scispace - formally typeset
Search or ask a question
Author

Jacob D. Eccles

Bio: Jacob D. Eccles is an academic researcher from University of Virginia. The author has contributed to research in topics: Lymphatic Endothelium & Immunoglobulin E. The author has an hindex of 11, co-authored 13 publications receiving 2623 citations. Previous affiliations of Jacob D. Eccles include Oregon Health & Science University.

Papers
More filters
Journal ArticleDOI
16 Jul 2015-Nature
TL;DR: In searching for T-cell gateways into and out of the meninges, functional lymphatic vessels lining the dural sinuses are discovered, which may call for a reassessment of basic assumptions in neuroimmunology and sheds new light on the aetiology of neuroinflammatory and neurodegenerative diseases associated with immune system dysfunction.
Abstract: One of the characteristics of the central nervous system is the lack of a classical lymphatic drainage system. Although it is now accepted that the central nervous system undergoes constant immune surveillance that takes place within the meningeal compartment, the mechanisms governing the entrance and exit of immune cells from the central nervous system remain poorly understood. In searching for T-cell gateways into and out of the meninges, we discovered functional lymphatic vessels lining the dural sinuses. These structures express all of the molecular hallmarks of lymphatic endothelial cells, are able to carry both fluid and immune cells from the cerebrospinal fluid, and are connected to the deep cervical lymph nodes. The unique location of these vessels may have impeded their discovery to date, thereby contributing to the long-held concept of the absence of lymphatic vasculature in the central nervous system. The discovery of the central nervous system lymphatic system may call for a reassessment of basic assumptions in neuroimmunology and sheds new light on the aetiology of neuroinflammatory and neurodegenerative diseases associated with immune system dysfunction.

2,897 citations

Journal ArticleDOI
TL;DR: The contribution of S1R to the restraint of the inflammatory response is revealed and this work identifies sigma-1 receptor (S1R) as an essential inhibitor of cytokine production in a preclinical model of septic shock.
Abstract: Sepsis is an often deadly complication of infection in which systemic inflammation damages the vasculature, leading to tissue hypoperfusion and multiple organ failure. Currently, the standard of care for sepsis is predominantly supportive, with few therapeutic options available. Because of increased sepsis incidence worldwide, there is an urgent need for discovery of novel therapeutic targets and development of new treatments. The recently discovered function of the endoplasmic reticulum (ER) in regulation of inflammation offers a potential avenue for sepsis control. Here, we identify the ER-resident protein sigma-1 receptor (S1R) as an essential inhibitor of cytokine production in a preclinical model of septic shock. Mice lacking S1R succumb quickly to hypercytokinemia induced by a sublethal challenge in two models of acute inflammation. Mechanistically, we find that S1R restricts the endonuclease activity of the ER stress sensor IRE1 and cytokine expression but does not inhibit the classical inflammatory signaling pathways. These findings could have substantial clinical implications, as we further find that fluvoxamine, an antidepressant therapeutic with high affinity for S1R, protects mice from lethal septic shock and dampens the inflammatory response in human blood leukocytes. Our data reveal the contribution of S1R to the restraint of the inflammatory response and place S1R as a possible therapeutic target to treat bacterial-derived inflammatory pathology.

189 citations

Journal ArticleDOI
TL;DR: Lymphatic endothelial cells (LECs) serve as an antigen reservoir for CD4 T-cell tolerance, and MHC-II molecules on LECs are used to induce CD8 T- cell tolerance via LAG-3.
Abstract: Lymphatic endothelial cells (LECs) directly express peripheral tissue antigens and induce CD8 T-cell deletional tolerance. LECs express MHC-II molecules, suggesting they might also tolerize CD4 T c ...

