Autophagy in human health and disease Choi, Augustine M K; Ryter, Stefan W; Levine, Beth
The New England journal of medicine,
05/2013, Volume:
368, Issue:
19
Journal Article
Calprotectin in rheumatic diseases Ometto, Francesca; Friso, Lara; Astorri, Davide ...
Experimental biology and medicine (Maywood, N.J.),
04/2017, Volume:
242, Issue:
8
Journal Article
Peer reviewed
Open access
Calprotectin is a heterodimer formed by two proteins, S100A8 and S100A9, which are mainly produced by activated monocytes and neutrophils in the circulation and in inflamed tissues. The implication ...of calprotectin in the inflammatory process has already been demonstrated, but its role in the pathogenesis, diagnosis, and monitoring of rheumatic diseases has gained great attention in recent years. Calprotectin, being stable at room temperature, is a candidate biomarker for the follow-up of disease activity in many autoimmune disorders, where it can predict response to treatment or disease relapse. There is evidence that a number of immunomodulators, including TNF-α inhibitors, may reduce calprotectin expression. S100A8 and S100A9 have a potential role as a target of treatment in murine models of autoimmune disorders, since the direct or indirect blockade of these proteins results in amelioration of the disease process. In this review, we will go over the biologic functions of calprotectin which might be involved in the etiology of rheumatic disorders. We will also report evidence of its potential use as a disease biomarker.
Impact statement
Calprotectin is an acute-phase protein produced by monocytes and neutrophils in the circulation and inflamed tissues. Calprotectin seems to be more sensitive than CRP, being able to detect minimal residual inflammation and is a candidate biomarker in inflammatory diseases. High serum levels are associated with some severe manifestations of rheumatic diseases, such as glomerulonephritis and lung fibrosis. Calprotectin levels in other fluids, such as saliva and synovial fluid, might be helpful in the diagnosis of rheumatic diseases. Of interest is also the potential role of calprotectin as a target of treatment.
Abstract Patients affected with systemic lupus erythematosus (SLE) display poor-long term prognosis and increased mortality in respect of general population. This may be due to continuous organ ...damage accrual which is fostered both by persistent disease activity (mainly in the short term) and prolonged corticosteroid exposure (mainly in the long term). The effort of defining novel therapeutic goals to which patients should be treated in order to have their prognosis improved is named treat-to-target. Remission in SLE was shown to be associated with better outcome and prolonged survival; in clinical practice, patients may experience either complete or clinical remission, which are defined as complete clinical/serological healing or no clinical signs of lupus with active serology, respectively. The main treat-to-target in SLE is complete remission, however since longitudinal observations suggest that clinical remission or low disease activity even with minimal corticosteroid intake do improve patients prognosis and survival as well, they may be assumed as acceptable alternative targets. Suitable therapeutic strategies have to be defined in order for these goals to be achieved including early diagnosis, effective treatment and proper corticosteroid tapering which in turn require development of more reliable serum biomarkers for early disease detection and less toxic targeted therapies with a steroid-sparing potential.
To identify the shortest duration of remission associated with improved outcomes in systemic lupus erythematosus (SLE).
We studied 293 Caucasian patients with SLE during 7-year follow-up. Disease ...activity was assessed by SLE Disease Activity Index 2000 and damage by Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI). We defined three remission levels: complete, clinical off-corticosteroids, clinical on-corticosteroids (prednisone 1-5 mg/day). The effect of different durations of remission (1, 2, 3, 4 and ≥5 consecutive years) on damage was evaluated by multivariate logistic regression analysis.
Among patients achieving 1-year (27 patients), 2-year (47 patients), 3-year (45 patients), 4-year (26 patients) remission, damage was similar irrespective of the level of remission achieved, whereas, among patients achieving ≥5-year remission (113 patients), damage was higher in those in clinical remission on-corticosteroids (p<0.001).In multivariate analysis, ≥2 consecutive year remission was protective against damage (OR (95% CI)): 2 years 0.228 (0.061 to 0.850); 3 years 0.116 (0.031 to 0.436); 4 years 0.118 (0.027 to 0.519) and ≥5 years 0.044 (0.012 to 0.159). Predictors of damage were cumulative prednisone dose ≥180 mg/month (3.136 (1.276 to 7.707)), antiphospholipid antibody syndrome (5.517 (2.092 to 14.546)), vasculitis (3.107 (1.030 to 9.307)) and number of flare/year (8.769 (1.692 to 45.449)).
