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  Immune mechanisms, both intrinsic to the brain and spinal cord and derived from the periphery, are important in fighting central nervous system infections and mediating repair after injury.

  
  
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  There are two main components of the immune system. The innate immune system is the first line of defense and responds to conserved components of microbes and evidence of tissue injury.

  
  
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  The adaptive immune system mounts immune responses against specific microbes, which includes humoral immunity (mediated by antibody production by B lymphocytes) and cell-based immunity (mediated by T lymphocytes).

  
  
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  Such immune responses can damage the nervous system through many mechanisms and contribute to a range of disorders through processes referred to as neuroinflammation.

  
  
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  Autoimmune diseases are a prominent example of immune-mediated damage of the nervous system, which is mediated by antibodies or T cells reacting against self antigens.

  
  
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  Many systemic autoimmune disorders can affect the nervous system. Additionally, several autoimmune disorders, such as multiple sclerosis (MS) and myasthenia gravis, selectively target the nervous system.

  
  
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  MS occurs primarily via cell-mediated destruction of myelin sheaths and consequent damage to underlying axons.

  
  
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  Myasthenia gravis and the related Lambert–Eaton syndrome occur primarily via antibody-mediated destruction of the neuromuscular junction.

  
  
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  Treatments for these autoimmune disorders are based largely on targeting specific components of the immune system or the use of general immunosuppressive agents.

  
  
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  Additionally, myasthenia gravis is treated with agents that promote the function of acetylcholine, the neurotransmitter at the neuromuscular junction.

Under normal conditions the central nervous system (CNS) is immunologically privileged, meaning that immune cells from the periphery cannot penetrate the brain and spinal cord due to the blood–brain barrier (Chapter 1). Nevertheless, immune mechanisms and the inflammatory responses they mediate—generated both by the CNS’s resident immune system and by the recruitment of peripheral immune mechanisms—are important in helping the CNS recover from acute infection or injury. By contrast, chronic autoimmune and inflammatory responses contribute importantly to numerous disease states. Immune-mediated damage to the nervous system can present in diverse ways, reflecting injury to specific neural substrates. In some instances immune damage affects primarily motor function but in other situations can cause selective behavioral abnormalities. Several common systemic autoimmune conditions, such as lupus erythematosus, affect the CNS and indeed often present initially with neurologic and psychiatric symptoms. Certain autoimmune disorders target the CNS selectively; examples include multiple sclerosis (MS) and other demyelinating illnesses (eg, neuromyelitis optica or Devic syndrome), paraneoplastic forms of encephalitis, stiff person syndrome (caused by autoantibodies directed against glutamic acid decarboxylase; Chapter 5), and myasthenia gravis and related conditions (eg, Lambert–Eaton syndrome). Chronic neuroinflammation also plays an important role in several disorders not classically considered neuroimmune, such as neuropathic pain (Chapter 11), Alzheimer disease and Parkinson disease (Chapter 18), and stroke (Chapter 20). Finally, inflammatory processes have been implicated, albeit more speculatively, in several psychiatric disorders as well as in normal aging.

The last decade, taking advantage of the growing understanding of interactions between the nervous and immune systems, has seen great advances in treating immune-based CNS disorders. The reader is referred elsewhere for detailed consideration of basic immunobiology and systemic autoimmune illnesses that can affect the CNS. This chapter briefly reviews the basic principles of neuroimmunology and focuses on the pathogenesis of two of the best studied neuroimmune disorders, MS and myasthenia gravis.

The immune system is designed to protect the host from invading pathogens and to eliminate disease. It responds to invading pathogens and has the capacity to distinguish “self” from “nonself” (foreign) antigens. The immune system is broadly divided into two major components: the innate and the adaptive (acquired) immune systems. The innate immune system includes physical (eg, skin), biochemical (eg, complement, lysozymes, cytokines), and cellular (dendritic cells, macrophages, neutrophils) components. Lysozymes and complement destroy microbial cell walls and membranes. Complement also enhances macrophage and neutrophil phagocytosis and attracts additional immune cells, while large families of cytokines (Chapter 8) exert proinflammatory or anti-inflammatory effects via actions on multiple cellular targets. Over the last decade, several pattern recognition receptors 12–1 have been identified on the surface and endosomal compartment of phagocytic cells. These receptors recognize conserved elements specific for viral, bacterial, and fungal constituents. During the inflammatory response triggered by infection, neutrophils and monocytes enter the affected tissue sites from the peripheral circulation. If these mechanisms are successful, the invading pathogen is eliminated, and illness is either prevented or mitigated.

When the innate immune response cannot clear an infection, the adaptive immune response is mobilized. Many effector mechanisms of the innate immune response are used to activate the adaptive immune response. The adaptive immune system has several key features that contribute to its ability to combat infections. These include the ability: (1) to recognize a variety of antigens in a specific as opposed to a patterned-recognized manner; (2) to discriminate between nonself and self antigens; and (3) to “remember” previously encountered antigens and respond in a heightened fashion. The adaptive response culminates in humoral immunity via the production of antibodies by B lymphocytes (B cells or plasma cells) and in cell-mediated immunity via activation of T lymphocytes (T cells).