115 citations

Journal ArticleDOI
TL;DR: The lower airways of children with severe asthma display a dominant TH1 signature and atypical cytokine profiles that link to allergic status and deviate from established paradigms and warrant further assessment of the pathogenicity of TH1 cells in patients withsevere asthma.
Abstract: Background The pathogenesis of severe asthma in childhood remains poorly understood. Objective We sought to construct the immunologic landscape in the airways of children with severe asthma. Methods Comprehensive analysis of multiple cell types and mediators was performed by using flow cytometry and a multiplex assay with bronchoalveolar lavage (BAL) specimens (n = 68) from 52 highly characterized allergic and nonallergic children (0.5-17 years) with severe treatment-refractory asthma. Multiple relationships were tested by using linear mixed-effects modeling. Results Memory CCR5 + T H 1 cells were enriched in BAL fluid versus blood, and pathogenic respiratory viruses and bacteria were readily detected. IFN-γ + IL-17 + and IFN-γ − IL-17 + subsets constituted secondary T H types, and BAL fluid CD8 + T cells were almost exclusively IFN-γ + . The T H 17-associated mediators IL-23 and macrophage inflammatory protein 3α/CCL20 were highly expressed. Despite low T H 2 numbers, T H 2 cytokines were detected, and T H 2 skewing correlated with total IgE levels. Type 2 innate lymphoid cells and basophils were scarce in BAL fluid. Levels of IL-5, IL-33, and IL-28A/IFN-λ2 were increased in multisensitized children and correlated with IgE levels to dust mite, ryegrass, and fungi but not cat, ragweed, or food sources. Additionally, levels of IL-5, but no other cytokine, increased with age and correlated with eosinophil numbers in BAL fluid and blood. Both plasmacytoid and IgE + FceRI + myeloid dendritic cells were present in BAL fluid. Conclusions The lower airways of children with severe asthma display a dominant T H 1 signature and atypical cytokine profiles that link to allergic status. Our findings deviate from established paradigms and warrant further assessment of the pathogenicity of T H 1 cells in patients with severe asthma.

88 citations

Journal ArticleDOI
TL;DR: The ability of lymphatic endothelial cells to alter immune responses under steady-state or inflammatory conditions is explored, and the therapeutic potential of bypassing lymphatichelial cell-induced tolerance to enhance cancer immunotherapy is discussed.
Abstract: Lymphatic endothelial cells are most often thought of as structural cells that form the lymphatic vasculature, which transports fluid out of peripheral tissues and transports antigens and antigen presenting cells to lymph nodes. Recently, it has been shown that lymphatic endothelial cells also dynamically respond to and influence the immune response in several ways. Here, we describe how lymphatic endothelial cells induce peripheral T-cell tolerance and how this relates to tolerance induced by other types of antigen presenting cells. Furthermore, the ability of lymphatic endothelial cells to alter immune responses under steady-state or inflammatory conditions is explored, and the therapeutic potential of bypassing lymphatic endothelial cell-induced tolerance to enhance cancer immunotherapy is discussed.

40 citations


Cited by
More filters
Journal ArticleDOI
TL;DR: Current understanding of the mechanisms by which the innate and adaptive immune systems interact with neurotransmitters and neurocircuits to influence the risk for depression are detailed.
Abstract: Crosstalk between inflammatory pathways and neurocircuits in the brain can lead to behavioural responses, such as avoidance and alarm, that are likely to have provided early humans with an evolutionary advantage in their interactions with pathogens and predators. However, in modern times, such interactions between inflammation and the brain appear to drive the development of depression and may contribute to non-responsiveness to current antidepressant therapies. Recent data have elucidated the mechanisms by which the innate and adaptive immune systems interact with neurotransmitters and neurocircuits to influence the risk for depression. Here, we detail our current understanding of these pathways and discuss the therapeutic potential of targeting the immune system to treat depression.

