Summary
Macrophage activation syndrome (MAS) is hyperinflammatory life‐threatening syndrome, associated typically with high levels of serum ferritin. This is an iron storage protein including heavy ...(H) and light (L) subunits, categorized on their molecular weight. The H‐/L subunits ratio may be different in tissues, depending on the specific tissue and pathophysiological status. In this study, we analysed the bone marrow (BM) biopsies of adult MAS patients to assess the presence of: (i) H‐ferritin and L‐ferritin; (ii) CD68+/H‐ferritin+ and CD68+/L‐ferritin+; and (iii) interleukin (IL)‐1β, tumour necrosis factor (TNF) and interferon (IFN)‐γ. We also explored possible correlations of these results with clinical data. H‐ferritin, IL‐1β, TNF and IFN‐γ were increased significantly in MAS. Furthermore, an increased number of CD68+/H‐ferritin+ cells and an infiltrate of cells co‐expressing H‐ferritin and IL‐12, suggesting an infiltrate of M1 macrophages, were observed. H‐ferritin levels and CD68+/H‐ferritin+ cells were correlated with haematological involvement of the disease, serum ferritin and C‐reactive protein. L‐ferritin and CD68+/L‐ferritin+ cells did not correlate with these parameters. In conclusion, during MAS, H‐ferritin, CD68+/H‐ferritin+ cells and proinflammatory cytokines were increased significantly in the BM inflammatory infiltrate, pointing out a possible vicious pathogenic loop. To date, H‐ferritin and CD68+/H‐ferritin+ were associated significantly with haematological involvement of the disease, suggesting biomarkers assessing severity of clinical picture.
Our study suggests the hypothesis that the high levels of tissue H‐ferritin and CD68+/H‐ferritin+ macrophages, observed during MAS, may not only be considered a consequence of the inflammation but possibly involved in a vicious loop perpetuating the inflammatory process.
Objective
Systemic autoimmune diseases, in particular systemic lupus erythematosus and rheumatoid arthritis, are characterized by a high risk of premature cardiovascular (CV) events. Disease‐related ...characteristics and traditional CV disease risk factors may contribute to atherosclerotic damage. However, there are limited data on the risk of overt CV events in primary Sjögren's syndrome (pSS).
Methods
We retrospectively analysed a cohort of patients with 1343 pSS. Disease‐related clinical and laboratory data, traditional CV disease risk factors and overt CV events were recorded. Prevalence of traditional CV disease risk factors and of major CV events was compared between a subgroup of 788 female patients with pSS aged from 35 to 74 years and 4774 age‐matched healthy women.
Results
Hypertension and hypercholesterolaemia were more prevalent, whereas smoking, obesity and diabetes mellitus were less prevalent, in women with pSS than in control subjects. Cerebrovascular events (2.5% vs. 1.4%, P = 0.005) and myocardial infarction (MI) (1.0% vs. 0.4%, P = 0.002) were more common in patients with pSS. In the whole population, central nervous system involvement (odds ratio (OR) 5.6, 95% confidence interval (CI) 1.35–23.7, P = 0.02) and use of immunosuppressive therapy (OR 1.9, 95% CI 1.04–3.70, P = 0.04) were associated with a higher risk of CV events. Patients with leucopenia had a higher risk of angina (P = 0.01).
Conclusions
pSS is associated with an increased risk of cerebrovascular events and MI. Disease‐related clinical and immunological markers may have a role in promoting CV events.
Summary
Systemic sclerosis (SSc) is an autoimmune disease characterized by significant vascular alterations and multi‐organ fibrosis. Microvascular alterations are the first event of SSc and injured ...endothelial cells (ECs) may transdifferentiate towards myofibroblasts, the cells responsible for fibrosis and collagen deposition. This process is identified as endothelial‐to‐mesenchymal transition (EndMT), and understanding of its development is pivotal to identify early pathogenetic events and new therapeutic targets for SSc. In this review, we have highlighted the molecular mechanisms of EndMT and summarize the evidence of the role played by EndMT during the development of progressive fibrosis in SSc, also exploring the possible therapeutic role of its inhibition.
During Systemic Sclerosis (SSc), the alteration of endothelial cells (ECs) functions plays a pivotal role during vascular remodelling, playing as trigger for fibroproliferative disorder. After pathological stimuli, such as TGF‐β, ET‐1, TNF‐α, IL‐1, INF, hypoxia, ROS and miRs, ECs may trans‐differentiate toward myofibroblasts, through the endothelial‐to‐mesenchymal transition (EndMT), losing vascular ECs markers, gaining mesenchymal cell markers and invading the surrounding tissue. A better understanding of EndMT mechanisms is pivotal, to identify clinically useful biomarkers, in order to develop effective anti‐fibrotic therapies during SSc, a condition in which an appropriated therapy is still lacking.