Activation of the numerous cellular constituents of the immune system by cytokines, complement, and many other stimuli is governed by a very large number of intracellular signaling pathways that display complex cross-talk. A detailed discussion of these pathways is beyond the scope of this book, although many of the same intracellular pathways that mediate the actions of neurotransmitters and neurotrophic factors on the CNS (Chapters 4 and 8) are also crucial in the immune system. Likewise, many intracellular pathways first characterized for their important role in the regulation of immune cells, for example, NF-κB signaling (see 4–23) or toll-like receptor signaling 12–1, have more recently been demonstrated to contribute to synaptic transmission and plasticity in the nervous system. In fact, this has contributed to some confusion of what constitutes an “inflammatory response” in the CNS. For instance, if a certain cytokine, NF-κB, or toll-like receptor influences a neural phenomenon—from induction of long-term potentiation in the hippocampus to depression-related behavioral abnormalities (Chapter 15)—it does not automatically mean that a true immune response is involved. This somewhat semantic distinction is an important one to keep in mind as neuroinflammation is implicated in an ever-expanding range of neuropsychiatric disorders.

Autoimmunity arises when the body mounts an immune response against itself due to failure to distinguish self from nonself antigens. This phenomenon derives from multiple potential regulatory failures of the immune system, but results ultimately in the activation of self-reactive T and B lymphocytes that generate, respectively, cell-mediated or humoral immune responses directed against self antigens. Autoimmune reactions might also occur when antibodies are generated against nonself antigens, but cross-react with self antigens, so-called molecular mimicry. One proposed example is Sydenham chorea, which arises as a long-term consequence of infection by group A β-hemolytic streptococci and may be mediated by production of antibacterial antibodies that cross-react with and damage cells in the striatum. A similar mechanism has been implicated in rare psychiatric consequences (tics, obsessive–compulsive symptoms) of streptococcal infection, a process termed pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS). However, the involvement of molecular mimicry as the major pathogenic mechanism of these conditions remains unproven.

The relative contribution of T and B cells to various organ-specific autoimmune diseases, including neurologic autoimmune disorders such as MS and myasthenia gravis, remains controversial. According to some models, autoimmunity arises from a failure of T-cell tolerance: errors made by T cells in distinguishing nonself from self antigens. However, there is also evidence for a causative role for B cells in presenting self antigens to and consequently activating T cells. In any event, B cells play crucial roles in disease pathophysiology via production of autoantibodies that exert a direct effect on self antigens by functioning as neutralizing antibodies or activating and fixing complement on and thereby damaging the targeted tissues. Activated B cells are also an important source of cytokine secretion, which can lead to further tissue damage. These considerations illustrate that the adaptive immune system (T and B cells) is in a dynamic, constantly changing relationship with cells constituting the innate immune system. Although current therapies are targeted primarily against the adaptive immune system, a better understanding of the innate immune system will likely inform future therapeutic advances.

While the CNS is an immune-privileged site, shielded from the peripheral immune system under normal conditions as stated earlier, it contains its own resident innate immune system mediated via microglia and astrocytes. Microglia are macrophage-like cells that reside in the CNS and are crucial for recognizing nonself antigens and neutralizing them through phagocytosis. They are also an important source of cytokines. Activated astrocytes contribute to innate CNS immunity through the release of cytokines and neurotrophic factors and the formation of glial scars. Infection or traumatic brain injury can disrupt the blood–brain barrier and allow entry of cells of the peripheral immune system into the CNS, leading to further immune reactions. For example, the CNS innate immune system interacts with infiltrating monocytes and dendritic cells from the blood, which can result in peripheral blood-derived antigen-presenting cells leaving the CNS and traveling to cervical lymph nodes where they encounter cells of the adaptive immune system. Activated T cells may then emigrate from the lymph nodes and travel to the CNS, while activated B cells may generate antibodies that target antigens within the CNS. Migration of neutrophils into the CNS may also occur through a tightly regulated process involving cellular activation and migration of activated cells through vascular junctions and the basement membrane into CNS tissue, where they contribute further to inflammatory responses. These various processes can help resolve the acute infection or injury, but can also trigger downstream deleterious consequences including autoimmune diseases and frank neural injury. An improved understanding of the steps and specific molecules involved in the trafficking of peripheral immune cells into the CNS has played a major role in the development of current drug therapies for disorders such as MS.

The large majority of mechanisms established in neuroimmunology have come from the study of MS and myasthenia gravis, which are discussed in greater detail in the sections that follow. Lessons learned from these two disorders highlight the two main disease pathogenesis pathways described earlier. In the case of MS, the primary defect centers around loss of T-cell tolerance. In contrast, myasthenia gravis is an example of an antibody-mediated disorder.

MS is a common cause of neurologic disability in young adults. It is roughly three times more common in women. Clinically it is marked by periods of disease activity and relative quiescence termed relapses and remissions manifesting as neurologic deficits lasting at least 24 hours and supported by objective findings.

The pathologic hallmark of MS is multiple focal areas of myelin loss and associated axonal damage within the CNS called plaques or lesions 12–1. Demyelination is accompanied by variable inflammation and gliosis with increasingly recognized damage to axons as well. Lesions are disseminated throughout the CNS but are most frequently observed involving optic nerves, subpial spinal cord, brainstem, cerebellum, and juxtacortical and periventricular white matter regions. MS is diagnosed based on clinical evidence of neurologic deficits combined with the presence of characteristic MS plaques or lesions by magnetic resonance imaging (MRI) 12–2. Cerebrospinal fluid shows evidence of inflammatory responses in a majority of patients, including characteristic oligoclonal bands of immunoglobulins revealed with electrophoretic methods.