Effects of dexamethasone on TNF-alpha-induced release of cytokines from purified human blood eosinophils

BACKGROUND: TNF-alpha is an important mediator in allergy also for its effects on eosinophils. METHODS: The effect of dexamethasone on TNF-alpha induced eosinophils survival, degranulation (ECP), cytokines release (IL-8, GM-CSF) and adhesion to VCAM-1, ICAM-1 and IgG coated wells (EPO release) were evaluated. RESULTS: The drug inhibited IL-8 and GM-CSF production, but not viability, degranulation or adhesion in human peripheral blood eosinophils. CONCLUSION: These results indicate that part of the activity of glucocorticosteroids on eosinophils may be mediated by their ability to inhibit cytokine secretion that in turn is important for the perpetuation of the allergic inflammation

Evaluating the levels of interleukin-1 family cytokines in sporadic amyotrophic lateral sclerosis

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease leading to the death of affected individuals within years. The involvement of inflammation in the pathogenesis of neurodegenerative diseases, including ALS, is increasingly recognized but still not well understood. The aim of this study is to evaluate the levels of inflammation-related IL-1 family cytokines (IL-1β, IL-18, IL-33, IL-37) and their endogenous inhibitors (IL-1Ra, sIL-1R2, IL-18BP, sIL-1R4) in patients with sporadic ALS (sALS), METHODS: Sera were collected from 144 patients (125 patients were characterized by disease form, duration, and disability, using the revised ALS functional rating scale (ALSFRS-R) and from 40 matched controls. Cerebrospinal fluid (CSF) was collected from 54 patients with sALS and 65 patients with other non-infectious non-oncogenic diseases as controls. Cytokines and inhibitors were measured by commercial ELISA. RESULTS: Among the IL-1 family cytokines tested total IL-18, its endogenous inhibitor IL-18BP, and the active form of the cytokine (free IL-18) were significantly higher in the sALS sera than in controls. No correlation between these soluble mediators and different clinical forms of sALS or the clinical setting of the disease was found. IL-18BP was the only mediator detectable in the CSF of patients. CONCLUSIONS: Among the IL-1 family cytokines, only IL-18 correlates with this disease and may therefore have a pathological role in sALS. The increase of total IL-18 suggests the activation of IL-18-cleaving inflammasome. Whether IL-18 upregulation in circulation of sALS patients is a consequence of inflammation or one of the causes of the pathology still needs to be addressed

Effectiveness of enzymatic hydrolysis for reducing the allergenic potential of legume by-products

The interest in agri-food residues and their valorization has grown considerably, and many of them are today considered to be valuable, under-exploited sources of different compounds and notably proteins. Despite the beneficial properties of legumes by-products, there are also some emerging risks to consider, including their potential allergenicity. In this work the immunoreactivity of chickpea, pea, and white bean by-products was assessed, and whether the production of enzymatic hydrolysates can be an effective strategy to reduce this allergenic potential. The results presented clearly indicate that the efficiency of this strategy is strongly related to the enzyme used and the food matrix. All legume by-products showed immunoreactivity towards serum of legume-allergic patients. Hydrolysates from alcalase did not show residual immunoreactivity for chickpea and green pea, whereas hydrolysates from papain still presented some immunoreactivity. However, for white beans, the presence of antinutritional factors prevented a complete hydrolysis, yielding a residual immunoreactivity even after enzymatic hydrolysis with alcalase

Antibodies from patients with rheumatoid arthritis target citrullinated histone 4 contained in neutrophils extracellular traps.

Histone deimination regulates gene function and contributes to antimicrobial response, allowing the formation of neutrophil extracellular traps (NETs). Deiminated proteins are target of anti-citrullinated peptides antibodies (ACPA) in rheumatoid arthritis (RA). OBJECTIVE: The objective of this paper is to test the hypothesis that RA sera react with deiminated histones contained in NETs. METHODS: Neutrophils from peripheral blood were stimulated with A23187 and acid treated; NETosis was induced by phorbol myristate acetate, and NET proteins were isolated. Sera were tested by immunoblot on acid extracted proteins from neutrophils and from NETs, and by ELISA on deiminated histone H4 or H4-derived peptides. Bands reactive with RA sera were excised from gels, digested with trypsin and subjected to matrix-assisted laser desorption/ionisation time of flight (MALDI-TOF) analysis, before and after derivatisation to detect citrullinated peptides. RESULTS: RA sera reacted with a deiminated antigen of 11 KDa from activated neutrophils, recognised also by anti-H4 and antideiminated H4 antibodies. A similar reactivity was observed with NET proteins. The antigen from neutrophils or NETs was identified as citrullinated H4 by MALDI-TOF analysis. By ELISA, RA sera bound in vitro citrullinated H4. Citrullinated H4 14-34 and 31-50 peptides detected antibodies in 67% and 63% of RA sera and in less than 5% of controls; antibody titre was correlated with anti-CCP2. CONCLUSIONS: Citrullinated H4 from activated neutrophils and NETs is a target of antibodies in RA, and synthetic citrullinated H4-derived peptides are a new substrate for ACPA detection. As NETosis can generate antigens for ACPA, these data suggest a novel connection between innate and adaptive immunity in RA

