Protective Autoimmunity - Background

Background

The adaptive immune system primarily consists of T and B cells (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).