Summary A better understanding about the mechanisms involved in the pathogenesis of type 2 diabetes mellitus (T2D) showed that inflammatory cytokines such as tumour necrosis factor (TNF) and ...interleukin (IL)-1beta play a pivotal role, mirroring data largely reported in rheumatoid arthritis (RA). IL-1beta is produced mainly by monocytes (MO), and hyperglycaemia may be able to modulate, in the cytoplasm of these cells, the assembly of a nucleotide-binding domain and leucine-rich repeat containing family pyrin (NLRP3)-inflammosome, a cytosolic multi-protein platform where the inactive pro-IL-1beta is cleaved into active form, via caspase-1 activity. In this paper, we evaluated the production of IL-1 beta and TNF, in peripheral blood MO of patients affected by RA or T2D or both diseases, in order to understand if an alteration of the glucose metabolism may influence their proinflammatory status. Our data showed, after 24 h of incubation with different glucose concentrations, a significantly increased production of IL-1beta and TNF in all evaluated groups when compared with healthy controls. However, a significant increase of IL-1beta secretion by T2D/RA was observed when compared with other groups. The analysis of relative mRNA expression confirmed these data. After 24 h of incubation with different concentrations of glucose, our results showed a significant increase in NLRP3 expression. In this work, an increased production of IL-1beta by MO obtained from patients affected by both RA and T2D via NLRP3-inflammasome activation may suggest a potential IL-1beta targeted therapy in these patients.
Summary
A better understanding about the mechanisms involved in the pathogenesis of type 2 diabetes mellitus (T2D) showed that inflammatory cytokines such as tumour necrosis factor (TNF) and ...interleukin (IL)‐1β play a pivotal role, mirroring data largely reported in rheumatoid arthritis (RA). IL‐1β is produced mainly by monocytes (MO), and hyperglycaemia may be able to modulate, in the cytoplasm of these cells, the assembly of a nucleotide‐binding domain and leucine‐rich repeat containing family pyrin (NLRP3)‐inflammosome, a cytosolic multi‐protein platform where the inactive pro‐IL‐1β is cleaved into active form, via caspase‐1 activity. In this paper, we evaluated the production of IL‐1 β and TNF, in peripheral blood MO of patients affected by RA or T2D or both diseases, in order to understand if an alteration of the glucose metabolism may influence their proinflammatory status. Our data showed, after 24 h of incubation with different glucose concentrations, a significantly increased production of IL‐1β and TNF in all evaluated groups when compared with healthy controls. However, a significant increase of IL‐1β secretion by T2D/RA was observed when compared with other groups. The analysis of relative mRNA expression confirmed these data. After 24 h of incubation with different concentrations of glucose, our results showed a significant increase in NLRP3 expression. In this work, an increased production of IL‐1β by MO obtained from patients affected by both RA and T2D via NLRP3‐inflammasome activation may suggest a potential IL‐1β targeted therapy in these patients.
Summary
The aim of this study was to investigate the expression of the interleukin (IL)‐36 axis in patients with primary Sjögren's syndrome (pSS). Blood and minor labial salivary glands (MSG) ...biopsies were obtained from 35 pSS and 20 non‐Sjögren's syndrome patients (nSS) patients. Serum IL‐36α was assayed by enzyme‐linked immunosorbent assay (ELISA). IL‐36α, IL‐36R, IL‐36RA, IL‐38, IL‐22, IL‐17, IL‐23p19 and expression in MSGs was assessed by reverse transcription–polymerase chain reaction (RT–PCR), and tissue IL‐36α and IL‐38 expression was also investigated by immunohistochemistry (IHC). αβ and γδ T cells and CD68+ cells isolated from MSGs were also studied by flow cytometry and confocal microscopy analysis. IL‐36α was over‐expressed significantly in the serum and in the salivary glands of pSS. Salivary gland IL‐36α expression was correlated with the expression levels of IL‐17, IL‐22 and IL‐23p19. IL‐38, that acts as inhibitor of IL‐36α, was also up‐regulated in pSS. αβ+ CD3+ T cells and CD68+ cells were the major source of IL‐36α in minor salivary glands of pSS. γδ T cells were not significantly expanded in the salivary glands of pSS but produced more IL‐17, as their percentage correlated with the focus score. Higher expression of IL‐36α and IL‐36R was also demonstrated in γδ T cells isolated from pSS compared to controls. In this study we demonstrate that a significant increase in circulating and tissue levels of IL‐36α occurs in pSS patients.
