Biomedical subjects

Jonathan Kipnis

Publications and source records attributed to Jonathan Kipnis.

At least 19 recordsLinked to original sources

PubMed2026

Priming of CD8+ T cells by peripheral dendritic cells exacerbates tau-mediated neurodegeneration.

Alzheimer's disease and primary tauopathies are marked by changes in adaptive immunity, with increased brain CD8+ T cells correlating with tau pathology severity. However, how peripheral T cells get primed to enter the brain and contribute to tau-mediated neurodegeneration remains unclear. In different disease conditions, conventional type 1 dendritic cells (cDC1s) cross-present antigens to prime CD8+ T cells into effector cells. We show that tauopathy mice lacking cDC1s or antigen cross-presentation are protected from neurodegeneration, with reduced brain CD8+ T cell infiltration and glial activation. The remaining CD8+ T cells exhibit limited clonal expansion, consistent with impaired priming. We further demonstrate that brain-derived antigens are presented in secondary lymphoid tissues, suggesting a site of T cell activation. Together, these findings establish cDC1-dependent peripheral priming as a key driver of CD8+ T cell accumulation in the brain and tau-mediated neurodegeneration.

Journal Article↗

PubMed2026

Brain perivascular macrophages regulate endothelial cell function via a cMAF-dependent transcriptional program in mouse and human.

Brain perivascular macrophages maintain brain physiology, yet their transcriptional regulators and functions in health and disease remain unclear. Using single-cell multi-omics and functional experiments, we identify cellular musculoaponeurotic fibrosarcoma oncogene (cMAF) as a key transcription factor for brain perivascular macrophages, and conditional deletion of cMAF disrupts their phenotype in vivo. Functionally, cMAF drives insulin-like growth factor-1 (IGF1) expression in perivascular macrophages, enabling communication with endothelial cells. Consistently, cMAF deletion in perivascular macrophages causes transcriptional alterations in cerebral arteries, affecting vascular functions. Notably, cMAF emerges as the main transcription factor for human perivascular macrophages, suggesting conservation of this transcriptional module. During Alzheimer's disease (AD), human perivascular macrophages upregulate cMAF and IGF1 to enhance communication with vascular cells, and this response is abrogated in APOE4 carriers. Lastly, we explore an uncharacterized polymorphism in cMAF, providing evidence that the cMAF program is protective against AD. Targeting cMAF in perivascular macrophages may offer new therapeutic strategies for neurodegenerative and cerebrovascular diseases.

APOE4↗

PubMed2006

Neuroprotection induced by mucosal tolerance is epitope-dependent: conflicting effects in different strains.

The ability to cope with ongoing neurodegeneration after injury to the central nervous system of mammals differs among strains and depends in part on the animal's ability to manifest a T-cell-mediated protective response. After CNS injury, strain-related differences were observed. Moreover, the post-injury effect of naturally occurring regulatory CD4+CD25+ T cells was found to differ in different strains. In this study, using partially injured optic nerves of Balb/c/OLA and C57BL/6J mice as models, we observed strain-related differences in the T-cell-mediated protection obtained by antigens administered via the nasal route. Active immunization with myelin-related antigens emulsified in complete Freund's adjuvant had a beneficial effect on both strains, whereas mucosal administration of the same antigens was destructive in mice of the Balb/c/OLA strain but protective in C57BL/6J mice.

Administration, Intranasal↗

PubMed2006

Loss of autoimmune T cells correlates with brain diseases: possible implications for schizophrenia?

T-cell-mediated autoimmunity participates in physiological defense, maintenance and repair of the adult brain. However, unless such autoimmune responses to insults are rigorously controlled, they might lead to an autoimmune disease or other immune-related defects, where destructive activity outweighs the beneficial effect. Here, we discuss these apparently contradictory effects of autoimmunity in schizophrenic patients, whose typical immune aberrations have prompted recent speculation about an autoimmune-related etiology. We found that, although schizophrenic patients have active immune systems, they often lack autoimmune clones specifically reactive to a major myelin protein, myelin basic protein (MBP). This, in conjunction with our discovery in rodents that T cells that recognize brain-resident proteins are needed for normal cognitive functioning, led us to propose an immune-based neurodevelopmental hypothesis, in which autoimmune-T-cell deficiency is suggested to cause onset or progression of schizophrenia.

