Defects in lysosomal maturation facilitate the activation of innate sensors in systemic lupus erythematosus

Activation of innate sensors by self-antigen contributes to autoimmunity, although how intracellular sensors are chronically exposed to self-antigen has remained unknown. Here, we identify a previously unidentified defect in which lupus-prone macrophages fail to mature the lysosome, promoting the accumulation of apoptotic debris-containing IgG–immune complexes (IgG-ICs). Interestingly, macrophages from other autoimmune diseases accumulate IgG-ICs, indicating that lysosomal defects may underlie multiple autoimmune diseases. Furthermore, the prolonged intracellular residency chronically activates Toll-like receptors and permeabilizes the phagolysosomal membrane, allowing activation of cytosolic sensors. These findings identify lysosomal maturation as a unique defect in MRL/lpr mice that impacts multiple events known to underlie SLE, including pathogenic cytokine secretion

MTORC2 activity disrupts lysosome acidification in systemic lupus erythematosus by impairing caspase-1 cleavage of Rab39a

Lysosomes maintain immune homeostasis through the degradation of phagocytosed apoptotic debris; however, the signaling events regulating lysosomal maturation remain undefined. In this study, we show that lysosome acidification, key to the maturation process, relies on mTOR complex 2 (mTORC2), activation of caspase-1, and cleavage of Rab39a. Mechanistically, the localization of cofilin to the phagosome recruits caspase-11, which results in the localized activation of caspase-1. Caspase-1 subsequently cleaves Rab39a on the phagosomal membrane, promoting lysosome acidification. Although caspase-1 is critical for lysosome acidification, its activation is independent of inflammasomes and cell death mediated by apoptosis-associated speck-like protein containing a caspase recruitment domain, revealing a role beyond pyroptosis. In lupus-prone murine macrophages, chronic mTORC2 activity decouples the signaling pathway, leaving Rab39a intact. As a result, the lysosome does not acidify, and degradation is impaired, thereby heightening the burden of immune complexes that activate FcgRI and sustain mTORC2 activity. This feedforward loop promotes chronic immune activation, leading to multiple lupus-associated pathologies. In summary, these findings identify the key molecules in a previously unappreciated signaling pathway that promote lysosome acidification. It also shows that this pathway is disrupted in systemic lupus erythematosus

Association between Food Insecurity and Procurement Methods among People Living with HIV in a High Resource Setting

Objective: People living with HIV in high-resource settings suffer severe levels of food insecurity; however, limited evidence exists regarding dietary intake and sub-components that characterize food insecurity (i.e. food quantity, quality, safety or procurement) in this population. We examined the prevalence and characteristics of food insecurity among people living with HIV across British Columbia, Canada. Design: This cross-sectional analysis was conducted within a national community-based research initiative. Methods: Food security was measured using the Health Canada Household Food Security Scale Module. Logistic regression was used to determine key independent predictors of food insecurity, controlling for potential confounders. Results: Of 262 participants, 192 (73%) reported food insecurity. Sub-components associated with food insecurity in bivariate analysis included: < RDI consumption of protein (p = 0.046); being sick from spoiled/unsafe food in the past six months (p = 0.010); and procurement of food using non-traditional methods (p <0.05). In multivariable analyses, factors significantly associated with food insecurity included: procurement of food using non-traditional methods [AOR = 11.11, 95% CI: 4.79–25.68, p = <0.001]; younger age [AOR = 0.92, 95% CI: 0.86–0.96, p = <0.001]; unstable housing [AOR = 4.46, 95% CI: 1.15–17.36, p = 0.031]; household gross annual income [AOR = 4.49, 95% CI: 1.74–11.60, p = 0.002]; and symptoms of depression [AOR = 2.73, 95% CI: 1.25–5.96, p = 0.012]. Conclusions: Food insecurity among people living with HIV in British Columbia is characterized by poor dietary quality and food procurement methods. Notably, participants who reported procuring in non-traditional manners were over 10 times more likely to be food insecure. These findings suggest a need for tailored food security and social support interventions in this setting

