Protective autoimmunity
Encyclopedia
Protective autoimmunity is a condition in which cells of the adaptive immune system
contribute to maintenance of the functional integrity of a tissue, or facilitate its repair following an insult. The term ‘protective autoimmunity’ was coined by Prof. Michal Schwartz of the Weizmann Institute of Science
(Israel), whose pioneering studies were the first to demonstrate that autoimmune T lymphocytes can have a beneficial role in repair, following an injury to the central nervous system (CNS). Most of the studies on the phenomenon of protective autoimmunity were conducted in experimental settings of various CNS pathologies and thus reside within the scientific discipline of neuroimmunology
.
s), which can respond to specific antigen
s and subsequently acquire an immunological memory. The activity of adaptive immunity is critically important for host defense against pathogens. Cells of the adaptive immunity that respond to self-antigens are termed ‘autoimmune cells’. Autoimmunity
, the activity of autoimmune cells, is generally considered in the context of an autoimmune disease
—a pathological condition induced by an overwhelming activity of autoimmune cells. One of the hallmarks of immunity is the ability to transfer a substantial amount of lymphocytes or antibodies from one animal to another in a way that results in immunity to a certain pathogen (adaptive transfer). Similarly, autoimmune diseases can be induced experimentally by the adaptive transfer of autoimmune cells or antibodies from an animal that suffers from an autoimmune disease into a healthy animal. In a seminal study of 1999, Schwartz and colleagues demonstrated that the same autoimmune T cells that can cause an experimental autoimmune encephalomyelitis
(EAE, a common model for multiple sclerosis) can also be harnessed to protect injured CNS tissue from secondary degeneration following a traumatic insult. The experiment showed that after a partial crush injury of the optic nerve
, rats injected with activated T cells which are specific for myelin basic protein
(MBP, a common protein in the CNS) retained 3-fold more retinal ganglion cells with functionally intact axons than did rats injected with activated T cells specific for other (control) antigens. These findings indicated that at least under certain circumstances, autoimmune activity could exert a beneficial effect by protecting injured neurons from the spread of damage. Additional work by the Schwartz group has shown that protective autoimmunity is a naturally occurring physiological phenomenon that takes place spontaneously following a CNS injury. Mutant mice which lack T cells (such as SCID
and nude), and mice that lack T cells that can recognize CNS antigens, exhibit reduced levels of neuronal survival following CNS injury relative to normal (wild type) mice. On the other hand, mice that were genetically engineered so that most of their T cells will recognize a CNS antigen—such as transgenic mice overexpressing a T cell receptor (TcR) for MBP—exhibit elevated rates of neuronal survival after CNS injury. Experiments conducted in animal models of spinal cord injury
, brain injury, glaucoma
, stroke
, motor neuron degeneration, Parkinson’s and Alzheimer's disease have demonstrated the relevance of immune cells and in particular T cells that recognize CNS antigens in promoting neuronal survival and functional recovery from acute and chronic neurodegenerative conditions. T cells that recognize CNS antigens have also been shown to be important for maintaining the functional integrity of the adult CNS under normal non-pathological conditions. Immune deficient mice and mice which lack T cells that recognize brain antigens exhibit impairments in spatial learning and memory, and have reduced levels of cell renewal in the hippocampus
and sub-ventricular zone (the brain structures where neurogenesis
takes place in the adult brain).
cells, a population of CNS-resident immune cells, which can act as phagocytes, and antigen-presenting cell
s. CD4+ T helper cell
s that were specifically activated by antigens associated with the lesion, arrive at the site of injury and locally interact with microglia and other blood-derived antigen presenting cells (e.g. dendritic cell
s). Local properties of antigen presenting cells (i.e. the levels of MHC-II-self antigen complexes and the type of co-stimulatory molecules) dictate the profile of the subsequent T cell response. The interaction between the T cells and the microglia/dendritic cells results in the production of a set of inflammatory cytokine
s (such as interferon gamma) and chemokines (chemoatractant proteins) that, in turn, orchestrate the ensuing repair process in which many cell types participate. Microglia and myeloid cells recruited from the circulating blood restrict the spread of damage by buffering excessive levels of toxic self-compounds (such as the neurotransmitter glutamate
), and by producing growth factors (such as insulin-like growth factor-1) that prevent neuronal death and induce axonal re-growth. In addition, the chemokines produced at the site of injury attract endogenous stem or progenitor cells
that can further contribute to repair by providing a source for new neurons and glial cells, and by restricting the local immune response.
