116 research outputs found
Broad MICA/B expression in the small bowel mucosa: a link between cellular stress and celiac disease
The MICA/B genes (MHC class I chain related genes A and B) encode for non conventional class I HLA molecules which have no role in antigen presentation. MICA/B are up-regulated by different stress conditions such as heat-shock, oxidative stress, neoplasic transformation and viral infection. Particularly, MICA/B are expressed in enterocytes where they can mediate enterocyte apoptosis when recognised by the activating NKG2D receptor present on intraepithelial lymphocytes. This mechanism was suggested to play a major pathogenic role in active celiac disease (CD). Due to the importance of MICA/B in CD pathogenesis we studied their expression in duodenal tissue from CD patients. By immunofluorescence confocal microscopy and flow cytometry we established that MICA/B was mainly intracellularly located in enterocytes. In addition, we identified MICA/B+ T cells in both the intraepithelial and lamina propria compartments. We also found MICA/B+ B cells, plasma cells and some macrophages in the lamina propria. The pattern of MICA/B staining in mucosal tissue in severe enteropathy was similar to that found in in vitro models of cellular stress. In such models, MICA/B were located in stress granules that are associated to the oxidative and ER stress response observed in active CD enteropathy. Our results suggest that expression of MICA/B in the intestinal mucosa of CD patients is linked to disregulation of mucosa homeostasis in which the stress response plays an active role.Fil: Allegretti, Yessica Lorena. Universidad Nacional de la Plata. Facultad de Ciencias Exactas. Departamento de Ciencias Biologicas. Laboratorio de Investigaciones del Sistema Inmune; Argentina. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas; ArgentinaFil: Bondar, Constanza MarĂa. Universidad Nacional de la Plata. Facultad de Ciencias Exactas. Departamento de Ciencias Biologicas. Laboratorio de Investigaciones del Sistema Inmune; Argentina. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas; ArgentinaFil: GuzmĂĄn, Luciana. Provincia de Buenos Aires. Ministerio de Salud. Hospital de Niños "Sor MarĂa Ludovica" de la Plata; ArgentinaFil: Cueto Rua, Eduardo. Provincia de Buenos Aires. Ministerio de Salud. Hospital de Niños "Sor MarĂa Ludovica" de la Plata; ArgentinaFil: Chopita, Nestor. Provincia de Buenos Aires. Hospital Interzonal General de Agudos Gral. San Martin; ArgentinaFil: Fuertes, Mercedes Beatriz. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Instituto de BiologĂa y Medicina Experimental. FundaciĂłn de Instituto de BiologĂa y Medicina Experimental. Instituto de BiologĂa y Medicina Experimental; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de QuĂmica BiolĂłgica; ArgentinaFil: Zwirner, Norberto Walter. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Instituto de BiologĂa y Medicina Experimental. FundaciĂłn de Instituto de BiologĂa y Medicina Experimental. Instituto de BiologĂa y Medicina Experimental; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de MicrobiologĂa; ArgentinaFil: Chirdo, Fernando Gabriel. Universidad Nacional de la Plata. Facultad de Ciencias Exactas. Departamento de Ciencias Biologicas. Laboratorio de Investigaciones del Sistema Inmune; Argentina. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas; Argentin
Adaptive individual variation in phenological responses to perceived predation levels
The adaptive evolution of timing of breeding (a component of phenology) in response to environmental change requires individual variation in phenotypic plasticity for selection to act upon. A major question is what processes generate this variation. Here we apply multi-year manipulations of perceived predation levels (PPL) in an avian predator-prey system, identifying phenotypic plasticity in phenology as a key component of alternative behavioral strategies with equal fitness payoffs. We show that under low-PPL, faster (versus slower) exploring birds breed late (versus early);the pattern is reversed under high-PPL, with breeding synchrony decreasing in conjunction. Timing of breeding affects reproductive success, yet behavioral types have equal fitness. The existence of alternative behavioral strategies thus explains variation in phenology and plasticity in reproductive behavior, which has implications for evolution in response to anthropogenic change
The unfolded protein response in immunity and inflammation.