Imaging Transient Blood Vessel Fusion Events in Zebrafish by Correlative Volume Electron Microscopy

The study of biological processes has become increasingly reliant on obtaining high-resolution spatial and temporal data through imaging techniques. As researchers demand molecular resolution of cellular events in the context of whole organisms, correlation of non-invasive live-organism imaging with electron microscopy in complex three-dimensional samples becomes critical. The developing blood vessels of vertebrates form a highly complex network which cannot be imaged at high resolution using traditional methods. Here we show that the point of fusion between growing blood vessels of transgenic zebrafish, identified in live confocal microscopy, can subsequently be traced through the structure of the organism using Focused Ion Beam/Scanning Electron Microscopy (FIB/SEM) and Serial Block Face/Scanning Electron Microscopy (SBF/SEM). The resulting data give unprecedented microanatomical detail of the zebrafish and, for the first time, allow visualization of the ultrastructure of a time-limited biological event within the context of a whole organism

Militer par le témoignage public : défis et retombées pour les communautés sexuelles et de genres

Dans cet article, nous nous penchons sur l’expérience du militantisme par le biais des témoignages de personnes qui luttent pour l’inclusion sociale de leurs communautés sexuelles et de genres. Nous décrivons l’expérience de militantes et militants issus de trois groupes sociaux minorisés en raison de leur sexualité et de leur expression de genre ou du développement de leur corps sexué : les personnes lesbiennes, gaies, bisexuelles, trans, queer et intersexes (LGBTQI), les personnes vivant avec le VIH et les personnes ayant une expérience de travail du sexe — ainsi que leurs intersections. Nous mettons de l’avant une conception politique, sensible et intersectionnelle de la notion de communauté afin de dresser un portrait transversal des expériences de militance par le témoignage tout en relevant les singularités des points de vue qui la composent. En guise de conclusion, nous dégageons les éléments qui permettent d’entrevoir ces militantes et militants et leurs prises de parole publiques comme le prolongement des interventions féministes du siècle dernier et comme lieu de nombreux défis épistémiques et de mobilisation.This article examines the experience of activism by individuals who use personal testimonials delivered in a public forum to advocate for the social inclusion of their sexual and gender communities. We describe the experience of activists from three social groups who are the target of stigma and discrimination due to their sexual identity, sexual practices, gender expression or the development of their bodies: people who identify as lesbian, gay, bisexual, trans, queer or intersex (LGBTQI), people living with HIV and people with sex work experience – and their intersections. A political, sensitive and intersectional conception of community is put forward in order to capture the transversal aspects of this militancy while highlighting the singularities of the multiple perspectives that compose it. We conclude by noting similarities between such community testimonials and twentieth century feminist interventions and the epistemic and mobilization challenges they raise

Community mobilisation to optimize access to combination HIV prevention for MSM in Montreal: initial results from the MOBILISE! project

International audienceBackground: Using multiple prevention options and services together (“combination prevention”) could significantly reduce HIV infections among MSM, but a coordinated, synergistic strategy is needed to achieve this. MOBILISE ! is a community-based research project initiated in Montreal that aims to develop a strategy for optimizing access to combination prevention for MSM through participatory evaluation and community mobilization. Method: A coalition of 33 partners has collaborated to implement peer-led community discussions and an online survey to gather data on: 1) what MSM across Quebec know about combination prevention; 2) their experiences accessing health services in Montreal. Qualitative data from discussions were gathered using logbooks and analyzed thematically. Descriptive analyses of means and proportions were generated for quantitative data from survey responses. A deliberative process was used to leverage this data to identify priorities for action.Results: Between November 2015 and October 2016, 20 peer researchers were recruited to lead small-group discussions with a total of 83 MSM, and 394 respondents completed the survey. Over 70 participants attended a community forum to discuss key findings including: 1) barriers in access to PEP and PrEP; 2) discrepancies in attitudes and knowledge about serosorting and undetectable viral load depending on HIV status; 3) the need for better coordination between medical and non-medical care providers. MSM unaware of their HIV status were identified as a priority group that knows less about and makes less use of risk reduction strategies. Structural change within the health care system, capacity building, and psychosocial interventions were identified as potential solutions.Conclusion: Results from the forum will be used to develop a community consensus statement. The mobilization strategies used in Montreal are being adapted by partners in Toronto, Ottawa, and Vancouver and a framework is being developed to evaluate the impact of structural interventions on access to services and health outcomes

