What is the correlation between central nervous system and the peripheral nervous system

Normal Structure and Function

The central nervous system (CNS) is the most complex system in the body, able to function both as a self-contained unit and the coordinating centre for activities of the peripheral nervous system (PNS), skeletal muscles and other organ systems.

The CNS is composed of three principal structures: the brain, brainstem and spinal cord. The brain comprises two hemispheres covered by grey matter that are joined by a band of white matter known as the corpus callosum. The cerebral cortex is located on the outer surface of the hemispheres, and is composed of six layers of neurones. It is divided into four main regions: the frontal, temporal, parietal and occipital lobes. Each of these has distinct functions, which are summarised inFig. 26.1. The white matter beneath the cerebral cortex is composed of axons surrounded by myelin that connect the cortical neurones with neurones elsewhere. In the centre of the hemispheres are groups of grey matter nuclei (deep grey nuclei), the basal ganglia and the thalamus, whose principal functions are motor and sensory coordination, and the regulation of tone and posture. The cerebellum is connected by white matter bundles to the posterior surface of the brainstem. The cortex of the cerebellum lies on its outer surface, but its structure is different from that of the cerebral cortex. The cerebellum has a major role in movement coordination and the regulation of stance, posture and gait.

The brainstem contains many ascending and descending white matter fibre bundles that connect the spinal cord to the brain. It also contains many nuclei, including cranial nerves 3 to 12, the substantia nigra, the respiratory centre and the vomiting centre. The spinal cord is largely composed of ascending and descending white matter fibre bundles, for example, the lateral columns (descending motor fibres) and the posterior columns (ascending sensory fibres). The grey matter of the spinal cord is located centrally, and contains several groups of neurones, including the anterior horn cells that are lower motor neurones supplying all the skeletal muscle in the trunk and limbs. Motor nerve roots leave the anterior spinal cord to form peripheral motor nerves; sensory input from the skin, joints and organs enters the spinal cord by the posterior nerve roots, which pass into the ascending posterior columns.

Despite the structural and functional complexities of the CNS, the constituent cells can be divided into just five main groups:

neurones

glial cells

microglial cells

connective tissue cells

vascular cells.

I General Organization of the Peripheral Nervous System

Traditionally, the nervous system is divided into central and peripheral components. The brain (cerebrum, cerebellum, and brain stem) and spinal cord form the central nervous system (CNS). The peripheral nervous system (PNS) connects the CNS to the different tissues and organs of the body. The modern view of the organization of the PNS is based on the work of the English physiologist John Newport Langley (1852–1925). The PNS has two components, a sensory (afferent) and a motor (efferent) component. The sensory component, also known as the afferent component (ad meaning to +ferre meaning carry), is responsible for conveying information to the CNS from the body itself and from the environment (Fig. 1). We receive sensory information through the sensory endings (receptors) that are scattered throughout the body. These receptors are biological transducers, associated with the peripheral ends of afferent axons, which transform different stimuli into action potentials in these axons. Sensory nerve fibers are the axons of a group of neurons situated within the dorsal root ganglia (DRG) at the distal end of dorsal roots (Fig. 1). These ganglia are also known as sensory or spinal ganglia and convey information from the body. The sensory information from the face travels through the specialized cranial nerves. The motor or efferent (ex meaning from +ferre) component carries information from the CNS to the muscles. The target organs, which respond to the stimuli carried by the efferents, are called effectors (Fig. 1). The motorneurons that innervate skeletal muscles are localized within the ventral horns of the spinal cord.

The elements of the efferent component of the PNS can be further categorized into a somatic and an autonomic division. The somatic division controls skeletal muscles and acts mainly under the direction of conscious voluntary control from the brain. The autonomic division innervates smooth muscles, cardiac muscle, and glands. The term autonomic comes from auto (meaning self) and nomos (meaning law). The autonomic nervous system exerts control over the functions of many organs and brings the fine internal adjustments necessary for the maintenance of the optimal internal environment of the body. This system functions according to its own internal laws, largely unconsciously.