Adolescent↗

PubMed2006

Immune cells contribute to the maintenance of neurogenesis and spatial learning abilities in adulthood.

Neurogenesis is known to take place in the adult brain. This work identifies T lymphocytes and microglia as being important to the maintenance of hippocampal neurogenesis and spatial learning abilities in adulthood. Hippocampal neurogenesis induced by an enriched environment was associated with the recruitment of T cells and the activation of microglia. In immune-deficient mice, hippocampal neurogenesis was markedly impaired and could not be enhanced by environmental enrichment, but was restored and boosted by T cells recognizing a specific CNS antigen. CNS-specific T cells were also found to be required for spatial learning and memory and for the expression of brain-derived neurotrophic factor in the dentate gyrus, implying that a common immune-associated mechanism underlies different aspects of hippocampal plasticity and cell renewal in the adult brain.

Animals↗

PubMed2006

Maladaptation to mental stress mitigated by the adaptive immune system via depletion of naturally occurring regulatory CD4+CD25+ cells.

Peripheral cellular immunity was recently shown to play a critical role in brain plasticity and performance. The antigenic specificity of the participating T cells, however, was not investigated, and nor was their relevance to psychological stress. Here we show, using a mouse model, that adaptive immunity mitigates maladaptation to the acute psychological stress known to trigger abnormal behaviors reminiscent of human post-traumatic stress disorder. Assessment of behavioral adaptation (measured by the acoustic startle response and avoidance behavior) in mice after their exposure to predator odor revealed that maladaptation was several times more prevalent in T cell-deficient mice than in their wild-type counterparts. A single population of T cells reactive to central nervous system (CNS)-associated self-protein was sufficient to endow immune-deficient mice with the ability to withstand the psychological stress. Naturally occurring CD4+CD25+ regulatory T cells were found to suppress this endogenous anti-stress attribute. These findings suggest that T cells specific to abundantly expressed CNS antigens are responsible for brain tissue homeostasis and help the individual to cope with stressful life episodes. They might also point the way to development of immune-based therapies for mental disorders, based either on up-regulation of T cells that partially cross-react with self-antigens or on weakening of the activity of regulatory T cells.

Adaptation, Physiological↗

PubMed2005

Protective autoimmunity and neuroprotection in inflammatory and noninflammatory neurodegenerative diseases.

Autoimmune diseases are traditionally viewed as an outcome of a malfunctioning of the immune system, in which an individual's immune system reacts against the body's own proteins. In multiple sclerosis (MS), a disease of the white matter of the central nervous system (CNS), the attack is directed against myelin proteins. In this article we summarize a paradigm shift proposed by us in the perception of autoimmune disease. Observations by our group indicating that an autoimmune response is the body's mechanism for coping with CNS damage led us to suggest that all individuals are apparently endowed with a purposeful autoimmune response to CNS injuries, but have only limited inherent ability to control this response so that its effect will be beneficial. In animals susceptible to autoimmune diseases, the same autoimmune T cells are responsible both for neuroprotection and for disease development; the timing and strength of their activity will determine which of these effects is expressed. Individuals with non-inflammatory neurodegenerative diseases need a heightened autoimmunity. We discovered that autoimmunity could be boosted without risk of disease induction, even in susceptible strains, by the use of Copolymer-1 (Copaxone(R)), a weak agonist of a wide range of self-reactive T cells. Here we summarize the basic findings that led us to formulate the concept of protective autoimmunity, the mechanisms underlying its constitutive presence and its on/off regulation, and its therapeutic implications. We also offer an explanation for the commonly observed presence of cells and antibodies directed against self-components in healthy individuals.

Animals↗

PubMed2005

Therapeutic T cell-based vaccination for neurodegenerative disorders: the role of CD4+CD25+ regulatory T cells.