The mechanism by which protective autoimmunity maintains the brain’s functional integrity under non-injurious conditions is still not known. One model suggests that CNS-specific autoimmune T cells which constantly circulate through the cerebrospinal fluid
(CSF) interact with perivascular dendritic cells that reside at the choroid plexus
and meninges. Cytokines and growth factors secreted into the CSF by the T cells and dendritic cells then diffuse into the neural parenchyma were they locally affect neurons, glial cells and stem cells. This model infers that the level of antigen presentation (i.e. the amount of MHC-II-self antigen complexes) serves as an indicator of the level of immune activity required for maintenance of the uninjured brain.
s’ (previously known as ‘suppressor T cells’), which restrict autoimmune activity. Experiments in animal models of CNS injury have shown that depletion of regulatory T cells allows an enhanced neuroprotective autoimmune response to take place after the insult. Importantly, however, such an experimental manipulation can at the same time increase the susceptibility to development of an autoimmune disease. Under certain conditions, an initially protective autoimmune response can reach a tipping point, after which it will have a detrimental effect on the tissue, and might even develop into an autoimmune disease. Both genetic and environmental factors (such as infection) can underlie such a transition from a neuroprotective autoimmune response into an overwhelming and detrimental autoimmune disease.
Other cell types, such as B cells and even neural progenitor cells, can promote regulation of immune response in the CNS. Stem and progenitor cells are usually regarded with respect to their potential to serve as a source for newly differentiated cells, but recently stem and progenitor cells have also been acknowledged for their ability to modulate immune activity. Experiments have shown that injection of neural progenitor cells into the brain’s ventricles can modulate an immune response taking place at multiple inflammatory foci in a mouse model of multiple sclerosis, or at a single site at the injured spinal cord.
Several approaches have been used experimentally in order to harness naturally occurring immune cell activity in CNS pathologies. Here are key examples:
1. Therapeutic vaccination
: This approach utilizes a common immunological manipulation. Inoculation of an antigen that is associated with the pathology, in this case the site of injury, evokes the activation and proliferation of lymphocytes which can specifically respond to the antigen used. For therapeutic purposes, vaccination with an antigen associated with the site of injury (for example peptides derived from myelin proteins) is problematic, because it carries the risk of inducing, in individuals susceptible to autoimmune diseases, an overwhelming inflammatory response that is detrimental for recovery. To circumvent this problem researchers have been using lower affinity agonists (termed ‘altered peptide ligands’) which induce a weaker immune response. Experiments in animal models of spinal cord injury revealed that the use of such altered peptide ligands is effective in promoting functional recovery without the risk of inducing a deleterious autoimmune response.
2. Alteration of regulatory T cell activity: Suppressing regulatory T cell activity following injury can allow a more robust autoimmune response to take place. For therapeutic purpose, the mere removal of regulatory T cells is, again, highly problematic because it increases the risk of inducing autoimmune diseases. Overcoming this limitation is possible using agents that transiently suppress regulatory T cell activity. Such an agent has been used successfully in an animal model of ischemic stroke, where treated animals exhibited improved neurological recovery relative to non-treated animals.
Adaptive immune system
The adaptive immune system is composed of highly specialized, systemic cells and processes that eliminate or prevent pathogenic growth. Thought to have arisen in the first jawed vertebrates, the adaptive or "specific" immune system is activated by the “non-specific” and evolutionarily older innate...
contribute to maintenance of the functional integrity of a tissue, or facilitate its repair following an insult. The term ‘protective autoimmunity’ was coined by Prof. Michal Schwartz of the Weizmann Institute of Science
Weizmann Institute of Science
The Weizmann Institute of Science , known as Machon Weizmann, is a university and research institute in Rehovot, Israel. It differs from other Israeli universities in that it offers only graduate and post-graduate studies in the sciences....
(Israel), whose pioneering studies were the first to demonstrate that autoimmune T lymphocytes can have a beneficial role in repair, following an injury to the central nervous system (CNS). Most of the studies on the phenomenon of protective autoimmunity were conducted in experimental settings of various CNS pathologies and thus reside within the scientific discipline of neuroimmunology
Neuroimmunology
Neuroimmunology is a field combining neuroscience, the study of the nervous system, and immunology, the study of the immune system. Neuroimmunologists seek to better understand the interactions of these two complex systems during development, homeostasis, and response to injuries...
.
