Objective: Diffuse central nervous system manifestations, referred to as neuropsychiatric lupus (NPSLE), are observed in 20-40% of lupus patients and involve complex mechanisms that have not yet been adequately elucidated. In murine NPSLE models, choroid plexus (ChP)-infiltrating T cells have not been fully evaluated as drivers of neuropsychiatric disease.
Method: Droplet-based single-cell transcriptomic analysis (single-cell RNA sequencing) and immune T-cell receptor profiling were performed on ChP tissue from MRL/lpr mice, an NPSLE mouse model, at an 'early' and 'late' disease state, to investigate the infiltrating immune cells that accumulate with NPSLE disease progression.
Arthritis Rheumatol
November 2022
Objective: T cells are critical in the pathogenesis of systemic lupus erythematosus (SLE) in that they secrete inflammatory cytokines, help autoantibody production, and form autoreactive memory T cells. Although the contribution of T cells to several forms of organ-mediated damage in SLE has been previously demonstrated, the role of T cells in neuropsychiatric SLE (NPSLE), which involves diffuse central nervous system manifestations and is observed in 20-40% of SLE patients, is not known. Therefore, we conducted this study to evaluate how behavioral deficits are altered after depletion or transfer of T cells, to directly assess the role of T cells in NPSLE.
View Article and Find Full Text PDFChaperone-mediated autophagy (CMA) contributes to regulation of energy homeostasis by timely degradation of enzymes involved in glucose and lipid metabolism. Here, we report reduced CMA activity in vascular smooth muscle cells and macrophages in murine and human arteries in response to atherosclerotic challenges. We show that in vivo genetic blockage of CMA worsens atherosclerotic pathology through both systemic and cell-autonomous changes in vascular smooth muscle cells and macrophages, the two main cell types involved in atherogenesis.
View Article and Find Full Text PDFCircadian rhythms align physiological functions with the light-dark cycle through oscillatory changes in the abundance of proteins in the clock transcriptional programme. Timely removal of these proteins by different proteolytic systems is essential to circadian strength and adaptability. Here we show a functional interplay between the circadian clock and chaperone-mediated autophagy (CMA), whereby CMA contributes to the rhythmic removal of clock machinery proteins (selective chronophagy) and to the circadian remodelling of a subset of the cellular proteome.
View Article and Find Full Text PDFH1 linker histones are the most abundant chromatin-binding proteins. In vitro studies indicate that their association with chromatin determines nucleosome spacing and enables arrays of nucleosomes to fold into more compact chromatin structures. However, the in vivo roles of H1 are poorly understood.
View Article and Find Full Text PDFIn systemic lupus erythematosus (SLE), widespread T cell infiltration into target organs contributes to inflammation and organ damage. Autoreactive T cells become aberrantly activated in this disease due to dysfunctional T cell receptor signaling that lowers the activation threshold. Characterizing the T cell repertoire can provide further insight into the specific homing and proliferation of these T cells into lupus target organs.
View Article and Find Full Text PDFA significant number of people living with HIV (PLWH) develop HIV-associated neurocognitive disorders (HAND) despite highly effective antiretroviral therapy (ART). Dysregulated macroautophagy (autophagy) is implicated in HAND pathogenesis. The viral protein Nef, expressed even with suppressive ART, and certain antiretrovirals affect autophagy in non-CNS cells.
View Article and Find Full Text PDFObesity-related asthma disproportionately affects minority children and is associated with nonatopic T-helper type 1 (Th1) cell polarized inflammation that correlates with pulmonary function deficits. Its underlying mechanisms are poorly understood. To use functional genomics to identify cellular mechanisms associated with nonatopic inflammation in obese minority children with asthma.
View Article and Find Full Text PDFChagas disease, caused by , is a major public health issue. Limitations in immune responses to natural infection usually result in parasite persistence with significant complications. A safe, effective, and reliable vaccine would reduce the threat of infections; however, no suitable vaccine is currently available due to a lack of understanding of the requirements for induction of fully protective immunity.
View Article and Find Full Text PDFTo gain understanding on the mechanisms that drive immunosenescence in humans, we examined CD4 T cells obtained from younger (20-39 years-old) and older (70+ years-old) healthy participants of the Baltimore Longitudinal Study on Aging (BLSA). We found that mitochondrial proteins involved in the electron transport chain were overrepresented in cells from older participants, with prevalent dysregulation of oxidative phosphorylation and energy metabolism molecular pathways. Surprisingly, gene transcripts coding for mitochondrial proteins pertaining to oxidative phosphorylation and electron transport chain pathways were underrepresented in older individuals.
View Article and Find Full Text PDFFocal ablative therapies have been primarily used for local tumor ablation. However, they often fail to impact systemic disease. Here we propose the use of low intensity focused ultrasound (LOFU), a noninvasive, nontoxic, conformal therapy, to deliver acoustic stress to the tumor for immune priming.