Neurons do not function in isolation; they are organized into specific neuronal circuits that process particular different kinds of information and control particular efferent organs. The simplest type of circuit is called a “reflex” or reflex arc and involves the interaction of sensory and motor neurons. The effector response mediated by such a circuit is called a reflex response or simply a reflex. Some reflexes are extremely important in the diagnosis and localization of neurologic problems. Several neuronal components of the PNS and CNS are involved in a reflex arc. The first component of the reflex arc is a receptor, such as a special cutaneous receptor or a neuromuscular spindle, the stimulation of which initiates an action potential in afferent fibers. The second component is an afferent neuron (sensory neuron with a soma within the DRG), which transmits impulses though the peripheral nerves to the CNS. The third component is an interneuron within the CNS, which relays the information to the efferent neuron. In some reflexes, known as monosynaptic reflexes (such as a stretch reflex, the circuits of which are shown in Fig. 1), this component is missing. The next component of the reflex arc is the efferent (motor) neuron, which delivers information from the CNS to the effector organ. At the point of contact between a neuron and the effector, where unidirectional transmission of information is occurs, there is a specialized structure called a synapse. Finally, the effector, such as a muscle or gland, will respond to the action potential delivered through the efferent fibers. Interruption of the reflex arc at any point will abolish the response.

Anatomy of the Spinal Nerves of the Peripheral Nervous System

The PNS is composed of those neural elements that extend between the CNS (in this case the spinal cord) and their target organs (Fig. 64.1). The peripheral motor system axons (somatic efferents) originate from the anterior horn cells and exit the spinal cord to form the ventral (anterior) rootlets. Muscle spindle fusimotor efferents and afferents travel with these fibers. Axons of the peripheral sensory system (somatic afferent) extend from specialized sensory organs within skin, muscle, tendon–muscle junctions, and viscera to their cell bodies, the dorsal root ganglia (DRG), which lie within the bony intervertebral foramen. These sensory fibers make up the dorsal (posterior, somatic afferent) rootlets that enter the posterior horn of the spinal cord. The mixed spinal nerves are formed when anterior and posterior rootlets combine within the neural foramen just distal to the DRG at the point where the dura ends. The short spinal nerve then divides into two branches: (1) a large anterior branch (ventral ramus) that extends forward to supply the trunk muscles and gives rise to the roots of the plexus, and (2) a small posterior branch (dorsal ramus) that extends backward to supply motor fibers to paravertebral muscles and ferry sensory fibers from posterior longitudinal ligaments, intervertebral discs, dura mater, facet joints, and the skin of the neck and back. Autonomic sympathetic axons communicate and travel with the mixed spinal nerves via the rami communicantes.

Multipotency and Fate Restrictions in Postmigratory Neural Crest Cells

The developmental potential of neural crest cells was originally addressed by heterotopic transplantation of neural tube fragments from quail embryos to chick recipients.1,2 These pioneering experiments revealed that the neural crest from all levels along the neuraxis has broad potential and is able to generate various cell types of the peripheral nervous system (PNS), including neuronal and glial cells in parasympathetic, sympathetic, and sensory ganglia. Subsequently, transplantation of postmigratory neural crest cells back into the neural crest migration pathway was used to demonstrate the potential of neural crest cells isolated from sites of terminal differentiation.1 Quail cells populating dorsal root ganglia (DRG) (where they normally differentiate into sensory neurons and satellite glia) were found in host DRG, nerves, and autonomic ganglia after grafting. In contrast, ciliary, Remak, and sympathetic ganglia contained cells that could contribute only to nerves and autonomic derivatives, not to host DRG. Similarly, late emigrating neural crest cells generated fewer derivatives than an early emigrating neural crest population.3 This indicates that during development, neural crest cells undergo progressive restrictions in their potential.2,4 Nonetheless, the back-transplantation experiments suggested that some PNS structures contain cells with broader potential than anticipated from their location and function.

Note that the transplantation experiments described here only allow the investigation of the potential of the neural crest as a population. Multipotency at the population level could reflect either the existence of multipotent individual cells or a mixture of lineage-committed cells, the composition of which might vary depending on the developmental stage and the location. To reveal multipotent cells in postmigratory targets of the neural crest, it is therefore imperative to assess the developmental potential of individual cells from these targets. As this is technically difficult to achieve in vivo, several researchers have developed systems for clonal culture of PNS tissues. Such systems allow monitoring of the fate and the potential of single neural crest cells by mapping individual cells immediately after isolation and by determining the cell-type composition of clones generated by the mapped founder cells. These kinds of experiments have been performed with various tissues containing crest-derived cells, such as dorsal root and sympathetic ganglia, sciatic nerves, the gut, visceral arches, and the developing skin.5–13 Consistently, they showed that progenitor cells capable of generating multiple cell types coexist in crest-derived tissues with cells that display fate restrictions in the chosen culture conditions. The number of multipotent cells, however, decreases with age. In the quail embryo, clones containing melanocytes, sensory neurons, and sympathoadrenal cells can only be derived from DRG and sympathetic ganglia at early stages of development.7 Similarly, the phenotypic diversity of clones obtained from quail enteric neural crest–derived cells decreased with increasing age.13 In the rat, 16% of all cells in the sciatic nerve at early stages (embryonic day 14.5) are able to produce neurons, glia, and myofibroblasts; this number is less than 2% at later embryonic stages.11 Thus, clonal analysis confirmed the progressive restriction in the potential of neural crest–derived cells during PNS development.

