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 DEFINITION AND THEN SUBDIVISION OF GUILLAIN–BARRé SYNDROME

Guillain–Barré syndrome (GBS) emerged from the confusion of nineteenth century descriptions of paralytic disorders with the descriptions of two case histories by Guillain, Barré and Strohl in 1916 (Guillain et al. 1916; Pritchard and Hughes 2004). Their patients had an acute paralysing disorder characterised by absent tendon reflexes and an increased cerebrospinal fluid protein with a normal cell count. They deduced that the disease involved the spinal nerve roots and Guillain insisted that it had a benign prognosis. This statement is sadly not true but does reflect the regenerative capacity of the Schwann cell, which turned out to be the principal focus of the pathology in the common form of the disease.

During the 1970s and 1980s the clinical picture was pinned down by a working definition which has continued in use (Asbury et al. 1978; Asbury and Cornblath 1990). The definition has inclusion criteria of progressive weakness of the limbs reaching its worst typically within four weeks, associated with loss or substantial loss of the tendon reflexes. It also has criteria of features which cast doubt on the diagnosis, such as marked asymmetry or bladder and bowel dysfunction at the onset, and exclusion criteria of alternative diagnoses, such as porphyria or toxin exposure. The characteristic features of GBS are that it occurs after, not during, an infection and that the pathology is largely confined, like Schwann cells, to the peripheral nervous system (PNS).

INTRODUCTION

Cytokines, first described as products of the cells of the inflammatory/immune system, are increasingly recognised as acting on non-inflammatory cells as well as being produced by non-inflammatory cells. Nowhere is this more apparent than with cells of the peripheral (PNS) and central (CNS) nervous systems. Studies have clearly indicated that neuroglial cells are targets of cytokines produced by infiltrating immune/inflammatory cells in inflammatory diseases of the PNS and CNS, and are not simply passive targets of lytic destructive processes. In addition there is evidence to show that neuroglial cells, in particular astrocytes, Schwann cells and microglia (cells of the monocyte/macrophage lineage), respond to cytokines by changes in function and phenotype and can themselves produce many of the classically described inflammatory cell cytokines. Perhaps even more interesting are recent studies showing that such cytokines, particularly when produced by cells that are endogenous to the PNS and CNS, are important in PNS and CNS development and perhaps in protection and regeneration of the PNS and CNS in inflammatory, traumatic and even some degenerative diseases.

We and others have been interested in the interactions of Schwann cells and cytokines in the pathogenesis of diseases, modulation and recovery from disease, and regeneration, as well as in normal PNS development and function. Schwann cell–cytokine interactions can be studied in various ways: examining tissue obtained at different stages of development, and at different phases of experimental and naturally occurring diseases, including human disorders of the PNS, and employing different in vitro models.

INTRODUCTION

The cellular components of the peripheral nervous system (PNS) – neurons and their axons, Schwann cells, perineurial cells, endoneurial fibroblasts and vessel endothelia – are surrounded by extracellular components such as collagens, fibronectin, laminins and proteoglycans. These components are either part of extracellular matrix or organised in the basal lamina. These molecules are recognised by cellular receptors on Schwann cells, such as integrins and dystroglycan. Engagement of matrix components by cognate receptors modulates nearly all aspects of Schwann cell development including: proliferation, survival, migration, interaction with axons, differentiation, myelination, and formation of the nodes of Ranvier. After a general review of the extracellular matrix molecules and their known functions in peripheral nerve, we will focus on the role of laminins in Schwann cell differentiation, Schwann cell/axon interactions, organisation of the axonal membrane and myelination.

EXTRACELLULAR MATRIX IN ENDONEURIUM

Every nerve is characterised by: the epineurium, surrounding the whole nerve; the perineurium, surrounding fascicles of nerve fibres; and the endoeurium, defined as the area contained within the perineurium, and in which the single fibres are contained. The adult endoneurium contains abundant amounts of extracellular matrix, which can be present in extracellular spaces among nerve fibres, associated with fibroblasts and organised in basal laminae around Schwann cells or endothelia; or anchored or spanning cell membranes in Schwann cells, endothelia or fibroblasts. The non-cell-associated matrix is mainly composed of fibrillary collagen, while most of the other extracellular matrix components are associated with fibroblasts (Joseph et al. 2004).