Two consecutive years is the shortest duration of remission associated with a decrease in damage progression in Caucasian patients with SLE.
Osteoarthritis is characterized by articular cartilage breakdown, and emerging evidence suggests that dysregulated innate immunity is likely involved. Here, we performed proteomic, transcriptomic, ...and electron microscopic analyses to demonstrate that mast cells are aberrantly activated in human and murine osteoarthritic joint tissues. Using genetic models of mast cell deficiency, we demonstrate that lack of mast cells attenuates osteoarthritis in mice. Using genetic and pharmacologic approaches, we show that the IgE/FcεRI/Syk signaling axis is critical for the development of osteoarthritis. We find that mast cell-derived tryptase induces inflammation, chondrocyte apoptosis, and cartilage breakdown. Our findings demonstrate a central role for IgE-dependent mast cell activation in the pathogenesis of osteoarthritis, suggesting that targeting mast cells could provide therapeutic benefit in human osteoarthritis.
This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter).
Galectin-3 in autoimmunity and autoimmune diseases de Oliveira, Felipe L; Gatto, Mariele; Bassi, Nicola ...
Experimental Biology and Medicine,
08/2015, Volume:
240, Issue:
8
Book Review, Journal Article
Peer reviewed
Open access
Galectin-3 (gal-3) is a β-galactoside-binding lectin, which regulates cell–cell and extracellular interactions during self/non-self-antigen recognition and cellular activation, proliferation, ...differentiation, migration and apoptosis. It plays a significant role in cellular and tissue pathophysiology by organizing niches that drive inflammation and immune responses. Gal-3 has some therapeutic potential in several diseases, including chronic inflammatory disorders, cancer and autoimmune diseases. Gal-3 exerts a broad spectrum of functions which differs according to its intra- or extracellular localization. Recombinant gal-3 strategy has been used to identify potential mode of action of gal-3; however, exogenous gal-3 may not reproduce the functions of the endogenous gal-3. Notably, gal-3 induces monocyte–macrophage differentiation, interferes with dendritic cell fate decision, regulates apoptosis on T lymphocytes and inhibits B-lymphocyte differentiation into immunoglobulin secreting plasma cells. Considering the influence of these cell populations in the pathogenesis of several autoimmune diseases, gal-3 seems to play a role in development of autoimmunity. Gal-3 has been suggested as a potential therapeutic agent in patients affected with some autoimmune disorders. However, the precise role of gal-3 in driving the inflammatory process in autoimmune or immune-mediated disorders remains elusive. Here, we reviewed the involvement of gal-3 in cellular and tissue events during autoimmune and immune-mediated inflammatory diseases.
Malnutrition plays a role in the development of poor physical performance, frailty and sarcopenia. The use of nutritional supplementations for improving physical performance and muscle strength ...parameters in older people is unclear. We therefore aimed to summarize the effect of nutritional supplementations compared to placebo on physical performance (i.e. tests more investigating physical function, utilising aerobic capacity & muscle power) and muscle strength (i.e. tests depending on muscle power) outcomes in older people in randomized controlled trials (RCTs). A literature search in major databases was undertaken until the 01st September 2018. Eligible studies were RCTs investigating the effect of nutritional supplementations vs. placebo in older people (people having an age >60 years). Standardized mean differences (SMD) and 95% confidence intervals (CIs) were used through a random effect model. Over 4007 potentially eligible articles, 32 RCTs for a total of 4137 older participants (2097 treated and 2040 placebo) (mean age: 76.3 years; 65% females) were included. Compared to placebo, multi-nutrient supplementations significantly improved chair rise time (n = 3; SMD=-0.90; 95%CI: -1.46 to -0.33; I
= 87%). Multi-nutrients significantly improved handgrip strength when compared to placebo (n = 6; 780 participants; SMD = 0.41; 95%CI: 0.06 to 0.76; I
= 79%), as did nutritional supplementations including protein (n = 7; 535 participants; SMD = 0.24; 95%CI: 0.07 to 0.41; I
= 16%).Nutritional supplementations also led to a significant improvement in chair rise time and in handgrip strength in participants affected by frailty/sarcopenia and in those affected by medical conditions. In conclusion, nutritional supplementation can improve a number of physical performance outcomes in older people, particularly when they include multi-nutrients and in people already affected by specific medical conditions, or by frailty/sarcopenia.