The study of multipotent stem cells requires markers that distinguish these cells from more restricted progenitor cells. Multipotent neural crest cells are characterized by the concomitant expression of the glycoprotein HNK-1, the low-affinity neurotrophin receptor p75, and the transcription factor Sox10 as well as by the absence of any differentiation markers.14–16 The surface expression of p75 enabled researchers to label living cells and thus to prospectively identify migratory and postmigratory multipotent neural crest cells as founder cells in clonogenic adhesive cultures8,15 or upon fluorescence-activated cell sorting11,17 (Fig. 21-1). The ability to prospectively identify multipotent neural crest cells and to enrich them by flow cytometry led to the discovery that such cells persist even in the adult PNS. Morrison and colleagues isolated a p75+ cell fraction from the postnatal rat gut that was highly enriched for multipotent cells relative to unfractionated cells.17 Although these cells are less mitotically active than neural crest cells from the embryonic gut, they produce neurons, glia, and myofibroblast in cell cultures. They also are able to migrate to neural crest–derived structures and to form neurons and glia in vivo upon transplantation into chick embryos. Still, neural crest cells isolated from the adult gut have lost the ability to make certain neuronal subtypes, in contrast to their embryonic counterparts. This shows that even if cell populations enriched for p75 expression are being compared, neural crest cells undergo restrictions in their developmental potential during the transition from the embryonic to the postnatal stage. Similarly, migratory p75+ neural crest cells isolated from neural tube explant cultures display broader developmental potential upon transplantation into chick embryos than postmigratory p75-expressing cells derived from the sciatic nerve.18

In a few cases, fate restrictions observed in vivo or in culture have been correlated with the expression of molecular markers on subpopulations of neural crest cells. However, for most of these markers, it is not clear whether their differential expression is also functionally associated with lineage restrictions. Although P0, a major component of peripheral myelin,19 marks multipotent neural crest cells both from early DRG and from sciatic nerves,8,11 increased P0 expression is associated with decreased frequency of multipotent progenitor cells.11 Similarly, the tyrosine kinase receptor c-Ret is expressed on a subpopulation of multipotent neural crest–derived cells in the enteric nervous system.9 Although able to generate neurons, glia, and nonneural cells, these c-Ret+ cells are different from migratory neural crest cells in that they display reduced proliferative capacity and, in culture, they rapidly segregate into neuronal and nonneuronal lineages. Furthermore, c-Ret+ cells isolated from the rat fetal gut generate fewer neuronal sublineages than migratory neural crest cells upon transplantation into the ventral neural crest pathway in chicken embryos.20 Another example for a direct correlation between gene expression and cell fate segregation is found at early stages of neural crest development. The receptor tyrosine kinases TrkC and c-kit are present on distinct subpopulations of neural crest cells as the cells emerge from the neural tube.21 Clonal analysis of molecularly identified neural crest cells revealed that these receptors mark lineages with distinct neurogenic and melanogenic potentials. The basic helix–loop–helix (bHLH) transcription factor neurogenin-2 (Ngn2) represents one of the few known molecules that not only serves as a marker for a neural crest sublineage but also has been functionally implicated in the specification of this lineage. Ngn2 is expressed on a subset of emigrating neural crest cells22,23 and is required for the generation of certain sensory neurons.24 Moreover, its ectopic expression biases the migrating neural crest to localize to DRG.25 Given its role in sensory neurogenesis, does expression of Ngn2 reflect commitment to a sensory lineage? To address this question, in vivo fate mapping of Ngn2-expressing neural crest cells has been performed using the Cre–loxP system.26 In this system, Cre recombinase is expressed in the cells whose fate is to be followed (i.e., to elucidate the fate of Ngn2-expressing cells, mice were generated that express Cre recombinase driven from Ngn2 regulatory promoter elements27). Mice expressing Cre in a cell type-specific manner are then mated with mice in which lacZ reporter gene expression is activated in a Cre-dependent manner. In embryos derived from such intercrosses, lacZ is stably expressed in all Cre+ cells and their progeny. Such experiments revealed that Ngn2-expressing neural crest cells are more likely to generate sensory than autonomic cells. Surprisingly, however, Ngn2+ cells produce both neurons and glia, indicating that the segregation between sensory and autonomic lineages occurs before neuronal vs glial fate restriction. Moreover, given the early expression of Ngn2, this lineage segregation takes place before or as neural crest cells emigrate from the neural tube. It is important to note, however, that a few autonomic neurons are generated from Ngn2-expressing neural crest cells. Therefore, Ngn2 biases neural crest cells to adopt a sensory fate but does not commit them to such a fate. Thus, an Ngn2+ cell, although fate restricted, might be multipotent.