INTRODUCTION

The glial cells of adult peripheral nerves, myelinating and non-myelinating Schwann cells, are generated during development from neural crest cells. The protracted embryonic period of gliogenesis involves first the generation of Schwann cell precursors and subsequently the generation of immature Schwann cells. The signals controlling these early steps of gliogenesis from multipotent neural crest cells can now be analysed using transgenic and other molecular approaches, and the findings integrated with our knowledge of organogenesis of peripheral nerves. The subsequent postnatal generation of myelinating or non-myelinating Schwann cells from immature Schwann cells involves cessation of proliferation and resistance to cell death. The maturation of the nerve is likely to be regulated by a balance between signals that act as brakes to provide orderly timing for myelination and signals that actively promote it.

THE INITIAL DEVELOPMENT OF PERIPHERAL NERVES

Schwann cells originate from Schwann cell precursors, which in turn arise from multipotent neural crest cells that delaminate from the dorsal neural tube (reviewed in Jessen and Mirsky 2005a, b). The growing nerves consist initially of outgrowing axons and closely adherent Schwann cell precursors. At this stage the nerve lacks blood vessels, and there is no significant fibrous protective connective tissue around or within the nerve. Later in development, around the time that nerves establish stable contacts with their target tissues, blood vessels invade and the nerve acquires its characteristic connective tissue layers (Ziskind-Conhaim 1988; Jessen and Mirsky 2005a; Wanner et al. 2006).

Chronic inflammatory demyelinating polyneuropathy (CIDP) is the most common chronic treatable neuropathy in the Western world with a prevalence of 1–2 per 100,000 (Lunn et al. 1999; McLeod et al. 1999). It is the chronic variety of the inflammatory demyelinating neuropathies, of which the Guillain–Barré syndrome (GBS) is the acute form. Because it is treatable, CIDP needs to be considered in the differential diagnosis whenever a patient presents with an acquired chronic or progressive neuropathy. The inflammatory demyelinating neuropathies are characterised pathologically by multifocal areas throughout the peripheral nervous system (PNS) of inflammatory infiltrates associated with demyelination. When demyelination is assessed by the study of teased nerve fibres it is seen to be segmental, i.e. by and large restricted to the territory of individual Schwann cells (Figure 10.1). This characteristic pathological description suggests that the myelin loss, which occurs in these neuropathies, results from some insult which targets Schwann cells rather than the myelin itself.

Despite considerable advances in treatment strategies, which have developed effective therapies for a majority of patients, the pathogenic mechanisms which disrupt Schwann cell function resulting in demyelination remain unknown in most patients. It is likely moreover that CIDP, like GBS, is comprised of a number of different subtypes, and the study of patients within these homogenous subgroups may permit the recognition of meaningful patterns of pathogenicity. To date, research into CIDP and indeed its acute counterpart GBS has centred largely around the animal model experimental autoimmune neuritis (EAN).

There are four classes of Schwann cells in the mature vertebrate nervous system: (1) myelinating Schwann cells, which wrap around large-diameter axons including motor axons; (2) non-myelinating Schwann cells, which associate with small-diameter axons of many sensory and all postganglionic sympathetic neurons; (3) satellite cells of peripheral ganglia; and (4) non-myelinating perisynaptic Schwann cells (PSCs), also known as terminal Schwann cells, which cap the nerve terminal at the neuromuscular junction (NMJ) (Corfas et al. 2004). While the role of motor and sensory axon-associated Schwann cells in saltatory conduction has been well-acknowledged and characterised, relatively little is known about the role of the synapse-associated Schwann cells. However, in the past decade, there has been widespread interest in unraveling the role of Schwann cells in peripheral synapses as well as the role of astrocytes in central synapses. Extensive studies on synapse–neuroglial interactions in both the peripheral nervous system (PNS) and central nervous system (CNS) have led to the concept of the tripartite synapse (Araque et al. 1999; Volterra et al. 2002; Kettenmann and Ransom 2005). The emerging concept suggests that neuroglia cells are active and essential participants in modulating synaptic function, promoting synapse repair and development and stabilising synapses. Thus, it is no longer tenable to view the neurochemical synapse as a synaptic contact made of only the presynaptic nerve terminal and the postsynaptic target, without taking into consideration the multiple active roles of the third element, neuroglia, specifically here the PSCs.

