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Biofilm Dispersal : Mechanisms, Clinical Implications, and Potential Therapeutic Uses
Like all sessile organisms, surface-attached communities of bacteria known as biofilms must release and disperse cells into the environment to colonize new sites. For many pathogenic bacteria, biofilm dispersal plays an important role in the transmission of bacteria from environmental reservoirs to human hosts, in horizontal and vertical cross-host transmission, and in the exacerbation and spread of infection within a host. The molecular mechanisms of bacterial biofilm dispersal are only beginning to be elucidated. Biofilm dispersal is a promising area of research that may lead to the development of novel agents that inhibit biofilm formation or promote biofilm cell detachment. Such agents may be useful for the prevention and treatment of biofilms in a variety of industrial and clinical settings. This review describes the current status of research on biofilm dispersal, with an emphasis on studies aimed to characterize dispersal mechanisms, and to identify environmental cues and inter- and intracellular signals that regulate the dispersal process. The clinical implications of biofilm dispersal and the potential therapeutic applications of some of the most recent findings will also be discussed.
Journal Article
The role of neutrophils and NETosis in autoimmune and renal diseases
Key Points
Neutrophils may have critical roles in the pathogenesis of autoimmune diseases by forming neutrophil extracellular traps (NETs), secreting proinflammatory cytokines and by directly causing tissue damage
NET formation externalizes autoantigens that might contribute to the pathophysiology and clinical manifestations of autoimmune diseases, either directly or by modulating other components of the immune system
An imbalance in NET formation and degradation might increase the half-life of NET products and augment the immune response
Novel therapies that target key pathways in neutrophil function and NET formation might improve the treatment of autoimmune diseases.
Neutrophils are crucial regulators of the innate immune response and act as a first line of defence against invading microorganisms. To target microorganisms, neutrophils release extracellular structures called neutrophil extracellular traps (NETs), which externalize key autoantigens. In this Review, Gupta and Kaplan explore the contribution of neutrophils and NETs to the pathophysiology of systemic autoimmune disorders that can affect the kidneys, and discuss neutrophils as novel therapeutic targets for these diseases.
Systemic autoimmune diseases are a group of disorders characterized by a failure in self-tolerance to a wide variety of autoantigens. In genetically predisposed individuals, these diseases occur as a multistep process in which environmental factors have key roles in the development of abnormal innate and adaptive immune responses. Experimental evidence collected in the past decade suggests that neutrophils — the most abundant type of white blood cell — might have an important role in the pathogenesis of these diseases by contributing to the initiation and perpetuation of immune dysregulation through the formation of neutrophil extracellular traps (NETs), synthesis of proinflammatory cytokines and direct tissue damage. Many of the molecules externalized through NET formation are considered to be key autoantigens and might be involved in the generation of autoimmune responses in predisposed individuals. In several systemic autoimmune diseases, the imbalance between NET formation and degradation might increase the half-life of these lattices, which could enhance the exposure of the immune system to modified autoantigens and increase the capacity for NET-induced organ damage. This Review details the role of neutrophils and NETs in the pathophysiology of systemic autoimmune diseases, including their effect on renal damage, and discusses neutrophil targets as potential novel therapies for these diseases.
Journal Article
Metabolic alterations of the immune system in the pathogenesis of autoimmune diseases
Systemic autoimmune diseases are characteristically associated with aberrant autoreactive innate and adaptive immune responses that lead to tissue damage and increased morbidity and mortality. Autoimmunity has been linked to alterations in the metabolic functions of immune cells (immunometabolism) and, more specifically, to mitochondrial dysfunction. Much has been written about immunometabolism in autoimmunity in general, so this Essay focuses on recent research into the role of mitochondrial dysfunction in the dysregulation of innate and adaptive immunity that is characteristic of systemic autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Enhancing the understanding of mitochondrial dysregulation in autoimmunity will hopefully contribute to accelerating the development of immunomodulatory treatments for these challenging diseases.
Journal Article
Bite of the wolf: innate immune responses propagate autoimmunity in lupus
The etiopathogenesis of systemic lupus erythematosus (SLE), a clinically heterogeneous multisystemic syndrome that derives its name from the initial characterization of facial lesions that resemble the bite of a wolf, is considered a complex, multifactorial interplay between underlying genetic susceptibility factors and the environment. Prominent pathogenic factors include the induction of aberrant cell death pathways coupled with defective cell death clearance mechanisms that promote excessive externalization of modified cellular and nuclear debris with subsequent loss of tolerance to a wide variety of autoantigens and innate and adaptive immune dysregulation. While abnormalities in adaptive immunity are well recognized and are key to the pathogenesis of SLE, recent findings have emphasized fundamental roles of the innate immune system in the initiation and propagation of autoimmunity and the development of organ damage in this disease. This Review focuses on recent discoveries regarding the role of components of the innate immune system, specifically neutrophils and interferons, in promoting various aspects of lupus pathogenesis, with potential implications for novel therapeutic strategies.
