doi:10.1111/cei.13279 NEURO-IMMUNE INTERACTIONS: HOW THE NERVOUS AND IMMUNE SYSTEMS INFLUENCE EACH OTHER Clinical and Experimental Immunology REVIEW ARTICLE Series Editor: Leonie S. Taams Neuroimmunology – the past, present and future OTHER ARTICLES PUBLISHED IN THIS REVIEW SERIES Neuroimmune interactions: how the nervous and immune systems influence each other. Clinical and Experimental Immunology 2019, 197: 276-277. The immune system and psychiatric disease: a basic science perspective. Clinical and Experimental Immunology 2019, 197: 294-307 Depressive symptoms in inflammatory bowel disease: an extraintestinal manifestation of inflammation? Clinical and Experimental Immunology 2019, 197: 308-318. From early adversities to immune activation in psychiatric disorders: the role of the sympathetic nervous system. Clinical and Experimental Immunology 2019, 197: 319-328. E. Nutma,* H. Willison,† Summary ‡ § G. Martino and S. Amor * Neuroimmunology as a separate discipline has its roots in the fields of neu- * Department of Pathology, Amsterdam UMC, rology, neuroscience and immunology. Early studies of the brain by Golgi VUmc site, Amsterdam, the Netherlands, and Cajal, the detailed clinical and neuropathology studies of Charcot and † University of Glasgow, Institute of Infection, Immunity and Inflammation, College of Thompson’s seminal paper on graft acceptance in the central nervous system, Medical, Veterinary and Life Sciences, kindled a now rapidly expanding research area, with the aim of understand- Glasgow, UK, ‡ Neuroimmunology Unit, ing pathological mechanisms of inflammatory components of neurological Division of Neuroscience, Institute of disorders. While neuroimmunologists originally focused on classical neuro- Experimental Neurology (INSpe), San Raffaele inflammatory disorders, such as multiple sclerosis and infections, there is Scientific Institute and Vita-Salute San strong evidence to suggest that the immune response contributes to genetic Raffaele University, Milan, Italy, and§ Centre white matter disorders, epilepsy, neurodegenerative diseases, neuropsychiatric for Neuroscience and Trauma, The Blizard disorders, peripheral nervous system and neuro-oncological conditions, as Institute, Barts and The London School of well as ageing. Technological advances have greatly aided our knowledge of Medicine and Dentistry, London, UK. how the immune system influences the nervous system during development Accepted for publication 20 December 2018 and ageing, and how such responses contribute to disease as well as regen- Correspondence: S. Amor, Department of eration and repair. Here, we highlight historical aspects and milestones in Pathology, Amsterdam UMC, VUmc site, De the field of neuroimmunology and discuss the paradigm shifts that have helped Boelelaan 1117, 1081 HV Amsterdam, the provide novel insights into disease mechanisms. We propose future perspec- Netherlands.E-mail: [email protected] tives including molecular biological studies and experimental models that may have the potential to push many areas of neuroimmunology. Such an understanding of neuroimmunology will open up new avenues for therapeutic approaches to manipulate neuroinflammation. Keywords: central nervous system, inflammation, neurodegeneration, neuroimmunology, neuroinflammation Introduction nervous system receive messages from the immune system, but that signals from the brain regulate immune functions Neuroimmunology encompasses fundamental and applied that subsequently control inflammation in other tissues [1]. biology, immunology, chemistry, neurology, pathology, Communication between the immune system and the CNS psychiatry and virology of the central nervous system is exemplified by the finding that many molecules associated (CNS). Scientists in the field study the interactions of with the immune system are widely expressed and functional the immune and nervous system during development, in the nervous system and vice versa. Cross-talk between homeostasis and response to injuries with the major aim microglia and neurones is known to be essential for main- of developing approaches to treat or prevent neuroim- taining homeostasis, yet such cross-talk also occurs between munological diseases. oligodendrocytes and microglia [2]. Disturbance in this com- The immune system has been generally regarded as autono- munication due to peripheral infections in mice are known mous and the brain protected by the blood–brain barrier, to trigger microglia activation and augment neurodegenera- (BBB) and in the words of Rudyard Kipling (Barrack-room tion [3]. Similarly, recent experimental studies show that ballads , 1892), ‘never the twain shall meet’. In