Immune-mediated mechanisms in multiple sclerosis

Abstract

Sirs: We recently read with interest the report on cerebrospinal fluid (CSF) C D 4 + / C D 8 + T-cell ratio and myelin basic protein in relapsing multiple sclerosis (MS) patients by Salmaggi et al. [8]. Abnormali t ies in lymphocyte phenotypes appear to exist primarily in the CSF rather than in peripheral blood, which is in line with earlier reports by others [7]. Immune response may be responsible for demyelination during progressing disease. Indeed, markers of immune activation such as interleukin-2 [4], interleukin-2 receptor-bearing lymphocytes [1], tumour necrosis factor-ct (TNF-ct) [5] and neopterin [2] have been found with increased incidence in CSF of MS patients. The presence of increased neopterin indicates intrathecal activation of human macrophages by 7-interferon [3]. Other cytokines, for instance TNF-a, can amplify the effect of 7-interferon on macrophages to produce neopterin [11]. The referenced data further support the concept that local immune response contributes to demyelination in MS leading to irreversible damage of the central nervous system (CNS). However , this model alone cannot explain the full spectrum of MS, which is also characterized by reversibility of symptoms. The presence of high neopterin levels during immune activation processes shows that cytokines influence pteridine metabol ism [3,11]. The mono-oxygenases involved in the biosynthetic pathway of the neurotransmit ters serotonin, D O P A , and adrenal medullary hormones strictly depend on tetrahydrobiopter in as cofactor [6]. Thus, altered pteridine metabol ism may influence the supply of these neurotransmitters. In addition, we have shown that neopterin release by human macrophages is paralleled by activation of indoleamine (2,3)-dioxygenase ( IDO) in vitro and in vivo [11]. In a variety of human cells and cell lines I D O is activated in response to 7-interferon and TNF-c~ [10]. As a consequence, t ryptophan is degraded and t ryptophan metabolites such as kynurenine and quinolinic acid accumulate [9]. Subnormal availability of t ryptophan may result in diminished product ion of serotonin by neuroendocrine cells, and neurotoxicity of the t ryptophan metaboli tes formed [9] could precipitate neurological symptoms in patients. Clearly, cytolytic immune mechanisms may cause demyelination and irreversible damage of the CNS. However, 7-interferon and TNF-ct are released f rom immune cells during long-lasting inf lammatory conditions and may initiate metabolic changes which affect the CNS. These interactions between the immune system and the CNS may be of particular relevance in MS because cytokines are released f rom immune cells in close proximity to neuroendocrine cells. In contrast to demyelinat ion in MS patients the metabolic disturbances are reversible when the underlying immune activation process is stopped. This fact may in part explain the disappearance of some neurological symptoms in patients when the underlying immune activation ceases, e.g. during immunosuppressive therapy.