The unfolded protein response (UPR) is a highly conserved pathway that allows the cell to manage endoplasmic reticulum (ER) stress that is imposed by the secretory demands associated with environmental forces. In this role, the UPR has increasingly been shown to have crucial functions in immunity and inflammation. In this Review, we discuss the importance of the UPR in the development, differentiation, function and survival of immune cells in meeting the needs of an immune response. In addition, we review current insights into how the UPR is involved in complex chronic inflammatory diseases and, through its role in immune regulation, antitumour responses.This work was supported by the Netherlands Organization for Scientific Research Rubicon grant 825.13.012 (J.G.); US National Institutes of Health (NIH) grants DK044319, DK051362, DK053056 and DK088199, and the Harvard Digestive Diseases Center (HDDC) grant DK034854 (R.S.B.); National Institutes of Health grants DK042394, DK088227, DK103183 and CA128814 (R.J.K.); and European Research Council (ERC) Starting Grant 260961, ERC Consolidator Grant 648889, and the Wellcome Trust Investigator award 106260/Z/14/Z (A.K.).This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/nri.2016.6
Gut mucosal DAMPs in IBD: From mechanisms to therapeutic implications
Endogenous damage-associated molecular patterns (DAMPs) are released during tissue damage and have increasingly recognized roles in the etiology of many human diseases. The inflammatory bowel diseases (IBD), ulcerative colitis (UC) and Crohnâs disease (CD), are immune-mediated conditions where high levels of DAMPs are observed. DAMPs such as calprotectin (S100A8/9) have an established clinical role as a biomarker in IBD. In this review, we use IBD as an archetypal common chronic inflammatory disease to focus on the conceptual and evidential importance of DAMPs in pathogenesis and why DAMPs represent an entirely new class of targets for clinical translation. </p
Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)1.
In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field
Mitochondrial damage-associated molecular patterns (DAMPs) in inflammatory bowel disease
Background
The inflammatory bowel diseases (IBD) ulcerative colitis (UC) and Crohnâs
disease (CD) are chronic relapsing inflammatory disorders which have a rising
incidence and cause significant morbidity. There are currently several
treatment options with many more in the drug pipeline, but there are a lack of
accurate biomarkers for decisions on treatment choice, assessment of disease
activity and prognostication. There is a growing interest and desire for
personalised or âprecisionâ medicine in IBD where novel biomarkers may help
individualise IBD care in terms of diagnosis, choice of therapy, monitoring of
response and detection of relapse. One class of functionally active biomarkers
which have yet to be thoroughly investigated in IBD is damage-associated
molecular patterns (DAMPs) including mitochondrial DNA (mtDNA). It has
been recently shown that gut mitochondrial dysfunction can result in loss of
epithelial barrier function and the development of colitis. Mitochondrial DAMPs
have recently been described as elevated in several inflammatory diseases.
Hypothesis
The primary hypothesis of this thesis is that circulating levels of mtDNA is
elevated in IBD. Secondary hypotheses are: (a) levels of other mitochondrial
DAMPs are elevated in IBD, (b) circulating mtDNA can be used as a novel
biomarker in IBD and (c) mtDNA is released locally at sites of inflammation in
IBD.
Methods
Plasma and serum were collected prospectively from recruited IBD patients
and non-IBD controls. Faeces and colonic tissue were collected from a subset
of these patients. mtDNA in serum, plasma and faeces was measured using
qPCR (amplifying COXIII/ND2 genes). Mass spectrometry was used to detect
mitochondrial formylated peptides in the plasma of a subset of patients. IBD
tissue was assessed for (a) mitochondrial damage using transmission electron
microscopy (TEM) and (b) TLR9 expression, the target for mtDNA.
Results
97 patients with IBD (67 UC and 30 CD), and 40 non-IBD controls were
recruited. Plasma mtDNA levels were increased in UC and CD (both p<0.0001)
compared to non-IBD controls; with significant correlations with blood (CRP,
albumin, white cell count), clinical and endoscopic markers of severity; and
disease activity. In active UC, we detected significantly higher circulating
mitochondrial formylated peptides and faecal mtDNA levels (vs. non-IBD
controls [p<0.01 and <0.0001 respectively]) with demonstrable TEM evidence
of intestinal mucosal mitochondrial damage. In active IBD, TLR9+ lamina
propria inflammatory cells were significantly higher in UC/CD compared to
controls (both p<0.05).
Conclusions
Taken together, the findings suggest mtDNA is released during active
inflammation in inflammatory bowel disease and is a potential novel
mechanistic biomarker
Protein translation associated to PERK arm is a new target for regulation of metainflammation: A connection with hepatocyte cholesterol
Antimicrobial peptides and the enteric mucus layer act in concert to protect the intestinal mucosa
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