Background
The adaptive immune system primarily consists of T and B cells (lymphocyteLymphocyte
A lymphocyte is a type of white blood cell in the vertebrate immune system.Under the microscope, lymphocytes can be divided into large lymphocytes and small lymphocytes. Large granular lymphocytes include natural killer cells...
s), which can respond to specific antigen
Antigen
An antigen is a foreign molecule that, when introduced into the body, triggers the production of an antibody by the immune system. The immune system will then kill or neutralize the antigen that is recognized as a foreign and potentially harmful invader. These invaders can be molecules such as...
s and subsequently acquire an immunological memory. The activity of adaptive immunity is critically important for host defense against pathogens. Cells of the adaptive immunity that respond to self-antigens are termed ‘autoimmune cells’. Autoimmunity
Autoimmunity
Autoimmunity is the failure of an organism to recognize its own constituent parts as self, which allows an immune response against its own cells and tissues. Any disease that results from such an aberrant immune response is termed an autoimmune disease...
, the activity of autoimmune cells, is generally considered in the context of an autoimmune disease
Autoimmune disease
Autoimmune diseases arise from an overactive immune response of the body against substances and tissues normally present in the body. In other words, the body actually attacks its own cells. The immune system mistakes some part of the body as a pathogen and attacks it. This may be restricted to...
—a pathological condition induced by an overwhelming activity of autoimmune cells. One of the hallmarks of immunity is the ability to transfer a substantial amount of lymphocytes or antibodies from one animal to another in a way that results in immunity to a certain pathogen (adaptive transfer). Similarly, autoimmune diseases can be induced experimentally by the adaptive transfer of autoimmune cells or antibodies from an animal that suffers from an autoimmune disease into a healthy animal. In a seminal study of 1999, Schwartz and colleagues demonstrated that the same autoimmune T cells that can cause an experimental autoimmune encephalomyelitis
Experimental autoimmune encephalomyelitis
Experimental autoimmune encephalomyelitis, sometimes Experimental Allergic Encephalomyelitis is an animal model of brain inflammation. It is an inflammatory demyelinating disease of the central nervous system...
(EAE, a common model for multiple sclerosis) can also be harnessed to protect injured CNS tissue from secondary degeneration following a traumatic insult. The experiment showed that after a partial crush injury of the optic nerve
Optic nerve
The optic nerve, also called cranial nerve 2, transmits visual information from the retina to the brain. Derived from the embryonic retinal ganglion cell, a diverticulum located in the diencephalon, the optic nerve doesn't regenerate after transection.-Anatomy:The optic nerve is the second of...
, rats injected with activated T cells which are specific for myelin basic protein
Myelin basic protein
Myelin basic protein is a protein believed to be important in the process of myelination of nerves in the central nervous system .MBP was initially sequenced in 1971 after isolation from myelin membranes...
(MBP, a common protein in the CNS) retained 3-fold more retinal ganglion cells with functionally intact axons than did rats injected with activated T cells specific for other (control) antigens. These findings indicated that at least under certain circumstances, autoimmune activity could exert a beneficial effect by protecting injured neurons from the spread of damage. Additional work by the Schwartz group has shown that protective autoimmunity is a naturally occurring physiological phenomenon that takes place spontaneously following a CNS injury. Mutant mice which lack T cells (such as SCID
Severe combined immunodeficiency
Severe combined immunodeficiency , is a genetic disorder in which both "arms" of the adaptive immune system are impaired due to a defect in one of several possible genes. SCID is a severe form of heritable immunodeficiency...
and nude), and mice that lack T cells that can recognize CNS antigens, exhibit reduced levels of neuronal survival following CNS injury relative to normal (wild type) mice. On the other hand, mice that were genetically engineered so that most of their T cells will recognize a CNS antigen—such as transgenic mice overexpressing a T cell receptor (TcR) for MBP—exhibit elevated rates of neuronal survival after CNS injury. Experiments conducted in animal models of spinal cord injury
Spinal cord injury
A spinal cord injury refers to any injury to the spinal cord that is caused by trauma instead of disease. Depending on where the spinal cord and nerve roots are damaged, the symptoms can vary widely, from pain to paralysis to incontinence...
, brain injury, glaucoma
Glaucoma
Glaucoma is an eye disorder in which the optic nerve suffers damage, permanently damaging vision in the affected eye and progressing to complete blindness if untreated. It is often, but not always, associated with increased pressure of the fluid in the eye...
, stroke
Stroke
A stroke, previously known medically as a cerebrovascular accident , is the rapidly developing loss of brain function due to disturbance in the blood supply to the brain. This can be due to ischemia caused by blockage , or a hemorrhage...
