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.
Background The adaptive immune system primarily consists of T and B lymphocytes, which can respond to specific antigens 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).
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 microglia cells, a population of CNS-resident immune cells, which can act as phagocytes, and antigen-presenting cells. CD4+ T helper cells 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 cells). 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 cytokines (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.
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