged as an important component of cancer pathogenesis that is able to promote tumor initiation and progression, and the acquisition of the known hallmark capabilities, including evasion from immunosurveillance. Several soluble and cellular mediators participate in tumor microenvironment formation, leading to cancer initiation and progression. In this view, Tumor-Associated Macrophages (TAMs) are pivotal players and, due to their characteristic plasticity, can acquire a variety of distinct phenotypes and contribute in different ways to the different phases of carcinogenesis. Different stimuli have been shown to modulate macrophage polarization. Secreted phospholipase A2 enzymes (sPLA2s) exert multiple biological effects on cancer-related inflammation due to their enzymatic activity and ability to activate inflammatory cells by non-enzymatic mechanisms. Among the different sPLA2 isoforms, several studies have suggested that group IIA and group X are mainly involved in a wide variety of cancer types. A deeper insight into the molecular mechanisms regulating the link between tumor-infiltrating immune cells and cancer could lead to identifying new prognostic/predictive biomarkers and a broader view of cancer immunotherapy.

Immunosuppressive Treatment in Antiphospholipid Syndrome: Is It Worth It?

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.

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

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.

Phenotypic and Functional Heterogeneity of Low-Density and High-Density Human Lung Macrophages.

BACKGROUND: Pulmonary macrophages are a highly heterogeneous cell population distributed in different lung compartments. METHODS: We separated two subpopulations of macrophages from human lung parenchyma according to flotation over density gradients. RESULTS: Two-thirds 65.4% of the lung macrophages have a density between 1.065 and 1.078 (high-density macrophages: HDMs), and the remaining one-third (34.6) had a density between 1.039 and 1.052 (low-density macrophages: LDMs). LDMs had a larger area (691 vs. 462 µm2) and cell perimeter (94 vs. 77 µm) compared to HDMs. A significantly higher percentage of HDMs expressed CD40, CD45, and CD86 compared to LDMs. In contrast, a higher percentage of LDMs expressed the activation markers CD63 and CD64. The release of TNF-α, IL-6, IL-10 and IL-12 induced by lipopolysaccharide (LPS) was significantly higher in HDMs than in LDMs. CONCLUSION: The human lung contains two subpopulations of macrophages that differ in buoyancy, morphometric parameters, surface marker expression and response to LPS. These subpopulations of macrophages probably play distinct roles in lung inflammation and immune responses.