, motor neuron degeneration, Parkinson’s and Alzheimer's disease have demonstrated the relevance of immune cells and in particular T cells that recognize CNS antigens in promoting neuronal survival and functional recovery from acute and chronic neurodegenerative conditions. T cells that recognize CNS antigens have also been shown to be important for maintaining the functional integrity of the adult CNS under normal non-pathological conditions. Immune deficient mice and mice which lack T cells that recognize brain antigens exhibit impairments in spatial learning and memory, and have reduced levels of cell renewal in the hippocampus
Hippocampus
The hippocampus is a major component of the brains of humans and other vertebrates. It belongs to the limbic system and plays important roles in the consolidation of information from short-term memory to long-term memory and spatial navigation. Humans and other mammals have two hippocampi, one in...
and sub-ventricular zone (the brain structures where neurogenesis
Neurogenesis
Neurogenesis is the process by which neurons are generated from neural stem and progenitor cells. Most active during pre-natal development, neurogenesis is responsible for populating the growing brain with neurons. Recently neurogenesis was shown to continue in several small parts of the brain of...
takes place in the adult brain).
Mechanism of action
An immune response that takes place following CNS injury elicits a cascade of molecular and cellular events that can eventually affect the organism’s functional recovery. Immediately after an injury to the CNS, there is a local innate immune response. This response is mediated primarily by microgliaMicroglia
Microglia are a type of glial cell that are the resident macrophages of the brain and spinal cord, and thus act as the first and main form of active immune defense in the central nervous system . Microglia constitute 20% of the total glial cell population within the brain...
cells, a population of CNS-resident immune cells, which can act as phagocytes, and antigen-presenting cell
Antigen-presenting cell
An antigen-presenting cell or accessory cell is a cell that displays foreign antigen complexes with major histocompatibility complex on their surfaces. T-cells may recognize these complexes using their T-cell receptors...
s. CD4+ T helper cell
T helper cell
T helper cells are a sub-group of lymphocytes, a type of white blood cell, that play an important role in the immune system, particularly in the adaptive immune system. These cells have no cytotoxic or phagocytic activity; they cannot kill infected host cells or pathogens. Rather, they help other...
s that were specifically activated by antigens associated with the lesion, arrive at the site of injury and locally interact with microglia and other blood-derived antigen presenting cells (e.g. dendritic cell
Dendritic cell
Dendritic cells are immune cells forming part of the mammalian immune system. Their main function is to process antigen material and present it on the surface to other cells of the immune system. That is, dendritic cells function as antigen-presenting cells...
s). Local properties of antigen presenting cells (i.e. the levels of MHC-II-self antigen complexes and the type of co-stimulatory molecules) dictate the profile of the subsequent T cell response. The interaction between the T cells and the microglia/dendritic cells results in the production of a set of inflammatory cytokine
Cytokine
Cytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...
s (such as interferon gamma) and chemokines (chemoatractant proteins) that, in turn, orchestrate the ensuing repair process in which many cell types participate. Microglia and myeloid cells recruited from the circulating blood restrict the spread of damage by buffering excessive levels of toxic self-compounds (such as the neurotransmitter glutamate
Glutamic acid
Glutamic acid is one of the 20 proteinogenic amino acids, and its codons are GAA and GAG. It is a non-essential amino acid. The carboxylate anions and salts of glutamic acid are known as glutamates...
), and by producing growth factors (such as insulin-like growth factor-1) that prevent neuronal death and induce axonal re-growth. In addition, the chemokines produced at the site of injury attract endogenous stem or progenitor cells
Stem cell
This article is about the cell type. For the medical therapy, see Stem Cell TreatmentsStem cells are biological cells found in all multicellular organisms, that can divide and differentiate into diverse specialized cell types and can self-renew to produce more stem cells...
that can further contribute to repair by providing a source for new neurons and glial cells, and by restricting the local immune response.
The mechanism by which protective autoimmunity maintains the brain’s functional integrity under non-injurious conditions is still not known. One model suggests that CNS-specific autoimmune T cells which constantly circulate through the cerebrospinal fluid
Cerebrospinal fluid
Cerebrospinal fluid , Liquor cerebrospinalis, is a clear, colorless, bodily fluid, that occupies the subarachnoid space and the ventricular system around and inside the brain and spinal cord...
(CSF) interact with perivascular dendritic cells that reside at the choroid plexus
Choroid plexus
The choroid plexus is a structure in the ventricles of the brain where cerebrospinal fluid is produced...
and meninges. Cytokines and growth factors secreted into the CSF by the T cells and dendritic cells then diffuse into the neural parenchyma were they locally affect neurons, glial cells and stem cells. This model infers that the level of antigen presentation (i.e. the amount of MHC-II-self antigen complexes) serves as an indicator of the level of immune activity required for maintenance of the uninjured brain.