A well-controlled local immune response is needed for recovery from CNS injury, and autoimmune T cells play a key role in mediating this response. Autoimmunity, at least in the context of the CNS, is the body's fighting force against self-derived destructive compounds, and "tolerance to self" (traditionally though mistakenly equated with nonresponsiveness) should be viewed as the ability to tolerate autoimmune responses without developing an autoimmune disease. This physiological repair mechanism is controlled by naturally occurring CD4(+)CD25(+) regulatory T cells (Treg cells), with an on/off switch regulated by brain-derived compounds. We suggest that ongoing neurodegeneration after acute injuries results from insufficiency of the endogenous fighting force, and chronic neurodegenerative diseases reflect age-related deterioration of the body's two principal regulators: the central nervous system (CNS) and the immune system. If so, then the restoration or boosting of immune function might bridge the gap between such manifestations of CNS-related risk factors and the defensive capacity of the immune system. Boosting of peripheral immunity by the use of weak agonists of CNS self-antigens, might offer a promising potential therapy for different neurodegenerative conditions. This could be accomplished either by vaccination with a universal weak T cell-reactive antigen or with altered peptide ligands of self-antigens, or by weakening the suppressive effect of autoimmunity (e.g., by eliminating Treg cells). T cells that home to the damaged CNS might then help restore local homeostasis by controlling the local microglial response. Because neurodegenerative diseases possess common features (deriving from the local chaos), the same vaccine might protect against several different disorders associated with impaired motor, sensory, cognitive, or mental functions of the brain.

Animals↗

PubMed2005

Controlled autoimmunity in CNS maintenance and repair: naturally occurring CD4+CD25+ regulatory T-Cells at the crossroads of health and disease.

T-cells directed to self-antigens ("autoimmune" T-cells) have traditionally been perceived as tending to attack the body's own tissues, and likely to exert their destructive effects unless they undergo deletion in the thymus during ontogeny. Naturally occurring CD4+CD25+ regulatory T-cells were viewed as thymus-derived cells that constitutively suppress any autoimmune T-cells that escaped thymic deletion. Studies in recent years suggest, however, that some autoimmune T-cells are necessary, at least in the central nervous system for neural maintenance and repair, possibly in part by rendering the resident microglia capable of fighting off adverse conditions, as well as for neural maintenance and repair. In line with this notion, the regulatory T-cells are thought to allow autoimmunity to exist in healthy individuals without causing an autoimmune disease. This proposed immune scenario and its implications for therapy are discussed.

Animals↗

PubMed2004

Dual effect of CD4+CD25+ regulatory T cells in neurodegeneration: a dialogue with microglia.

Autoimmune CD4(+) T cells can mediate the ability to withstand neurodegenerative conditions. Here we show that the ability to spontaneously manifest a T cell-dependent protective response is restricted by naturally occurring CD4(+)CD25(+) regulatory T cells (Treg); depletion of Treg was beneficial in two mouse strains (C57BL/6J and BALB/c/OLA) differing in their spontaneous T cell-dependent ability to withstand the consequences of optic nerve injury. Passive transfer of exogenous Treg was destructive in BALB/c/OLA mice (which can spontaneously manifest a T cell-dependent protective anti-self response to injury) but beneficial in C57BL/6J mice (which have only limited ability to manifest such a response). This dichotomy was resolved by the finding that, in severe combined immunodeficient mice, a beneficial effect is obtained by passive transfer of either Treg-free CD4(+) T cells (Teff) or Treg alone, indicating that neuroprotection can be achieved by either Treg or Teff in the absence of the other. We attribute these disparate effects of Treg to their differential interaction (in part via IL-10 and transforming growth factor beta) with local innate immune cells (microglia) in the presence and in the absence of effector T cells. Activation of microglia by pro- and antiinflammatory cytokines in suitably controlled amounts might trigger different signal transduction pathways, each of which induces a neuroprotective microglial phenotype. These results suggest that, under neurodegenerative conditions, the effects of Treg, and possibly also of other regulatory T cells, might not be uniform, and that their expression in different individuals might be genetically determined. Therefore, therapeutic intervention based on induction of regulatory T cells might have limitations.

Animals↗

PubMed2004

Dopamine, through the extracellular signal-regulated kinase pathway, downregulates CD4+CD25+ regulatory T-cell activity: implications for neurodegeneration.

