The distinction blurs between an autoimmune versus microbial hypothesis in multiple sclerosis.

Abstract

527 Multiple sclerosis (MS) is an inflammatory disease limited to the central nervous system (CNS) white matter. The CNS inflammation varies among different patients, and consists of variable degrees of T lymphocytes, macrophages, B lymphocytes, and antibodies at the leading edge of the white matter destruction (1‐3). Among the fundamental questions yet to be answered in understanding the pathophysiology of MS, and for that matter, other autoimmune diseases, are (a) what is the antigenic target driving the inflammation in the target organ, and (b) what initiates the inflammation? There were thought to be 2 possibilities regarding the initiating event in MS. The first is that the CNS white matter is structurally normal, and that an autoimmune response initiated by autoreactive T cells, as shown possible by the experimental autoimmune encephalomyelitis (EAE) model, mediates the initial inflammatory insult. The second possibility is that the inflammation is a result of some alteration of the CNS white matter, which could be the result of a microbial CNS infection. The elucidation of the mechanism responsible for the initiation of MS has obvious implications for the further development of specific therapies. However, this distinction between an autoimmune hypothesis, where the CNS white matter is normal, and the microbial hypothesis, where there is an infected CNS with regard to the etiology of MS, may be more blurred then previously thought. One of the more important discoveries over the past decade in understanding the pathogenesis of MS is the concept of epitope spreading. In this scenario, first demonstrated by Sercarz and colleagues, it was shown that the inflammatory process initiated by Tcell recognition of 1 myelin protein epitope subsequently leads to the activation of autoreactive T cells recognizing other epitopes of the same protein (4). In time, there is activation of T cells recognizing other myelin proteins that presumably get degraded and then loaded into the MHC of local antigenpresenting cells (APCs). The discovery of epitope spreading was important for the investigation of MS, because it suggested that the answer to the first fundamental question — what is the antigenic target driving the disease? — was unlikely to be found in the discovery of a single antigen. By the time a patient with the disease and recurrent attacks is seen in the clinic, there is likely to be activation of myelin-reactive T cells recognizing many myelin epitopes and proteins. These experiments in the EAE model may explain data from our laboratory showing myelin-reactive T cells activated against both myelin basic protein and proteolipid protein in the same MS patient (5). What, then, is the initiating event leading to epitope spreading in patients with MS? The report by Katz-Levy et al. in this issue of the JCI provides new mechanistic insight into the understanding of how viruses can induce human autoimmune diseases (6). Here again, the investigation of the human disease is aided by the experimental animal. Theiler’s murine encephalomyelitis virus‐induced demyelinating disease (TMEV-IDD) is caused by direct