Cytokines in neuroinflammatory disease: role of myelin autoreactive T cell production of interferon-gamma

Abstract

Many cytokines must be considered as effector and immunoregulatory molecules in neuroinflammatory diseases such as multiple sclerosis (MS) and experimental allergic encephalomyelitis (EAE). We have studied the potential role of interferon-gamma (IFN-gamma) in the pathogenesis of these diseases, since this cytokine has a number of important effects such as macrophage activation, induction of MHC class I and class I antigens, and T cell homing. An immunospot assay that allows enumeration of single cells secreting IFN-gamma after short-term culture in vitro of mononuclear cell suspensions has been used. In EAE, increased numbers of IFN-gamma-secreting cells (IFN-gamma-sc) appear in the central nervous system shortly before onset of clinical signs. Such cells also increased during pharmacologically induced relapse of EAE. In later stages of EAE, memory T cells that produced IFN-gamma in response to presented antigen, recognized multiple regions of the myelin basic protein (MBP), showing that (i) myelin autoreactive T cells have the functional ability to produce this cytokine, (ii) the concept of immunodominance as to autoantigen peptide reactivity is non-absolute and time-dependent. In multiple sclerosis (MS) there are increased numbers of IFN-gamma-sc among the CSF cells. Also, there are increased numbers of memory T cells, strongly enriched to the cerebrospinal fluid, which upon recognition of several myelin antigens and several MBP peptide stretches, produce IFN-gamma. Taken together, the data are consistent with a role for IFN-gamma as a key mediator in inflammatory demyelinating diseases.