Fighting off neuronal degeneration requires a well controlled T-cell response against self-antigens residing in sites of the CNS damage. The ability to evoke this response is normally suppressed by naturally occurring CD4+CD25+ regulatory T-cells (Treg). No physiological compound that controls Treg activity has yet been identified. Here, we show that dopamine, acting via type 1 dopamine receptors (found here to be preferentially expressed by Treg), reduces the suppressive activity and the adhesive and migratory abilities of Treg. Treg activity was correlated with activation of the ERK1/2 (extracellular signal-regulated kinase 1/2) signaling pathway. Systemic injection of dopamine or an agonist of its type 1 receptors significantly enhanced, via a T-cell-dependent mechanism, protection against neuronal death after CNS mechanical and biochemical injury. These findings shed light on the physiological mechanisms controlling Treg and might open the way to novel therapeutic strategies for downregulating Treg activity (e.g., in neuronal degeneration) or for strengthening it (in autoimmune diseases).

Animals↗

PubMed2004

T cell deficiency leads to cognitive dysfunction: implications for therapeutic vaccination for schizophrenia and other psychiatric conditions.

The effects of the adaptive immune system on the cognitive performance and abnormal behaviors seen in mental disorders such as schizophrenia have never been documented. Here, we show that mice deprived of mature T cells manifested cognitive deficits and behavioral abnormalities, which were remediable by T cell restoration. T cell-based vaccination, using glatiramer acetate (copolymer-1, a weak agonist of numerous self-reactive T cells), can overcome the behavioral and cognitive abnormalities that accompany neurotransmitter imbalance induced by (+)dizocilpine maleate (MK-801) or amphetamine. The results, by suggesting that peripheral T cell deficit can lead to cognitive and behavioral impairment, highlight the importance of properly functioning adaptive immunity in the maintenance of mental activity and in coping with conditions leading to cognitive deficits. These findings point to critical factors likely to contribute to age- and AIDS-related dementias and might herald the development of a therapeutic vaccination for fighting off cognitive dysfunction and psychiatric conditions.

Amphetamine↗

PubMed2004

Vaccination with autoantigen protects against aggregated beta-amyloid and glutamate toxicity by controlling microglia: effect of CD4+CD25+ T cells.

Neurodegenerative diseases differ in etiology but are propagated similarly. We show that neuronal loss caused by intraocular injection of aggregated beta-amyloid was significantly greater in immunodeficient mice than in normal mice. The neurodegeneration was attenuated or augmented by elimination or addition, respectively, of naturally occurring CD4(+)CD25(+) regulatory T cells (Treg). Vaccination with retina-derived antigens or with the synthetic copolymer glatiramer acetate (Copolymer-1, Cop-1), but not with beta-amyloid, reduced the ocular neuronal loss. In mouse hippocampal slices, microglia encountering activated T cells overcame the cytotoxicity of aggregated beta-amyloid. These findings support the concept of "protective autoimmunity", show that a given T cell-based vaccination is protective at a particular site irrespective of toxicity type, and suggest that locally activated T cells induce a microglial phenotype that helps neurons withstand the insult. Alzheimer's and other neurodegenerative diseases might be arrested or retarded by vaccination with Cop-1 or related compounds or by treatment with compounds that weaken Treg suppression.

Amyloid beta-Peptides↗

PubMed2004

Early activation of microglia as antigen-presenting cells correlates with T cell-mediated protection and repair of the injured central nervous system.

After an injury to the central nervous system (CNS), activated microglia have been shown to contribute to the ongoing destructive processes leading to secondary neuronal degeneration. They can, however, also express neuroprotective activity. Studies from our laboratory point to the existence of a physiological T cell-mediated neuroprotective mechanism (adaptive immunity) that is amenable to boosting. We postulate that the beneficial or destructive outcome of the local microglial (innate) response is determined by a well-controlled dialog between the innate and the adaptive immune players. Here, we show that spontaneous or exogenously boosted T cell-mediated neuroprotection is correlated with early activation of microglia as antigen-presenting cells. We suggest that such microglial activity, if well controlled, is a crucial step in determining the fate of the neurons in a hostile environment.