Guillain-Barré Syndrome (Acute Idiopathic Polyneuritis)

Guillain-Barré syndrome is characterized by sudden onset of skeletal muscle weakness or paralysis that typically begins in the legs and spreads cephalad over the ensuing days to involve the arms, trunk, and face. Since the virtual elimination of poliomyelitis, this syndrome has become the most common cause of acute generalized paralysis, with an annual incidence of 1–2 cases per 100,000. Bulbar involvement typically manifests as bilateral facial paralysis. Difficulty swallowing due to pharyngeal muscle weakness and impaired ventilation due to intercostal muscle paralysis are the most serious signs of this process. Because of lower motor neuron involvement, paralysis is flaccid and corresponding tendon reflexes are diminished. Sensory disturbances (e.g., paresthesias) generally precede the onset of paralysis and are most prominent in the distal extremities. Pain is often present.

ANS dysfunction is a prominent finding in patients with Guillain-Barré syndrome and is usually manifested as fluctuations in blood pressure, sudden profuse diaphoresis, peripheral vasoconstriction, resting tachycardia, and cardiac conduction abnormalities. Orthostatic hypotension may be so severe that elevating the patient’s head onto a pillow may lead to syncope. Thromboembolism may occur secondary to immobility. Sudden death associated with this disease is most likely caused by ANS dysfunction.

Complete spontaneous recovery from acute idiopathic polyneuritis can occur within a few weeks if segmental demyelination is the predominant pathologic process. However, axonal degeneration (as detected by electromyographic screening) may result in slower recovery that takes several months and leaves some residual weakness. The mortality rate associated with Guillain-Barré syndrome is 3%–8%, and death is most often a result of sepsis, acute respiratory failure, pulmonary embolism, or cardiac arrest.

The diagnosis of Guillain-Barré syndrome is based on clinical signs and symptoms (Table 15.2) supported by finding an increased protein concentration in the cerebrospinal fluid. Cerebrospinal fluid cell counts typically remain within the normal range. In approximately half of patients, this syndrome develops after respiratory or gastrointestinal infection, which suggests that the cause may be related to either viral or mycoplasma infection.

Treatment of Guillain-Barré syndrome is symptomatic. Vital capacity is monitored, and when it decreases to less than 15 mL/kg, mechanical support of ventilation is initiated. Arterial blood gas measurements help in assessing the adequacy of ventilation and oxygenation. Pharyngeal muscle weakness, even in the absence of ventilatory failure, may requireinsertion of a cuffed endotracheal tube or tracheostomy to protect the lungs from aspiration of secretions or gastric fluid. ANS dysfunction may require treatment of hypertension or hypotension. Corticosteroids arenot useful. Plasma exchange or infusion of gamma globulin may benefit some patients but does not affect overall outcome.

a. Direct Cytopathic Effects of Borrelia burgdorferi Infection

PNS manifestations of Lyme disease in general respond well to antibiotic therapy, which implicates persistent Bb infection in their pathogenesis. Bb can bind in vitro to Schwann cells and galactocerebroside moieties and is cytotoxic toward neonatal brain cells and oligodendrocytes [1]. However, in contrast to other tissues, Bb has seldom been isolated from the PNS in human Lyme disease, although one recent report described the presence of Bb (on polymerase chain reaction) in a patient with a chronic sensorimotor polyneuropathy [6]. Although it has been suggested that local infection may be important in the pathogenesis of acute meningoradiculitis associated with early disseminated Lyme infection, the failure to isolate Bb from PNS tissue in most pathological studies argues against direct cytopathic effects of Bb as a dominant mechanism of PNS Lyme disease [1].