2,133 citations

Journal ArticleDOI
TL;DR: This Review discusses neuroimaging studies in the living human brain and post-mortem tissue as well as biomarker studies demonstrating BBB breakdown in Alzheimer disease, Parkinson disease, Huntington disease, amyotrophic lateral sclerosis, multiple sclerosis, HIV-1-associated dementia and chronic traumatic encephalopathy.
Abstract: The blood-brain barrier (BBB) is a continuous endothelial membrane within brain microvessels that has sealed cell-to-cell contacts and is sheathed by mural vascular cells and perivascular astrocyte end-feet The BBB protects neurons from factors present in the systemic circulation and maintains the highly regulated CNS internal milieu, which is required for proper synaptic and neuronal functioning BBB disruption allows influx into the brain of neurotoxic blood-derived debris, cells and microbial pathogens and is associated with inflammatory and immune responses, which can initiate multiple pathways of neurodegeneration This Review discusses neuroimaging studies in the living human brain and post-mortem tissue as well as biomarker studies demonstrating BBB breakdown in Alzheimer disease, Parkinson disease, Huntington disease, amyotrophic lateral sclerosis, multiple sclerosis, HIV-1-associated dementia and chronic traumatic encephalopathy The pathogenic mechanisms by which BBB breakdown leads to neuronal injury, synaptic dysfunction, loss of neuronal connectivity and neurodegeneration are described The importance of a healthy BBB for therapeutic drug delivery and the adverse effects of disease-initiated, pathological BBB breakdown in relation to brain delivery of neuropharmaceuticals are briefly discussed Finally, future directions, gaps in the field and opportunities to control the course of neurological diseases by targeting the BBB are presented

1,507 citations

Journal ArticleDOI
TL;DR: The current understanding of multiple sclerosis immunopathology is discussed, long-standing hypotheses regarding the role of the immune system in the disease are evaluated, and key questions that are still unanswered are delineated.
Abstract: Two decades of clinical experience with immunomodulatory treatments for multiple sclerosis point to distinct immunological pathways that drive disease relapses and progression. In light of this, we discuss our current understanding of multiple sclerosis immunopathology, evaluate long-standing hypotheses regarding the role of the immune system in the disease and delineate key questions that are still unanswered. Recent and anticipated advances in the field of immunology, and the increasing recognition of inflammation as an important component of neurodegeneration, are shaping our conceptualization of disease pathophysiology, and we explore the potential implications for improved healthcare provision to patients in the future.

1,482 citations

Journal ArticleDOI
TL;DR: The role of CNS-resident and peripheral immune pathways in microbiota–gut–brain communication during health and neurological disease is discussed.
Abstract: The diverse collection of microorganisms that inhabit the gastrointestinal tract, collectively called the gut microbiota, profoundly influences many aspects of host physiology, including nutrient metabolism, resistance to infection and immune system development. Studies investigating the gut-brain axis demonstrate a critical role for the gut microbiota in orchestrating brain development and behavior, and the immune system is emerging as an important regulator of these interactions. Intestinal microbes modulate the maturation and function of tissue-resident immune cells in the CNS. Microbes also influence the activation of peripheral immune cells, which regulate responses to neuroinflammation, brain injury, autoimmunity and neurogenesis. Accordingly, both the gut microbiota and immune system are implicated in the etiopathogenesis or manifestation of neurodevelopmental, psychiatric and neurodegenerative diseases, such as autism spectrum disorder, depression and Alzheimer's disease. In this review, we discuss the role of CNS-resident and peripheral immune pathways in microbiota-gut-brain communication during health and neurological disease.

1,168 citations

Journal ArticleDOI
TL;DR: The clearance systems of the brain as they relate to proteins implicated in AD pathology are described, with the main focus on Aβ.
Abstract: Accumulation of toxic protein aggregates-amyloid-β (Aβ) plaques and hyperphosphorylated tau tangles-is the pathological hallmark of Alzheimer disease (AD). Aβ accumulation has been hypothesized to result from an imbalance between Aβ production and clearance; indeed, Aβ clearance seems to be impaired in both early and late forms of AD. To develop efficient strategies to slow down or halt AD, it is critical to understand how Aβ is cleared from the brain. Extracellular Aβ deposits can be removed from the brain by various clearance systems, most importantly, transport across the blood-brain barrier. Findings from the past few years suggest that astroglial-mediated interstitial fluid (ISF) bulk flow, known as the glymphatic system, might contribute to a larger portion of extracellular Aβ (eAβ) clearance than previously thought. The meningeal lymphatic vessels, discovered in 2015, might provide another clearance route. Because these clearance systems act together to drive eAβ from the brain, any alteration to their function could contribute to AD. An understanding of Aβ clearance might provide strategies to reduce excess Aβ deposits and delay, or even prevent, disease onset. In this Review, we describe the clearance systems of the brain as they relate to proteins implicated in AD pathology, with the main focus on Aβ.

1,047 citations