View Article and Find Full Text PDFDysregulation of autophagy with age has been identified as a central mechanism of aging affecting many cells and tissues. T cells do also show decreased activity with age of different autophagic pathways. Here, we will review the current knowledge of the different functions that autophagy has in the regulation of T cell homeostasis, differentiation and function and explore how the age-associated decreased in autophagy activity may contribute to the altered T cell responses that characterize T cell immunosenescence.
View Article and Find Full Text PDFThe contractile perivascular cells, pericytes (PC), are hijacked by glioblastoma (GB) to facilitate tumor progression. PC's protumorigenic function requires direct interaction with tumor cells and contributes to the establishment of immunotolerance to tumor growth. Cancer cells up-regulate their own chaperone-mediated autophagy (CMA), a process that delivers selective cytosolic proteins to lysosomes for degradation, with pro-oncogenic effects.
View Article and Find Full Text PDFObesity is associated with changes in the immune system that significantly hinder its ability to mount efficient immune responses. Previous studies have reported a dysregulation of immune responses caused by lipid challenge; however, the mechanisms underlying that dysregulation are still not completely understood. Autophagy is an essential catabolic process through which cellular components are degraded by the lysosomal machinery.
View Article and Find Full Text PDFIn response to activation, CD4 T cells upregulate autophagy. However, the functional consequences of that upregulation have not been fully elucidated. In this study, we identify autophagy as a tolerance-avoidance mechanism.
View Article and Find Full Text PDFNeuropsychiatric symptoms in systemic lupus erythematosus (SLE) are not uncommon, yet the mechanisms underlying disease initiation and progression in the brain are incompletely understood. Although the role of T cells in other lupus target organs such as the kidney is well defined, which T cells contribute to the pathogenesis of neuropsychiatric SLE is not known. The present study was aimed at characterizing the CD4 T cell populations that are present in the choroid plexus (CP) of MRL/MpJ-fas mice, the primary site of brain infiltration in this classic lupus mouse model which exhibits a prominent neurobehavioral phenotype.
View Article and Find Full Text PDFAnnu Rev Food Sci Technol
March 2018
Increasingly, studies showing the protective effects of the Mediterranean diet (MedDiet) on different diseases (cardiovascular, diabetes, some cancers, and even total mortality and aging indicators) are being published. The scientific evidence level for each outcome is variable, and new studies are needed to better understand the molecular mechanisms whereby the MedDiet may exercise its effects. Here, we present recent advances in understanding the molecular basis of MedDiet effects, mainly focusing on cardiovascular diseases but also discussing other related diseases.
View Article and Find Full Text PDFAutophagy, a highly conserved catabolic process that involves the degradation and recycling of intracellular components in the lysosome, has emerged as a key process in the maintenance of T cell homeostasis and the regulation of T cell differentiation and function. In this review, we provide an overview of the mechanisms that mediate the regulation of autophagy in T cells and discuss different cellular processes that are under the control of autophagy in CD4 and CD8 T cells. A special emphasis is placed on the role that autophagy plays in the modulation of T cell metabolism and the consequences of this regulation on functional states and programs of differentiation in specific T cell populations.
View Article and Find Full Text PDFThe establishment of immune tolerance during Glioblastoma Multiforme (GBM) progression, is characterized by high levels expression of anti-inflammatory cytokines, which suppress the function of tumor assocciated myeloid cells, and the activation and expansion of tumor antigen specific T cells. However, the mechanisms underlying the failed anti-tumor immune response around the blood vessels during GBM, are poorly understood. The consequences of possible interactions between cancer cells and the perivascular compartment might affect the tumor growth.
View Article and Find Full Text PDFRepeated stimulation of T cells that occurs in the context of chronic infection results in progressively reduced responsiveness of T cells to pathogen-derived antigens. This phenotype, known as T cell exhaustion, occurs during chronic infections caused by a variety of pathogens, from persistent viruses to parasites. Unlike the memory cells that typically form after successful pathogen clearance following an acute infection, exhausted T cells secrete lower levels of effector cytokines, proliferate less in response to cognate antigen, and upregulate cell surface inhibitory molecules such as PD-1 and LAG-3.
View Article and Find Full Text PDFJ Gerontol A Biol Sci Med Sci
October 2017
Death from chronic lung disease is increasing and chronic obstructive pulmonary disease has become the third leading cause of death in the United States in the past decade. Both chronic and acute lung diseases disproportionately affect elderly individuals, making it likely that these diseases will become more frequent and severe as the worldwide population ages. Chronic lung diseases are associated with substantial morbidity, frequently resulting in exercise limiting dyspnea, immobilization, and isolation.
View Article and Find Full Text PDFJ Gerontol A Biol Sci Med Sci
September 2017
As with many other tissues and organs, the immune system is also affected by age. Immunosenescence is characterized by a decreased ability of immune cells to mount a productive response upon exposure to new antigens. Several studies have reported that members of families with exceptional longevity show improved immune function, which might contribute to the increased life- and health-span observed in those families.
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