May 6-13, 2017
Coordinator: Michal Schwartz
Weizmann Institute of Science, Rehovot, Israel
Saul Villeda, University of California, San Francisco, USA
Javier Francisco Quintana, Harvard University, Cambridge, USA
Alexander Flügel, University of Göttingen, Germany
Sandra Amor, VU University Medical Center, Amsterdam The Netherlands
Asya Rolls, Israel Institute of Technology, Haifa, Israel
Marco Bacigaluppi, San Raffaele Scientific Institute, Milan, Italy
The last two decades have seen a revolutionary change in the dogma suggesting that the CNS operates optimally without any assistance from circulating immune cells. Previously, attempts were made to globally mitigate any immune activity in the brain, assuming such activity was a sign of ongoing pathology. We now know that a continuous dialogue occurs between the brain and the circulation, and that soluble and cellular components derived from the circulation support brain plasticity. The implications of these finding for brain aging and neurodegenerative diseases are becoming critical issues in finding cures for these conditions. Moreover, the mechanisms whereby the brain controls the activity of the immune system is an additional mystery in this bi-directional relationship. The Advanced Course will feature contributions by scientists who have made fundamental contributions to understanding this evolving new field.
How does the immune system shape the brain?
The resident microglia and infiltrating monocyte-derived macrophages, non-redundant players in CNS pathology
The non-permissive and permissive barriers between the brain and the circulation
Breaking immune tolerance for fighting brain aging and neurodegenerative diseases
Regulation of immunity by the brain- information transfer from the brain to the immune system
Pathways from the brain to the immune system: sympathetic and parasympathetic stimulation
Use of optogenetic and pharmacogenetic tools in neuroimmunology
Common knowledge and extensive scientific evidence suggest that the brain affects the immune system. This relationship is manifested by responses such as increased disease prevalence following stress or cure following treatment with a placebo pill. Although we have reached significant comprehension of the effects of stress on immunity, we are limited in our understanding of the specific neuronal networks regulating the immune system and the modes through which this activity is transmitted to the immune system. Focus of discussion will be on what kind of information can the brain provide to the immune system, what are the potential pathways that mediate these effects and how we can use newly emerging tools such as optogenetics and DREADD to decipher brain-immune communication.
Aging, rejuvenation, and neuroinflammation: implications for cognitive function
Reversing brain aging by manipulating the blood composition.
Anti-aging factors in young blood, and pro-aging factors in old blood.
Functional changes in synaptic plasticity, and regenerative potential of the aged brain, mechanisms of microglial aging; assessing the crosstalk between these pro-aging processes.
Interventions with significant promise in reversing age-related neuronal, neural stem cell, and microglia alterations.
Aging is the most dominant risk factor for dementia-related neurodegenerative diseases, such as Alzheimer’s disease. Considering the rate at which the human population is aging, it is imperative to develop means to maintain functional integrity in the elderly, and consequently counteract vulnerability to neurodegenerative disease. Until recently, age-related functional decline was considered an inevitable aspect of human life; recent investigations into the cellular and systemic drivers of brain aging, however, strongly suggest otherwise. Brain aging is, in fact, a mutable process. We, and others, have shown that systemic manipulations such as heterochronic parabiosis (in which the circulatory system of a young and old animal are joined) can partially reverse age-related impairments in regenerative capacity and cognitive function in the aged brain. Interestingly, heterochronic parabiosis studies have revealed an age-dependent bi-directionality in the influence of the systemic environment indicating anti-aging factors in young blood elicit rejuvenation while pro-aging factors in old blood drive aging. It has been proposed that mitigating the effect of pro-aging factors may also provide an effective approach to rejuvenate aging phenotypes. Interestingly, a growing body of evidence has now identified immune molecules – including TGFb, CCL11, and major histocompatibility complex class 1 (MHC I) molecules – as pro-aging factors driving age-related changes in synaptic plasticity, regeneration, and inflammatory processes in the aged brain. These lectures will synthesize the mechanisms that drive brain aging and critically evaluate the potential for rejuvenation and will overview functional changes in synaptic plasticity and regenerative potential of the aged brain, followed by mechanisms of microglia aging, assessing the crosstalk between these pro-aging processes. Focus will also be placed on interventions showing significant promise in reversing age-related neuronal, neural stem cell, and microglia alterations. Finally, the future of the field will be critically analyzed, looking ahead towards novel therapeutics for brain aging.
