INTRODUCTION

Oligodendrocytes, as the myelin-producing cells of the central nervous system (CNS), are exactly what their Greek-derived name “oligodendroglia” suggests: they, alongside astrocytes, the non-neural microglia and ependymal cells, have been characterized as the “glue” that holds together the intricate apparatus of our brain. The fact that oligodendrocyte and astrocyte cells outnumber neurons by ten to one illustrates their importance, which is particularly highlighted by the oligodendrocyte's role in accelerating transmission of axonal action potentials. On the other hand, oligodendrocytes are involved in a number of serious diseases of viral, metabolic and immunological origin. This chapter tries to shed light on the immunobiological properties of oligodendroglial cells in the healthy and diseased CNS. We will begin with an overview of diseases featuring oligodendrocyte/immune system interactions and will then, in the second part, focus on the molecular repertoire that allows these cells to interact directly or indirectly with immune cells. Subsequently, we will discuss oligodendrocytes as antigen-presenting cells and finally we will present data on direct oligodendroglial/immune cell interactions.

IMMUNE-MEDIATED DISEASES AFFECTING OLIGODENDROCYTES

Multiple sclerosis

Multiple sclerosis (MS), which was first described by the French neurologist Jean-Martin Charcot in 1868 (Charcot, 1868), is a chronic inflammatory disease of the CNS of unknown etiology (Hemmer et al., 2006). Although an ideal system for the classification of different MS stages does not yet exist (Van der Valk and De Groot, 2000) there is broad consensus that loss of myelin due to oligodendrocyte damage or death together with axonal degeneration leading to reactive glial scar formation are the key hallmarks of this disease (Trapp and Nave, 2008).

INTRODUCTION

The nervous system has long been considered an immunologically privileged site. This concept was based on the premises that: (1) there is a more or less strict anatomic separation between the systemic immune compartment (blood) and the neural tissue; (2) molecules required for antigen presentation are absent under normal circumstances; (3) there is no lymphatic drainage; and (4) immune surveillance by T cells is lacking. It is now obvious that most of these assumptions are not tenable. The blood–nerve barrier (BNB) does restrict access of immune cells and soluble mediators to a certain degree; however, this restriction is not complete, either anatomically (e.g. the BNB is absent or relatively deficient at the roots, in the ganglia and the motor terminals) or functionally. Activated T lymphocytes can penetrate intact barriers irrespective of their antigen specificity, and, under certain circumstances, release cytokines that upregulate the expression of major histocompatibility complex (MHC) class II molecules, key molecules required for antigen presentation. In the central nervous system (CNS) tissue-resident neuroglial cells are present that actively participate in the regulation of immune responses within the tissue. In recent years, several lines of evidence have pointed to Schwann cells as immunocompetent cells within the peripheral nervous system (PNS), which, in addition to their physiological roles, exhibit a broad spectrum of immune-related functions and might be involved in the local immune response in the PNS. In this chapter we will elaborate on the expanding recognition of Schwann cells as immunocompetent cells that form part of the local immune circuitry within the PNS. Interestingly, present data suggest that the entire spectrum of an immune response can be displayed by Schwann cells; recognition of antigens, presentation of antigens, mounting an immune response, and, finally, terminating an immune response within the inflamed peripheral nerve.

The following chapter reviews principles of immunology to provide an understanding of how components of the nervous system are recognized by the immune system, how an autoimmune response is mounted, how immune cells and mediators enter the nervous tissue, and how tolerance against neural antigens is induced, maintained, and broken. Most of the general principles have been discovered since the 1980s but only with the new technology of targeted deletions and mutations (permanent and conditional knockout, knockin) can these principles be systematically explored at the molecular level. A brief discussion of multiple sclerosis, the Guillain–Barré syndrome, and myasthenia gravis will follow, while clinical aspects and disease-specific pathomechanisms of immune-mediated neurological disorders are presented in greater detail in individual chapters. Therapeutic consequences based on immunological principles are discussed in Chapter 93.

Categories of the immune response

The immune system is a multifaceted system of cells and molecules with specialized tasks in defending the organism from external agents, infectious or toxic. Moreover, the immune system plays a pivotal role in maintaining antigenic homeostasis in the body. Two types of responses to invading organisms can take place: an acute response launched within hours, and a delayed response occurring within days. The immediately responding system is termed innate immune system, and it evolves stereotypically and at the same magnitude regardless how often the infectious agent is encountered. In contrast, a more delayed response is delivered by the adaptive or acquired immune system and provides a more specific immunologic reaction which improves in efficiency on repeated exposure to a given infective agent, capitalizing on the formation of immunological memory. The immune system has traditionally been divided into innate and adaptive systems, each containing different cellular and molecular components. The main distinction between these two systems lies in the mechanisms and receptors used for immune recognition. These two systems are not separated, but are functionally connected allowing for intensive interactions (Carroll & Prodeus, 1998; Ochsenbein & Zinkernagel, 2000).

The innate immune system

During evolution, the innate immune system appeared before the adaptive immune system, and some form of innate immunity probably exists in all multicellular organisms. Characteristically, innate immune responses consist of all the immune defence mechanisms that do not require immunologic memory. Genetically, the molecular mediators and their receptors are highly conserved between species as far apart as Caenorhabditis elegans, Drosophila, and mammals.