INTRODUCTION

Myelinating Schwann cells have unique structural and molecular adaptations that promote saltatory conduction. The myelin lamellae itself can be divided into several domains – compact myelin, regions of specialised junctions between the layers of the myelin lamellae (‘non-compact myelin’), the abaxonal/outer membrane, and the adaxonal/inner membranes, and the regions at the node, paranode, and juxtaparanode. P0, myelin basic protein (MBP), and peripheral myelin protein 22 kD (PMP22) are the main proteins of compact myelin. Incisures and paranodes contain the molecular components of adherens junctions, tight junctions and gap junctions. Nodal microvilli contain cytoskeletal components, dystroglycan, syndecan-3 and -4, and possibly cell adhesion molecules (CAMs) that may interact with CAMs on the nodal axolemma (Nr-CAM and neurofascin 186 kD; NF186) to cluster voltage-gated Na+ (NaV) channels. The nodal axolemma also contains voltage-gated K+ channels (KCNQ2 and Kv3.1b). NaV channel α subunits are directly linked to the spectrin cytoskeleton by ankyrinG, and indirectly by their β subunits. The paranodal glial loops contain NF155, which interacts directly with contactin, and indirectly with contactin/Caspr heterodimers, forming septate-like junctions. In the juxtaparanodal region, connexin29 (Cx29) may form hemi-channels on the adaxonal Schwann cell membrane; these directly appose a complex of Kv1.1/Kv1.2 K+ channels and Caspr2 on the axonal membrane; trans-interacting, transiently expressed axonal surface glycoprotein-1 (TAG-1) dimers may join the two apposed membranes. Kv1.1, Kv1.2 and Caspr2 each have a PDZ binding site and may interact with the same PDZ protein.

It is now over 200 years since Theodore Schwann first described the cell which bears his name. Such early descriptions of nervous system components were done without the powerful microscopes we have today, yet Schwann and Ramon Y. Cajal made foundation observations which still stand. Cajal's papers, especially, show the power of careful observation, an essential element of good science.

The Schwann cell has been historically underrated and poorly understood. In particular, the myelin-forming Schwann cells or their myelin are still often referred to as a simple ‘sheath’ for the neuron. However, Schwann cells in all their complexity form essential partnerships with neurons, and muscles. This is of particular relevance in the case of the myelin-forming Schwann cell, an enormous cell that expresses unique molecules and complex relationships related to maintenance of the compact and non-compact myelin regions of its plasma membrane. Schwann cells have other complex interactions, not least of which are found where nerve terminals and muscle fibres form the tripartite synapse in association with the perisynaptic Schwann cells. There are also the poorly understood satellite cells that surround the dorsal root ganglion nerve cell bodies, and of course the complexity of non-myelinated Schwann cells and their axonal associations.

It may be that the histopathological prominence of abnormalities of compact myelin has focussed research on this region of the Schwann cell.

THEODOR SCHWANN 1810–1882

The Schwann cell is named in honour of the German physiologist Theodor Schwann (1810–1882, Figure 1.1) who is now acknowledged as the founder of modern histology. In addition to describing the Schwann cell, he made numerous contributions to the fields of biology, physiology and histology – not least as one of the instigators and main advocates of cell theory. The cell theory defined the cell as the base unit of all living organisms, and had great influence on the study of both plants and animals. The cell theory was radical for the time and irrevocably discredited Vitalism, the mainstream belief that life was attributed to a vital force. Among other things, Schwann is known for recognising that the crystals seen during fermentation, first reported by Leeuwenhoek in 1680, were in fact living organisms; although it was not until Pasteur in 1878 wrote to Schwann acknowledging this observation that Schwann's finding was accepted. In fact, Pasteur's germ theory stems from Schwann's work in which he showed that microorganisms were required for the putrefaction of meat.

Schwann spent his undergraduate years at the University of Bonn and then the equivalent of postgraduate study in Wuerzburg and Berlin. Schwann was appointed Professor of Anatomy at Louvain in 1839. In 1848 he moved to the Chair of Anatomy in Liege. In a biography of Schwann (Causey 1960), Causey reported that he avoided the strife of scientific controversy and appears to have risen above petty jealousies.