the past dec- maternal infections lead to long-term changes in microglia ades these dogmas have been strongly challenged and dispelled and abnormal brain development in the offspring [4,5]. with the wealth of evidence showing that not only does the 278 © 2019 The Authors. Clinical & Experimental Immunology published by John Wiley & Sons Ltd on behalf of British Society for Immunology, Clinical and Experimental Immunology, 197: 278–293 This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. NEURO-IMMUNE INTERACTIONS: HOW THE NERVOUS AND IMMUNE SYSTEMS INFLUENCE EACH OTHER History of Neuroimmunology Fig. 1. World map showing location of International School of Neuroimmunology (ISNI) meetings. Despite this evidence, it is surprising that the term Here, we review the developments in neuroimmunology ‘neuroimmunology’ was only first used on PubMed in since its roots in the first descriptions of immunological 1982, coinciding with the first Neuroimmunology Congress processes and neurological diseases, as well as the devel- in Stresa, Italy (Fig. 1) and following the launch of the opment of technologies and clinical trials for such diseases. Journal of Neuroimmunology in 1981. Although neuroim- Important events are given in major timelines or eras, munology research has focused on multiple sclerosis (MS; along with the Nobel Prizes considered relevant by their using the search term ‘neuroimmunology’, 43% of papers impact on the field of neuroimmunology. The review also on PubMed in 2018 were on MS), immune responses includes a perspective on the future of neuroimmunology are also observed in Guillain–Barré syndrome (GBS), white that should herald prospective approaches to understand- matter diseases, psychiatric disorders, infections, trauma ing these diseases, and we address several outstanding and neurodegenerative diseases traditionally considered questions in the field. The long-term goal of this rapidly to be ‘cell autonomous’ (Table 1). developing field of neuroimmunology is to further the One of the greatest misconceptions that impeded understanding of how immune responses shape the nerv- progress in neuroimmunology was the idea that the ous system during development and ageing, how such blood–brain barrier (BBB) and the perceived immu- responses lead to neurological diseases, and ultimately to nological privilege of the brain prevent cross-talk develop new pharmacological treatments. These aspects between the CNS and immune systems. This long- are thus the major topics of the International Society of standing dogma has been challenged by recent studies Neuroimmunology meetings (ISNI) (Fig. 1) and the and the discovery of glymphatics and meningeal lym- educational topics of the global schools in phatic vessels [43]. Although this paradigm shift is a neuroimmunology. recent advancement in thinking of nervous-immune system cross-talk, such changes in the field, beginning Historical beginnings over 150 years earlier, have been generally linked to technological advances, some of which have yielded The first descriptions of many neuroinflammatory disorders Nobel Prizes in neuroimmunology (Table 2), including come from personal notes, early authors and diarists. The the development of mutant and transgenic mice to earliest report purported to be MS was in an Icelandic examine disease mechanisms, stem cell technologies woman (in approximately 1200) and Saint Lidwina of and the novel CRISPR/cas9 system, that allows gene Schiedam (1380–1433), while the detailed personal diaries editing enabling personalized treatments. of Sir Augustus d’Esté, born in 1794 (grandson of King © 2019 The Authors. Clinical & Experimental Immunology published by John Wiley & Sons Ltd on behalf of British Society 279 for Immunology, Clinical and Experimental Immunology, 197: 278–293 NEURO-IMMUNE INTERACTIONS: HOW THE NERVOUS AND IMMUNE SYSTEMS INFLUENCE EACH OTHER E. Nutma et al. Table 1. Neuroimmune diseases Disease Clinical characteristics Immune involvement Ref ADEM Lethargy, visual problems, paralysis associated Demyelination, inflammation, axonal loss, [6] with viral infection or vaccination hypertrophic astrocytes, activated microglia ALS motor neurone disease Fatal motor neurone disease affecting the motor Systemic immune activation, microglia activation [7–9] neurones leading to weakness of voluntary and hypertrophic astrocytes. Complement muscles deposition AD Progressive cognitive decline. Amyloid plaques, Microglia, astrocytes, complement and cytokines in [10,11] synaptic loss and neurofibrillary tangles. plaques. Aβ binds and activates microglia. Aβ Anti-inflammatory drugs associated with reactive T cells in blood, immunoglobulin in