Immunoexcitoxicity as the possible major pathophysiology behind multiple sclerosis and other autoimmune disorders.

Abstract

Autoimmune disorders are destructive processes considered to be an attack on "self " antigens by the immune system CD-+4 T-cells that are directed toward antigens, in the case of multiple sclerosis (MS), particularly myelin antigens. Yet, there is growing evidence that the major destructive events in MS, as well as other non-central nervous system (CNS) autoimmune disorders, are much more than an immune attack on the CNS initiated by a misdirected immune system that attacks a "self " antigen or antigens by a process called molecular mimicry. Extensive evidence suggests that inflammation, in turn, initiates excitotoxicity, which is responsible for the majority of pathological findings in all stages of the disease, especially a loss of oligodendroglia (source of myelin) and axon injury in MS. Excitotoxicity also is a better explanation for progressive MS, in which the immune attack has either slowed or is halted; yet, the destructive pathology continues to progress. It also explains the destructive lesions seen in gray matter, which is essentially devoid of inflammation. It has recently been shown that most of the damage to the oligodendrocytes, as well as axonal injury, is secondary to excitotoxicity. While there is a growing appreciation that excitotoxicity plays a major role, there has been little effort to link the immune changes to the excitotoxic process, recently named immunoexcitotoxicity, even though the role of excitotoxicity has been shown to occur in the inflammatory stage in the beginning and throughout the process of the disease, particularly the chronic progressive stage. It is also known that peripheral glutamate receptors exist throughout the body, thus making the process of immunoexcitotoxicity a possible integral part of all or most autoimmune disorders in which the immune system is intimately linked to enhancing the excitotoxic process. This is of special concern now that peripheral glutamate receptors have been isolated in many peripheral tissues and are known to be fully functional.