Targeting SIRT1 Rescues Age- and Obesity-Induced Microvascular Dysfunction in Ex Vivo Human Vessels

ackground: Experimental evidence suggests a key role of SIRT1 (silent information regulator 1) in age- and metabolic-related vascular dysfunction. Whether these effects hold true in the human microvasculature is unknown. We aimed to investigate the SIRT1 role in very early stages of age- and obesity-related microvascular dysfunction in humans. Methods: Ninety-five subjects undergoing elective laparoscopic surgery were recruited and stratified based on their body mass index status (above or below 30 kg/m2) and age (above or below 40 years) in 4 groups: Young Nonobese, Young Obese, Old Nonobese, and Old Obese. We measured small resistance arteries' endothelial function by pressurized micromyography before and after incubation with a SIRT1 agonist (SRT1720) and a mitochondria reactive oxygen species (mtROS) scavenger (MitoTEMPO). We assessed vascular levels of mtROS and nitric oxide availability by confocal microscopy and vascular gene expression of SIRT1 and mitochondrial proteins by qPCR. Chromatin immunoprecipitation assay was employed to investigate SIRT1-dependent epigenetic regulation of mitochondrial proteins. Results: Compared with Young Nonobese, obese and older patients showed lower vascular expression of SIRT1 and antioxidant proteins (FOXO3 [forkhead box protein O3] and SOD2) and higher expression of pro-oxidant and aging mitochondria proteins p66Shc and Arginase II. Old Obese, Young Obese and Old Nonobese groups endothelial dysfunction was rescued by SRT1720. The restoration was comparable to the one obtained with mitoTEMPO. These effects were explained by SIRT1-dependent chromatin changes leading to reduced p66Shc expression and upregulation of proteins involved in mitochondria respiratory chain. Conclusions: SIRT1 is a novel central modulator of the earliest microvascular damage induced by age and obesity. Through a complex epigenetic control mainly involving p66Shc and Arginase II, it influences mtROS levels, NO availability, and the expression of proteins of the mitochondria respiratory chain. Therapeutic modulation of SIRT1 restores obesity- and age-related endothelial dysfunction. Early targeting of SIRT1 might represent a crucial strategy to prevent age- and obesity-related microvascular dysfunction. Keywords: aging; endothelial cells; microcirculation; mitochondria; obesity; sirtuin

One year in review 2018: pathogenesis of rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease that primarily affects joints. The several mechanisms involved in the development of the disease are not completely understood. It has been proposed that different environmental factors, such as cigarette smoking, occupational and atmospheric agents act as trigger stimuli for the development of RA in genetically predisposed individuals, leading to synovial hyperplasia and bone destruction. The initial disease stage of RA is associated with alteration of innate and adaptive immune system with consequent production of autoantibodies, targeting various molecules including modified self-epitopes. In the following stages of the disease, both the innate (e.g. dendritic cells, macrophages and neutrophils) and adaptive immune cells (e.g. B and T lymphocytes) contribute to the amplification and perpetuation of the chronic inflammatory state. The recognition of key cells, mediators and mechanisms implicated in the pathogenesis of RA could provide the basis for the development of new and precise disease-modifying anti-rheumatic drugs. Therefore, we reviewed the literature of the last year in order to find the new insights in RA pathogenesis

One year in review 2021: pathogenesis of rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterised by local and systemic inflammation where the close interaction between immune cells and soluble mediators leads to amplification and perpetuation of inflammatory and remodelling processes. The research carried out in the last year in the field of RA has made it possible to identify new mechanisms involved in the pathogenesis of the disease, enabling the discovery of new potential therapeutic targets. Thus, in this review we summarise new insights in RA pathogenesis, resulting from a literature research date published in the last year

One year in review 2020: pathogenesis of rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease influenced by both genetic, epigenetic and environmental factors. The discovery of new gene polymorphisms and their association with disease susceptibility have added new elements to better clarify RA pathogenesis. In the last year, important elements have been added to the current knowledge of mechanisms regulating innate and adaptive immunity in RA, leading to discovering new targets for the development of disease-modifying therapies. Thus, in this review we summarise the new insights resulting from a literature research data published in the last yea

Parotid mass as an early sign of Kaposi's sarcoma associated with human herpesvirus 8 infection

Kaposi's sarcoma of an intraparotid lymph node is extremely rare in non-immunocompromised human immuno-1 deficiency virus (HIV)-negative patients. We report a case of a left parotid mass as an early sign of Kaposi's sarcoma-associated human herpesvirus 8 (HHV-8) infection in a 57-year-old patient. After subtotal parotidectomy and histopathological diagnosis of lymph node localization of Kaposi's sarcoma, an accurate dermatological investigation revealed a solitary small lesion in the left foot. Chemotherapy with five cycles of vincristine gave a temporary response of the cutaneous lesion. Seven months later, a few small, firm, purplish-red lesions appeared in different areas of the body, but no adjuvant treatment was accepted by the patient since the lesions occasionally disappeared or remained stable in size. At four years follow-up, there has been no recurrence in the parotid region, and the patient is alive with cutaneous disease but in good general health. The problems related to the diagnosis, the management strategy of such a rare condition and the prognosis are also discussed