The history of what, in 1979, was called interleukin-1 (IL-1), orchestrator of leukocyte inter-communication, began many years before then, initially by the observation of fever induction via the ...endogenous pyrogen (EP) (1974) and then in rheumatology on the role in tissue destruction in rheumatoid diseases via the induction of collagenase and PGE
in human synovial cells by a mononuclear cell factor (MCF) (1977). Since then, the family has exploded to presently 11 members as well as many membrane-bound and soluble receptor forms. The discovery of a natural Interleukin-1 receptor antagonist (IL-1Ra) in human biological fluids has highlighted the importance of IL-1 and IL-1Ra in human diseases. Evidence delineating its role in autoinflammatory syndromes and the elucidation of the macromolecular complex referred to as "inflammasome" have been instrumental to our understanding of the link with IL-1. At present, the IL-1blockade as therapeutic approach is crucial for many hereditary autoinflammatory diseases, as well as for adult-onset Still's disease, crystal-induced arthropathies, certain skin diseases including neutrophil-triggered skin diseases, Behçet's disease and deficiency of IL-1Ra and other rare fever syndromes. Its role is only marginally important in rheumatoid arthritis and is still under debate with regard to osteoarthritis, type 2 diabetes mellitus, cardiovascular diseases and cancer. This brief historical review focuses on some aspects of IL-1, mainly IL-1β and IL-Ra, in rheumatology. There are many excellent reviews focusing on the IL-1 family in general or with regard to specific diseases or biological discoveries.
The aim of this study was to identify the molecules and pathways involved in the cross‐talk between meniscus and synovium that may play a critical role in osteoarthritis (OA) pathophysiology. Samples ...of synovium and meniscus were collected from patients with early and end‐stage OA and cultured alone or cocultured. Cytokines, chemokines, metalloproteases, and their inhibitors were evaluated at the gene and protein levels. The extracellular matrix (ECM) changes were also investigated. In early OA cultures, higher levels of interleukin‐6 (IL‐6) and IL‐8 messenger RNA were expressed by synovium and meniscus in coculture compared with meniscus cultured alone. RANTES release was significantly increased when the two tissues were cocultured compared with meniscus cultured alone. Increased levels of matrix metalloproteinase‐3 (MMP‐3) and MMP‐10 proteins, as well as increased release of glycosaminoglycans and aggrecan CS846 epitope, were observed when synovium was cocultured with meniscus. In end‐stage OA cultures, increased levels of IL‐8 and monocyte chemoattractant protein‐1 (MCP‐1) proteins were released in cocultures compared with cultures of meniscus alone. Chemokine (C‐C motif) ligand 21 (CCL21) protein release was higher in meniscus cultured alone and in coculture compared with synovium cultured alone. Increased levels of MMP‐3 and 10 proteins were observed when tissues were cocultured compared with meniscus cultured alone. Aggrecan CS846 epitope release was increased in cocultures compared with cultures of either tissue cultured alone. Our study showed the production of inflammatory molecules by synovium and meniscus which could trigger inflammatory signals in early OA patients, and induce ECM loss in the progressive and final stages of OA pathology.
Inflammatory mediators, metalloproteinases, and metalloproteinases inhibitors are produced by meniscus and synovium from early and end‐stage osteoarthritic patients. Production of inflammatory molecules by synovium and meniscus can trigger inflammatory signals in early osteoarthritis (OA) patients, and induce extracellular matrix loss in the progressive and final stages of OA pathology. The interaction between synovium and meniscus is suggested in early and late osteoarthritic patients and it may provide a basis for identifying the mechanisms contributing to the development of OA associated with meniscal tear.
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