Animals↗

PubMed2004

A common vaccine for fighting neurodegenerative disorders: recharging immunity for homeostasis.

Neurodegenerative conditions share common primary risk factors and mediators of disease progression. Because many degenerative disorders are age related, deteriorating immunity in aging patients might impose additional risk. Adaptive (T-cell-mediated) immunity is a defense mechanism that instructs microglia to fight off and clear away self-derived enemies. Such adaptive immunity can be boosted, without risking the development of autoimmune disease, by injecting weak agonists of self-antigens or by weakening the suppressive CD4+CD25+ regulatory T cells. If widely cross-reactive, the agonist might effectively counteract a variety of neurodegenerative disorders. Boosting of relevant T cells by vaccination could thus "recharge" a deteriorating immune system that has to contend with an increasing number of risk factors.

Animals↗

PubMed2004

Low-dose gamma-irradiation promotes survival of injured neurons in the central nervous system via homeostasis-driven proliferation of T cells.

Protective autoimmunity was only recently recognized as a mechanism for attenuating the progression of neurodegeneration. Using a rat model of optic nerve crush or contusive spinal cord injury, and a mouse model of neurodegenerative conditions caused by injection of a toxic dose of intraocular glutamate, we show that a single low dose of whole-body or lymphoid-organ gamma-irradiation significantly improved the spontaneous recovery. Animals with severe immune deficiency or deprived of mature T cells were unable to benefit from this treatment, suggesting that the irradiation-induced neuroprotection is immune mediated. This suggestion received further support from the findings that irradiation was accompanied by an increased incidence of activated T cells in the lymphoid organs and peripheral blood and an increase in mRNA encoding for the pro-inflammatory cytokines interleukin-12 and interferon-gamma, and that after irradiation, passive transfer of a subpopulation of suppressive T cells (naturally occurring regulatory CD4(+)CD25(+) T cells) wiped out the irradiation-induced protection. These results suggest that homeostasis-driven proliferation of T cells, induced by a single low-dose irradiation, leads to boosting of T cell-mediated neuroprotection and can be utilized clinically to fight off neurodegeneration and the threat of other diseases in which defense against toxic self-compounds is needed.

Animals↗

PubMed2003

Beneficial effect of orally administered myelin basic protein in EAE-susceptible Lewis rats in a model of acute CNS degeneration.

Axonal injury in the central nervous system (CNS) results in the degeneration of directly damaged fibers and also in the secondary degeneration of fibers that escaped the primary insult. Studies have shown that a protective T cell-mediated autoimmunity directed against myelin-related self-antigens is a physiological response to CNS insult, spontaneously elicited in strains that are constitutionally resistant to experimental autoimmune encephalomyelitis (EAE) but not in EAE-susceptible strains. The protective response following axonal injury can be induced in susceptible rats and boosted in resistant rats by passive or active immunization with myelin-related antigens. Here we show that oral administration of low-dose myelin basic protein (MBP) over a 5-day period is beneficial for post-traumatic survival of neurons in Lewis (EAE-susceptible) rats. Protection was accompanied by increased expression of the costimulatory molecule B7.2 in the traumatized nerves, similar to that seen after passive transfer of MBP-specific T cells. These results support the contention that properly controlled autoimmunity is the body's defense mechanism against non-infective insults. Oral immunization with MBP can be viewed as a way to control the autoimmunity capable of fighting off the consequences of CNS injury in EAE-susceptible strains.

Administration, Oral↗

PubMed2003

Autoimmunity as a special case of immunity: removing threats from within.

The function of the adaptive immune response against exogenous (non-self) agents is to help the innate arm of the immune system (represented by phagocytic cells) to fight and eliminate these agents. We suggest that the body also protects itself against potentially harmful self components using mechanisms similar to those used for fighting and eliminating non-self agents, and that the protective immune activity against self-components competes with the activity of self-destructive compounds. Tolerance to self is thus not a lack of response to self, but the ability to tolerate an active defense response to self without developing an autoimmune disease.

Autoimmune Diseases↗