Protective autoimmunity and neuroprotection in inflammatory and noninflammatory neurodegenerative diseases

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Abstract

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®), 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.

Section snippets

Multiple sclerosis: a failure of protective autoimmunity?

Multiple sclerosis (MS) is a relatively common autoimmune-related neurological disorder in young adults (for review see [1]). MS has long been viewed as a chronic inflammatory disease in which the patient's own immune cells mediate damage to myelin, and the resulting demyelination causes neuronal dysfunction, leading to neuronal loss [2], [3].

The etiology of MS is unclear [4], [5]. In patients with MS, sites of central nervous system (CNS) lesions, or plaques, contain T cells of different

Is the regulation that is needed for avoidance of autoimmune disease related to the regulation needed for protective autoimmunity?

Today we know that T cells circulate in the bloodstream both of individuals that are susceptible and of individuals that are resistant to autoimmune diseases, and that their presence in the circulation probably reflects not an escape from selection, but rather a positive selection of such clones in the thymus [41]. Autoreactive T cells are primed in the thymus and then released to the periphery. Myelin-specific proteins are now known to be expressed in the thymus [42], [43], [44].

Knowing that

Therapeutic implications: a paradigm shift

The perception of autoimmunity as the body's protective mechanism, at least in the CNS, and of autoimmune disease as a failure of protective autoimmunity, calls for therapeutic protocols to be revisited. For treatment of autoimmune diseases, our findings argue in favor of therapies based on immunomodulation rather than immunosuppression, with the object of maximizing the beneficial component rather than eliminating the immune effect altogether [38]. For treatment of CNS damage not caused by

Acknowledgments

We thank S.R. Smith for editing the manuscript. M.S. holds the Maurice and Ilse Katz Professorial Chair in Neuroimmunology. The work was supported by Proneuron Ltd., Industrial Park, Ness-Ziona, Israel and in part by grants from The Glaucoma Research Foundation and The Alan Brown Foundation for Spinal Cord Injury awarded to M.S.

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