- Protective autoimmunity
Protective autoimmunity is a condition in which cells of the
adaptive immune systemcontribute 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.
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 [Moalem, G. et al. (1999) Autoimmune T cells protect neurons from secondary degeneration after central nervous system axotomy. Nat. Med. 5 (1), 49-55] . 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 [Yoles, E. et al. (2001) Protective autoimmunity is a physiological response to CNS trauma. J Neurosci 21 (11), 3740-3748] . 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[Hauben, E. et al. (2001) Posttraumatic therapeutic vaccination with modified myelin self-antigen prevents complete paralysis while avoiding autoimmune disease. J. Clin. Invest. 108 (4), 591-599] [Hauben, E. et al. (2000) Passive or active immunization with myelin basic protein promotes recovery from spinal cord contusion. J Neurosci 20 (17), 6421-6430] , brain injury [Kipnis, J. et al. (2003) Therapeutic vaccination for closed head injury. J Neurotrauma 20 (6), 559-569] , glaucoma[Bakalash, S. et al. (2003) Antigenic specificity of immunoprotective therapeutic vaccination for glaucoma. Invest Ophthalmol Vis Sci 44 (8), 3374-3381] , stroke[Frenkel, D. et al. (2003) Nasal vaccination with myelin oligodendrocyte glycoprotein reduces stroke size by inducing IL-10-producing CD4+ T cells. J Immunol 171 (12), 6549-6555] [Ziv, Y. et al. (2007) A novel immune-based therapy for stroke induces neuroprotection and supports neurogenesis. Stroke 38 (2 Suppl), 774-782] , motor neuron degeneration [Angelov, D.N. et al. (2003) Therapeutic vaccine for acute and chronic motor neuron diseases: implications for amyotrophic lateral sclerosis. Proc Natl Acad Sci U S A 100 (8), 4790-4795] , Parkinson’s [Laurie, C. et al. (2007) CD4+ T cells from Copolymer-1 immunized mice protect dopaminergic neurons in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson's disease. J Neuroimmunol 183 (1-2), 60-68] and Alzheimer's disease [Frenkel, D. et al. (2005) Nasal vaccination with a proteosome-based adjuvant and glatiramer acetate clears beta-amyloid in a mouse model of Alzheimer disease. J Clin Invest 115 (9), 2423-2433] [Butovsky, O. et al. (2006) Glatiramer acetate fights against Alzheimer's disease by inducing dendritic-like microglia expressing insulin-like growth factor 1. Proc Natl Acad Sci U S A 103 (31), 11784-11789] 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 hippocampusand sub-ventricular zone (the brain structures where neurogenesistakes place in the adult brain) [Kipnis, J. et al. (2004) T cell deficiency leads to cognitive dysfunction: Implications for therapeutic vaccination for schizophrenia and other psychiatric conditions. Proc. Natl. Acad. Sci. U S A 101 (21), 8180-8185] [Ziv, Y. et al. (2006) Immune cells contribute to the maintenance of neurogenesis and spatial learning abilities in adulthood. Nat Neurosci 9 (2), 268-275] .
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 [Hanisch, U.K. and Kettenmann, H. (2007) Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat Neurosci 10 (11), 1387-1394] . This response is mediated primarily by
microgliacells, 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 [Butovsky, O. et al. (2005) Activation of microglia by aggregated beta-amyloid or lipopolysaccharide impairs MHC-II expression and renders them cytotoxic whereas IFN-gamma and IL-4 render them protective. Mol Cell Neurosci 29 (3), 381-393] and induce axonal re-growth [Rapalino, O. et al. (1998) Implantation of stimulated homologous macrophages results in partial recovery of paraplegic rats. Nat Med 4 (7), 814-821] . 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 [Schwartz, M. and Ziv, Y. (2008) Immunity to self and self-maintenance: a unified theory of brain pathologies. Trends Immunol] 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 plexusand 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.
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 cells’ (previously known as ‘suppressor T cells’), which restrict autoimmune activity [Shevach, E.M. (2000) Regulatory T cells in autoimmmunity. Annu. Rev. Immunol. 18, 423-449] . 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 [Kipnis, J. et al. (2002) Neuroprotective autoimmunity: naturally occurring CD4+CD25+ regulatory T cells suppress the ability to withstand injury to the central nervous system. Proc. Natl. Acad. Sci. U S A 99 (24), 15620-15625] . Importantly, however, such an experimental manipulation can at the same time increase the susceptibility to development of an autoimmune disease [McHugh, R.S. and Shevach, E.M. (2002) Cutting edge: depletion of CD4+CD25+ regulatory T cells is necessary, but not sufficient, for induction of organ-specific autoimmune disease. J. Immunol. 168 (12), 5979-5983] . 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 [Pluchino, S. et al. (2005) Neurosphere-derived multipotent precursors promote neuroprotection by an immunomodulatory mechanism. Nature 436 (7048), 266-271] [Ziv, Y. et al. (2006) Synergy between immune cells and adult neural stem/progenitor cells promotes functional recovery from spinal cord injury. Proc Natl Acad Sci U S A 103 (35), 13174-13179] . 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.
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:
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 succesfully in an animal model of ischemic stroke, where treated animals exhibited improved neurological recovery relative to non-treated animals.
List of autoimmune diseases
ISNI - International Society of NeuroImmunology [http://www.isniweb.org/]
The Psychoneuroimmunology Research Society [http://www.pnirs.org/]
1. Supplement on autoimmunity by Nature [http://www.nature.com/nature/supplements/insights/autoimmunity/]
2. Focus on autoimmunity by Nature Immunology [http://www.npg.nature.com/ni/focus/autoimmunity/classics/4.html]
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