Myelin basic protein

In PNS myelin, MBP varies from approximately 5 to 18% of total protein, in contrast to the CNS where it is close to 30% (Morell, 1984). In rodents, the same four 21, 18.5, 17 and 14 kDa MBPs found in the CNS are present in the PNS. In adult rodents, the 14 kDa MBP is the most prominent component and is termed Pr in the PNS nomenclature. The 18.5 kDa component is present and is often referred to as the P1 protein in the nomenclature of peripheral myelin proteins. Another species-specific variation in human PNS is that the major basic protein is not the 18.5 kDa isoform that is most prominent in the CNS, but rather a form of about 17 kDa. It appears that MBP does not play as critical a role in myelin structure in the PNS as it does in the CNS. This is probably because the cytoplasmic domain of P0 has an important role in stabilizing the major dense line of PNS myelin. This difference is illustrated in the shiverer mutant mouse, which expresses very little MBP (see Chapter 31), and a greatly reduced amount of CNS myelin, with no compaction of the major dense line. This contrasts with shiverer PNS, which has essentially normal myelin, both in amount and structure, despite the absence of MBP. On the other hand, animals doubly deficient for P0 and MBP have a more severe defect in compaction of the major dense line than P0-null mice, which indicates that both proteins contribute to compaction of the cytoplasmic surfaces in PNS myelin (Kirschner et al., 2004).

INTRODUCTION

The peripheral nervous system (PNS) is composed of a diverse array of cell types within various specialized compartments. It is an immunologically complex structure, and many sites within the PNS are subject to a wide range of inflammatory and autoimmune responses. Chapter 25, on immunologic responses, describes in detail the underlying immunologic principles pertaining to the PNS, and Chapter 97 describes the clinical immunology of PNS disease. The present chapter focuses particularly on a description of the PNS antigens that are capable of acting as autoimmune targets, and readers are referred to other chapters for further immunologic and clinical information. Some immunologic issues of special relevance to peripheral nerve, particularly innate immune mechanisms and molecular mimicry, are also included herein.

The PNS contains many molecules potentially capable of acting as antigens that are either unique to the PNS, such as some of the myelin proteins, or highly enriched in it, such as gangliosides. Additionally, the PNS contains a large number of molecules that are common to other sites, both in the central nervous system (CNS), such as the neuronal antigens Hu and CV2, and in non-neural regions of the body, such as basement membrane antigens. However, out of the many thousands of candidate antigens, only a limited number of molecular structures have been convincingly demonstrated to behave as peripheral nerve autoantigens. This chapter includes a description of these antigens, along with the relevant morphologic, pathophysiologic, and immunologic background, and the features of the antigenic repertoire within the PNS that make it an important site for both B- and T-cell responses to its constituent components.

14.2.2.1 Dorsal root ganglia injury model

PNS studies on axon regeneration have focused on the axons from sensory neurons in dorsal root ganglia (DRG) and in sympathetic ganglia. Sensory neurons in the DRG are particularly interesting for comparing the differential regenerative responses of the PNS versus the CNS and provide a favorable model for studying mammalian axon regeneration. This approach is simple and has a high degree of reproducibility. Each DRG neuron extends a unipolar axon that splits into two branches: one peripheral innervating targets such as skin and muscles and a central relaying the sensory information to the CNS, via the spinal cord. While injured peripheral axons are able to regenerate, the central branch fails to do so.21 However, if axotomy of the peripheral branch occurs prior to central branch axotomy (a preconditioning lesion), regeneration of the central axons is greatly enhanced.22, 23

4.4.1 Peripheral Nervous System Injury

PNS damages are frequent, and result in psychological and physical morbidity for the patient. In the U.S., approximately 2.8% of traumatic injuries affect the PNS (Noble et al., 1998).

During damage to the PNS, if the axon is completely damaged, the two ends of a nerve will retract, causing a gap. The proximal end is the one attached to the cell body, and the distal end is the free-floating end. Injury leads to Wallerian degeneration in the distal stump of the injured nerve, and axonal retrograde degeneration near the proximal stump. In Wallerian degeneration, the axons and myelin degenerate completely (Grinsell and Keating, 2014).

What happens during regeneration?

There is a migration of macrophages, monocytes, and SCs into the nerve stumps to remove myelin and axon debris (Burnett and Zager, 2004). SCs proliferate, maintain the endoneurium, and produce various neurotrophic factors and ECM molecules to stimulate axon regeneration. They also maintain the endoneurium. New axonal sprouts emerge from the nodes of Ranvier and undergo remyelination by SCs (Gaudet et al., 2011).

In humans, small nerves regenerate at an average rate of 2 mm/day and larger nerves regenerate at an average rate of 5 mm/day (Recknor and Mallapragada, 2006).