Introduction: Interactions between the Immune and Central Nervous Systems

Sandra Amor1 and Nicola Woodroofe2

1Department of Pathology, VU University Medical Center, Amsterdam, the Netherlands; and Neuroimmunology Unit, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK

2Biomedical Research Centre, Sheffield Hallam University, Sheffield, UK

In this introductory chapter, we briefly trace the history of the field and highlight the important influence that research in neuroimmunology has had on modern immunologic and neurological ideas. The link between many neurological diseases is the realisation that the immune and nervous systems are inextricably linked, and that perturbations in this delicate balance are involved in many disorders. This has opened up new avenues for therapeutic approaches to the treatment of central nervous system (CNS) inflammatory and neurodegenerative and neoplastic disorders. In this introduction to the book, we provide links to other chapters in the book that expand upon these key features. For those new to the field we have included a section (Chapters 1–5) highlighting the key basic concepts in the field, while the second section (Chapters 6–15) covers the role of the immune response in specific disorders of the CNS.

Origins

The field of neuroimmunology developed from sub-specialities in immunology and neurology into a rapidly expanding discipline of its own. While the first international congress of neuroimmunology was held in Stresa, Italy in 1982, the International Society of Neuroimmunology (ISNI) was only founded after the second congress in 1987 in Philadelphia, United States. The Journal of Neuroimmunology had been launched in March 1981, and the Journal of Clinical and Experimental Neuroimmunology in 1988. The origins of neuroimmunology predate the establishment of the society by nearly a century, and the discipline has its roots in several interdisciplinary topics. It is a discipline that now encompasses a wide range of disorders including peripheral neuropathies and those affecting the CNS (Table I.1) (Amor et al., 2010, Amor and Woodroofe, 2013; Peferoen et al., 2013). The milestones in the history of neuroimmunology are outlined in Table I.2.

Table I.1 Neuroimmunological aspects of disorders of the central nervous system (CNS)

Disorder Clinical characteristics and immune involvement Chapter Alzheimer's disease (AD) Pathology of human tissues, in vitro studies and animal models of AD provide evidence for involvement of immune activation pathways. Long-term use of anti-inflammatory drugs is linked with reduced risk of developing the disease. 6 Parkinson's disease Movement disorder due to deterioration of the nigrostriatal system. Chronic activation of microglia is observed to be associated with neurodegeneration. 6 Huntington's disease and other polyglutamine expansion diseases Microglia expressing a mutant huntingtin protein are blunted in their ability to migrate, leading to immune dysfunction. 6 Infections Encephalitis, encephalomyelitis, meningitis, polyradiculitis or polyneuritis. Characteristics depend on infectious agents [e.g. human T-lymphotropic virus type 1 (HTLV1)-associated myelopathy (HAM)]. Immune responses depend on infectious agents. 7 Amyotrophic lateral sclerosis (Lou Gehrig's disease) Immune abnormalities in the CNS and peripheral immune responses. Microglia activation is associated with the production of neurotoxic as well as neurotrophic factors. 8 Multiple sclerosis (MS) Demyelination and neurodegeneration in brain, spinal cord and optic nerve. Innate and adaptive immune activation. Oligoclonal immunoglobulin in cerebrospinal fluid. 9 Acute demyelinating encephalomyelitis (ADEM) Usually associated with or following a viral infection or following vaccination. Most cases are in children and adolescents (average ages 5–8). Demyelinating lesions are associated with immune activation (like MS). 9 Neuromyelitis optica (NMO) Inflammatory disorder of the CNS predominantly affecting the optic nerves and spinal cord. Most patients have antibodies to aquaporin-4 (AQP4) which are thought to directly attack astrocytes. 9 Systemic lupus erythematosus (SLE), diabetes and gluten ataxia Neurodegeneration and inflammation affect a large number of patients with SLE. Persons with gluten ataxia display a loss of Purkinje cells associated with immune activation in the CNS. 10 Depression Link between levels of pro-inflammatory cytokines and depression in susceptible individuals. Changes in serotonergic and/or glutamatergic transmission in the CNS and reduced neurotrophic factor expression. 11 Epilepsy A predisposition to develop seizures is frequently associated with cognitive and psychological sequelae. Both the innate and adaptive immune responses have been linked with disease. Anti-inflammatory agents are used to control some forms of epilepsy. 12 Stroke and intracerebral haemorrhage Dramatic increase in the systemic inflammation and innate immune activation triggered to resolve debris as well as neutrophil traffic into infarcted brain tissue. 13 Spinal cord injury Direct damage to axons, neuronal cell bodies and glia causes functional loss. The injury triggers an inflammatory response that contributes to secondary tissue damage. 14 Primary brain tumours Cellular and molecular mechanisms that mediate tumour escape from natural immune surveillance (e.g. tumours down-regulate major histocompatibility complex expression). 15

Table I.2 Milestones in the history of neuroimmunology

Year Milestone 1825–1893 Jean-Martin Charcot was a French neurologist and professor of anatomical pathology. He recognized the neurological diseases multiple sclerosis (MS), Charcot–Marie–Tooth disease and amyotrophic lateral sclerosis. 1949 Induction of experimental autoimmune encephalomyelitis in mice 1960 Nobel Prize: Peter B. Medawar (1915–1987) and Frank Macfarlane Burnet (1899–1985). The immune system can distinguish between self and non-self, and the brain is immune-privileged. 1980 Nobel Prize: Baruj Benacerraf (1920–2011), Jean Dausset (1916–2009) and George Davis Snell (1903–1996), “for discovery of the Major histocompatibility complex genes which encode cell surface molecules important for the immune system's distinction between self and non-self”. 1981 Launch of Journal of Neuroimmunology 1982 First international neuroimmunology meeting 1996 Nobel Prize: Peter C. Doherty and Rolf M. Zinkernagel. Importance of major histocompatibility complex molecules in the detection, removal and killing of virus-infected cells 1999 Alemtuzimab (antibody to CD52; Campath 1H) effective in suppression of active inflammation in MS 2005 Recognition that antibodies to aquaporin-4 (AQP4) are present in people with optic-spinal MS (now classified as neuromyelitis optica) and bind to the AQP4 water channel 2011 Effective use of Rituximab (to deplete B cells) in MS to reduce relapses 2011 Nobel Prize in Physiology or Medicine: Bruce Beutler, Jules Hoffman and Ralph M. Steinman. Identification of dendritic cells and importance in T cell activation and specifically the role of the innate immune response

By invitation only

It is widely assumed that the CNS is an immune-privileged tissue, suggesting that antigens gaining entry to the brain and spinal cord do not invoke an immune response (Chapter 1). While this idea was first discussed over 70 years ago, it is clear that immune privilege is not absolute since immune responses do take place in the CNS and are crucial for shaping the brain during development and controlling infections in the brain. However, immune cells do not freely patrol the brain as with other organs, and those that enter are by invitation only. The gatekeeper of the CNS is the blood–brain barrier, which when compromised is unable to control such selection, thereby contributing to the tissue damage. In many neurological disorders there is evidence that the blood–brain barrier, and indeed the barriers that maintain immune privilege in the spinal cord and...