Regulation
The outcome of autoimmune activity is determined by several factors, namely: the intensity, the location, and the duration of the autoimmune response. For an autoimmune response to be beneficial, its intensity, duration and site of activity must be tightly regulated. Although autoimmune T cells exist in all healthy individuals, a relatively small portion of the population develops autoimmune diseases. This is due to various mechanisms that constantly regulate the activity of autoimmmune cells. One of the prominent autoimmune regulatory mechanisms is a sub-population of T cells called ‘regulatory T cellRegulatory T cell
Regulatory T cells , sometimes known as suppressor T cells, are a specialized subpopulation of T cells which suppresses activation of the immune system and thereby maintains tolerance to self-antigens. The existence of regulatory T cells was the subject of significant controversy among...
s’ (previously known as ‘suppressor T cells’), which restrict autoimmune activity. Experiments in animal models of CNS injury have shown that depletion of regulatory T cells allows an enhanced neuroprotective autoimmune response to take place after the insult. Importantly, however, such an experimental manipulation can at the same time increase the susceptibility to development of an autoimmune disease. Under certain conditions, an initially protective autoimmune response can reach a tipping point, after which it will have a detrimental effect on the tissue, and might even develop into an autoimmune disease. Both genetic and environmental factors (such as infection) can underlie such a transition from a neuroprotective autoimmune response into an overwhelming and detrimental autoimmune disease.
Other cell types, such as B cells and even neural progenitor cells, can promote regulation of immune response in the CNS. Stem and progenitor cells are usually regarded with respect to their potential to serve as a source for newly differentiated cells, but recently stem and progenitor cells have also been acknowledged for their ability to modulate immune activity. Experiments have shown that injection of neural progenitor cells into the brain’s ventricles can modulate an immune response taking place at multiple inflammatory foci in a mouse model of multiple sclerosis, or at a single site at the injured spinal cord.
Therapeutic implications
The concept of protective autoimmunity is relatively new, and it has been shadowed by the historic and yet dominant view of autoimmunity as a damaging factor. Skepticism towards protective autoimmunity has been further fueled by the general concept of the CNS as being an immune privileged site in which immune cell activity is observed only under pathological conditions. Nevertheless, studies during the last decade have established that the immune system has the capacity to orchestrate a multitude of beneficial effects in the adult CNS under both normal and pathological conditions. Such effects range from the molecular level (growth factor production, buffering of toxic self compounds) through the cellular level (induction of axonal regrowth and neurogenesis) to the behavioral level (maintenance of spatial memory).Several approaches have been used experimentally in order to harness naturally occurring immune cell activity in CNS pathologies. Here are key examples:
1. Therapeutic vaccination
Vaccination
Vaccination is the administration of antigenic material to stimulate the immune system of an individual to develop adaptive immunity to a disease. Vaccines can prevent or ameliorate the effects of infection by many pathogens...
: This approach utilizes a common immunological manipulation. Inoculation of an antigen that is associated with the pathology, in this case the site of injury, evokes the activation and proliferation of lymphocytes which can specifically respond to the antigen used. For therapeutic purposes, vaccination with an antigen associated with the site of injury (for example peptides derived from myelin proteins) is problematic, because it carries the risk of inducing, in individuals susceptible to autoimmune diseases, an overwhelming inflammatory response that is detrimental for recovery. To circumvent this problem researchers have been using lower affinity agonists (termed ‘altered peptide ligands’) which induce a weaker immune response. Experiments in animal models of spinal cord injury revealed that the use of such altered peptide ligands is effective in promoting functional recovery without the risk of inducing a deleterious autoimmune response.
2. Alteration of regulatory T cell activity: Suppressing regulatory T cell activity following injury can allow a more robust autoimmune response to take place. For therapeutic purpose, the mere removal of regulatory T cells is, again, highly problematic because it increases the risk of inducing autoimmune diseases. Overcoming this limitation is possible using agents that transiently suppress regulatory T cell activity. Such an agent has been used successfully in an animal model of ischemic stroke, where treated animals exhibited improved neurological recovery relative to non-treated animals.
Further reading
- Supplement on autoimmunity by Nature http://www.nature.com/nature/supplements/insights/autoimmunity/
- Focus on autoimmunity by Nature Immunology http://www.npg.nature.com/ni/focus/autoimmunity/classics/4.html