Defects in lysosomal maturation facilitate the activation of innate sensors in systemic lupus erythematosus

Defects in clearing apoptotic debris disrupt tissue and immunological homeostasis, leading to autoimmune and inflammatory diseases. Herein, we report that macrophages from lupus-prone MRL/lpr mice have impaired lysosomal maturation, resulting in heightened ROS production and attenuated lysosomal acidification. Impaired lysosomal maturation diminishes the ability of lysosomes to degrade apoptotic debris contained within IgG-immune complexes (IgG-ICs) and promotes recycling and the accumulation of nuclear self-antigens at the membrane 72 h after internalization. Diminished degradation of IgG-ICs prolongs the intracellular residency of nucleic acids, leading to the activation of Toll-like receptors. It also promotes phagosomal membrane permeabilization, allowing dsDNA and IgG to leak into the cytosol and activate AIM2 and TRIM21. Collectively, these events promote the accumulation of nuclear antigens and activate innate sensors that drive IFN alpha production and heightened cell death. These data identify a previously unidentified defect in lysosomal maturation that provides a mechanism for the chronic activation of intracellular innate sensors in systemic lupus erythematosus

Association between Food Insecurity and Procurement Methods among People Living with HIV in a High Resource Setting.

ObjectivePeople living with HIV in high-resource settings suffer severe levels of food insecurity; however, limited evidence exists regarding dietary intake and sub-components that characterize food insecurity (i.e. food quantity, quality, safety or procurement) in this population. We examined the prevalence and characteristics of food insecurity among people living with HIV across British Columbia, Canada.DesignThis cross-sectional analysis was conducted within a national community-based research initiative.MethodsFood security was measured using the Health Canada Household Food Security Scale Module. Logistic regression was used to determine key independent predictors of food insecurity, controlling for potential confounders.ResultsOf 262 participants, 192 (73%) reported food insecurity. Sub-components associated with food insecurity in bivariate analysis included: &lt; RDI consumption of protein (p = 0.046); being sick from spoiled/unsafe food in the past six months (p = 0.010); and procurement of food using non-traditional methods (p &lt;0.05). In multivariable analyses, factors significantly associated with food insecurity included: procurement of food using non-traditional methods [AOR = 11.11, 95% CI: 4.79-25.68, p = &lt;0.001]; younger age [AOR = 0.92, 95% CI: 0.86-0.96, p = &lt;0.001]; unstable housing [AOR = 4.46, 95% CI: 1.15-17.36, p = 0.031]; household gross annual income [AOR = 4.49, 95% CI: 1.74-11.60, p = 0.002]; and symptoms of depression [AOR = 2.73, 95% CI: 1.25-5.96, p = 0.012].ConclusionsFood insecurity among people living with HIV in British Columbia is characterized by poor dietary quality and food procurement methods. Notably, participants who reported procuring in non-traditional manners were over 10 times more likely to be food insecure. These findings suggest a need for tailored food security and social support interventions in this setting

Bivariate comparison of participant socio-demographic and behavioural characteristics, by food security status (n = 262).

<p>Bivariate comparison of participant socio-demographic and behavioural characteristics, by food security status (n = 262).</p