Journal Article
Neutrophils in the pathogenesis and manifestations of SLE
Neutrophils, increasing evidence suggests, play an important part in the development and perpetuation of autoimmunity in patients with systemic lupus erythematosus (SLE). In this Review, the author highlights defects in the phenotype and function of SLE-derived neutrophils. Intriguing links between aberrant neutrophil death, production of proinflammatory mediators, and the presentation of and response to autoantigens are explored. The potential contribution of defective neutrophil activity to organ dysfunction is also discussed.
Systemic lupus erythematosus (SLE) is an autoimmune disease of unclear etiology that affects mostly women of childbearing age. Profound abnormalities in both innate and adaptive immunity triggered by genetic and environmental factors are well documented to play an important part in the pathogenesis of SLE. Nonetheless, the role of neutrophils—the most abundant immune cell type—in the pathology of this disease has been unclear. Over the past decade, compelling evidence has emerged that implicates neutrophils in the initiation and perpetuation of SLE and also in the resultant organ damage frequently observed in patients with this disease. SLE-derived low-density granulocytes (LDGs) induce vascular damage and synthesize increased amounts of type I interferons and, as such, could play a prominent part in the pathogenesis of SLE. Furthermore, increased cell death and enhanced extracellular trap formation observed in SLE-derived neutrophils might have key roles in the induction of autoimmunity and the development of organ damage in patients with SLE. Together, these events could have significant deleterious effects and promote aberrant immune responses in this disease. This Review highlights the role of neutrophils in the pathogenesis of SLE, with a particular focus on the putative deleterious effects of LDGs and neutrophil extracellular trap formation.
Key Points
Patients with systemic lupus erythematosus (SLE) display marked abnormalities in neutrophil phenotype and function, and enhanced neutrophil death through apoptosis and 'NETosis'
A distinct subset of proinflammatory low-density granulocytes isolated from patients with SLE induces vascular damage, displays enhanced bactericidal gene signatures and synthesizes increased amounts of type I IFNs
Enhanced NETosis observed in SLE-derived neutrophils might have key roles in the induction of autoimmunity and the development of organ damage in SLE
Neutrophil dysfunction and increased NETosis might contribute to SLE pathology and disease manifestations, such as vascular complications, lupus nephritis and cutaneous lupus erythematosus
Journal Article
Navigating an enigma: the continuing journey of autoimmunity discoveries
Kaplan discusses the continuing journey of autoimmunity discoveries. Autoimmune diseases (ADs) constitute about one hundred and fifty conditions that often afflict people in the prime of their life. ADs are strikingly more common in women and affect around 9% of the US population. Discoveries on the role of epigenetics in ADs have contributed to unraveling the complex interplay between genetic predisposition and environmental triggers. Epigenetic modifications, including DNA methylation, nucleic acid oxidation, histone acetylation, and microRNA expression, have been shown to play fundamental roles in regulating gene expression and immune responses in ADs. The development of groundbreaking technologies is increasing the promise of targeted therapeutic approaches. Furthermore, using artificial intelligence in autoimmunity research offers wonderful opportunities for data analysis, predictive modeling, and pattern recognition, including identifying complex relationships in genetic and clinical data and developing predictive tools for disease risk in real-time situations.
Journal Article
Reconstructing European forest management from 1600 to 2010
Because of the slow accumulation and long residence time of carbon in biomass and soils, the present state and future dynamics of temperate forests are influenced by management that took place centuries to millennia ago. Humans have exploited the forests of Europe for fuel, construction materials and fodder for the entire Holocene. In recent centuries, economic and demographic trends led to increases in both forest area and management intensity across much of Europe. In order to quantify the effects of these changes in forests and to provide a baseline for studies on future land-cover–climate interactions and biogeochemical cycling, we created a temporally and spatially resolved reconstruction of European forest management from 1600 to 2010. For the period 1600–1828, we took a supply–demand approach, in which supply was estimated on the basis of historical annual wood increment and land cover reconstructions. We made demand estimates by multiplying population with consumption factors for construction materials, household fuelwood, industrial food processing and brewing, metallurgy, and salt production. For the period 1829–2010, we used a supply-driven backcasting method based on national and regional statistics of forest age structure from the second half of the 20th century. Our reconstruction reproduces the most important changes in forest management between 1600 and 2010: (1) an increase of 593 000 km2 in conifers at the expense of deciduous forest (decreasing by 538 000 km2); (2) a 612 000 km2 decrease in unmanaged forest; (3) a 152 000 km2 decrease in coppice management; (4) a 818 000 km2 increase in high-stand management; and (5) the rise and fall of litter raking, which at its peak in 1853 resulted in the removal of 50 Tg dry litter per year.
Journal Article
Somatic Mutations in UBA1 and Severe Adult-Onset Autoinflammatory Disease
The discovery of the genetic cause of an inflammatory disorder shows that, in winnowing down candidate variants obtained by DNA sequencing screens, geneticists have been (so to speak) throwing the baby out with the bath water.
Journal Article