Summary
Interleukin (IL)‐9 is a 28‐30 kDa monomeric glycosylated polypeptide belonging to the IL‐7/IL‐9 family of proteins that bind to a composite receptor consisting of the private receptor IL‐9R ...and the IL‐2 receptor, gamma (IL‐2RG), a common gamma subunit shared by the receptors of many different cytokines. The IL‐9R is expressed widely and IL‐9 impacts a number of effector cells, such as effector T cells, B cells, innate lymphoid cells, mast cells, polymorphonuclear cells, epithelial cells and smooth muscle cells, playing an important role in regulating inflammatory immunity. The critical role of IL‐9 in promoting cellular and humoral immune responses makes it an important focus of potential therapeutic interventions. Recently, a defined subset of T helper type cells, Th9 cells, has been identified by the potent production of IL‐9. The involvement of the Th9 cell subset has been described in many types of inflammatory diseases, namely atopic diseases, helminth infections, experimental autoimmune encephalomyelitis and ulcerative colitis. In this review, we summarize the IL‐9 biological activities, highlighting roles for IL‐9 and Th9 cells in rheumatoid and psoriatic arthritis, systemic vasculitis, systemic lupus erythematosus and systemic sclerosis.
Summary The aim of this study was to investigate the expression of the interleukin (IL)-36 axis in patients with primary Sjögren's syndrome (pSS). Blood and minor labial salivary glands (MSG) ...biopsies were obtained from 35 pSS and 20 non-Sjögren's syndrome patients (nSS) patients. Serum IL-36alpha was assayed by enzyme-linked immunosorbent assay (ELISA). IL-36alpha, IL-36R, IL-36RA, IL-38, IL-22, IL-17, IL-23p19 and expression in MSGs was assessed by reverse transcription-polymerase chain reaction (RT-PCR), and tissue IL-36alpha and IL-38 expression was also investigated by immunohistochemistry (IHC). alphabeta and gammadelta T cells and CD68+ cells isolated from MSGs were also studied by flow cytometry and confocal microscopy analysis. IL-36alpha was over-expressed significantly in the serum and in the salivary glands of pSS. Salivary gland IL-36alpha expression was correlated with the expression levels of IL-17, IL-22 and IL-23p19. IL-38, that acts as inhibitor of IL-36alpha, was also up-regulated in pSS. alphabeta+ CD3+ T cells and CD68+ cells were the major source of IL-36alpha in minor salivary glands of pSS. gammadelta T cells were not significantly expanded in the salivary glands of pSS but produced more IL-17, as their percentage correlated with the focus score. Higher expression of IL-36alpha and IL-36R was also demonstrated in gammadelta T cells isolated from pSS compared to controls. In this study we demonstrate that a significant increase in circulating and tissue levels of IL-36alpha occurs in pSS patients.
Cytokines such as tumour necrosis factor (TNF)- alpha , interleukin (IL)-12, interferon (IFN)- gamma , IL-23 and, more recently, IL-9, have been implicated in the initiation/maintenance of ...inflammation in psoriasis and psoriatic arthritis (PsA). In the present study we aimed to characterize the role of gamma delta T cells in peripheral blood and synovial fluid of PsA patients and to investigate their response to in-vitro stimulation with antigen or cytokines (IL-9 and IL-23). gamma delta T cells isolated from peripheral blood mononuclear cells and synovial fluid were analysed by flow cytometry to evaluate the phenotype and cytokine production. IL-23R and IL-9R gene expression were also evaluated by reverse transcription-polymerase chain reaction (RT-PCR). Peripheral blood mononuclear cells (PBMC), sorted gamma delta T cells and gamma delta cell lines were also stimulated in vitro with isopentenyl pyrophosphate (IPP), recombinant IL-9 or recombinant IL-23. Our results show an expansion of gamma delta T cells with a predominant effector memory phenotype in peripheral blood and synovium of untreated PsA patients, which reverses significantly after treatment with anti-TNF- alpha or anti-IL-12/IL-23R monoclonal antibodies (mAbs). Moreover, in PsA patients gamma delta T cells activation is driven prevalently by IL-9/IL-9R interaction, and not only by IL-23/IL-23R. Together these findings indicate gamma delta T cells and IL-9 as new players in the pathogenesis of PsA. IL-9/IL-9R axis drives gamma delta T cells activation in psoriatic arthritis patients
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