Pathology of multiple sclerosis, animal models
Models of neuroimmune diseases
In vitro human microglia.
Animal Models. Animal models of human diseases represent useful and sometimes powerful tools to investigate the dynamics of a given pathology and to dissect its underlying mechanisms. Experimental Autoimmune Encephalomyelitis (EAE), most commonly induced in rodents, results in an inflammatory central nervous system (CNS) disease that recapitulates several important aspects of multiple sclerosis (MS). Acute and relapsing–remitting forms of EAE that are T-cell dependent are aptly suited to model relapsing remitting phases of MS. However, other EAE models, especially the secondary progressive EAE stage in Biozzi ABH mice is T cell independent, thus better representing the secondary progressive phase of MS, which is refractory to many immune therapies. Since there is no universally accepted view of the aetiology of MS several models of MS namely cuprizone and EAE are thus widely-used to understand pathological processes occurring during disease onset and progression in multiple sclerosis. During this session discussion will focus on the various animal models used to understand the pathological processes and to develop therapies for MS. Since the current therapies for MS reduce the frequency of relapses by modulating adaptive immune responses but fail to limit the irreversible neurodegeneration driving progressive disability, part of the session will be dedicated to models that better represent processes contributing to neurodegeneration.
Pathology of Multiple Sclerosis. Multiple sclerosis (MS) has been classically considered a typical inflammatory white matter disease, although recent histopathology and imaging studies have convincingly shown that cortical and subcortical gray matter damage play an important role contributing to the neurodegeneration and cognitive changes in MS and especially to disease progression. Infiltrated macrophages and resident microglia are considered to be the primary effector cells in MS and disease-related animal models. Similar to macrophages, microglia adopt diverse activation states and contribute to repair as well as tissue damage in MS. In this session, the differential activation states of microglia during lesion development and regression in MS will be analyzed and the possible triggers of microglia activation in MS will be discussed. One such trigger is alpha B-crystallin (HSPB5) an endogenous agonist for Toll-like receptor 2 (TLR2) in CD14+ cells. Following systemic administration, HSPB5 acts as a potent inhibitor of neuroinflammation in animal models, and reduces lesion development in MS patients. The potential triggers of HSPB5 its role in the pathogenesis of MS will also be discussed.
Regulatory mechanisms controlling CNS inflammation (adaptive and innate immunity, Tregs, cytokines)
Adaptive and Innate Immunopathology in Multiple Sclerosis.
Potential therapeutic interventions.
Effector T cells are considered important mediators of disease pathogenesis in multiple sclerosis and other inflammatory diseases. In addition, local innate inflammation at the target site also plays a central role in disease pathogenesis. For example, the chronic activation of astrocytes, microglia and peripheral monocytes recruited to the central nervous system promotes neurodegeneration and disease progression in multiple sclerosis and other neurologic diseases. The potential pathogenic activities of the adaptive and the innate immune response is limited by specific regulatory mechanisms involving specialized cell populations. In this session we will discuss the molecular events that control the development of pathogenic immune responses and their regulation in the context of multiple sclerosis.
T cells autoimmunity in the CNS.
Multiple sclerosis (MS) is caused by autoaggressive T cells, a type of immune cell, falsely reacting against the tissue of the central nervous system (CNS). The disease is initiated when the pathogenic T cells invade the CNS, recognize their cognate antigens there, and then initiate a disease-inducing inflammatory response. This scenario emerged from studies in experimental autoimmune encephalomyelitis (EAE) an animal model of MS. It should be noted that the autoimmune attack on CNS tissue is not a trivial undertaking. Healthy CNS tissue is virtually devoid of immune cells and is shielded from the periphery by the blood–brain barrier (BBB) which prevents uncontrolled access of cells and molecules. Added to this, healthy nervous tissue only has a sparse expression of immune factors necessary to attract immune cells and of the MHC molecules required to present autoantigens to them. Recent EAE studies furthermore revealed that the pathogenic effector T cells have to undertake a long and winding journey before they reach their target organ, the CNS, and can execute their effector functions there. We here give an overview of the nature of pathogenic T cells and their migration behavior and functionality in vivo. In addition we outline the therapeutic strategies currently available to interfere with the pathogenic potential of autoreactive effector T cells.
Neural Stem Cells and Neuroinflammation