An Introduction to Neuroimmunology

For decades, the brain was thought to be an immune-privileged organ that was physically separated from the immune system in a strategic effort to limit potentially deleterious actions of immune signaling on the central nervous system (CNS). However, emerging evidence now points to critical roles for immunology in almost every facet of fundamental neurobiology including normal brain development, cognition, and behavioral control. Moreover, the immune system is now recognized to be centrally involved in the vast majority of major neurological disorders including Alzheimer’s disease, amyotrophic lateral sclerosis (ALS), stroke, epilepsy, traumatic brain injury, glioblastoma, mental illness, autism, pain, and addiction just to name a few. Even less brain-centric disorders like obesity, cardiovascular disease, and intestinal disorders are now recognized to be highly influenced by neuroimmunology via the microbiome-neuroimmune and the vagus nerve-neuroimmune axes^1,2.

In contrast to other peripheral organs where immune cells can inflict significant collateral damage without serious consequences, damage to bystander CNS neurons by the immune system may be permanent, thus requiring neuroimmune responses to be tightly controlled. The brain is equipped with numerous unique structural, cellular, and molecular characteristics to keep immune responses in check. The specialized cell types, nervous system-derived molecular signals, and anatomical features that govern immune cells in the CNS will be discussed in this special issue of Immunological Reviews. This special issue will also explore how reciprocal crosstalk between the CNS and the immune system contributes to health and disease.

The first few reviews in this special issue introduce some of the unique anatomical features of the CNS and further highlight how they uniquely contribute to the regulation of neuroimmune responses. In the first review of the series, Dr. Louveau and colleagues provide a comprehensive overview of the immunological properties of the meninges, which is a thin membranous structure positioned between the skull and brain parenchyma that houses a rich collection of immune cells as well as the CNS lymphatics³. In this review article, they first outline key components of meningeal lymphatic development, function, and physiology. Next, they summarize an exciting body of recent literature which defines novel roles for defective brain lymphatic drainage in a spectrum of neurological disorders including Alzheimer’s disease, multiple sclerosis (MS), and traumatic brain injury.

In the second review of the collection, Dr. Eyo and colleagues describe how skull bone marrow-derived myeloid cells egress using vascular channels to the brain and into the cerebrospinal fluid⁴. A comprehensive review of the anatomical and molecular cues that govern myeloid cell trafficking is given to provide insight into the many essential functions provided by the calvarial bone marrow niche including antigen presentation and modulation of the blood-brain barrier. The authors conclude by discussing the importance of cerebrospinal fluid and the glymphatic system in signaling during physiological conditions, aging, and in disease.

Next, Dr. Williams and colleagues describe multiple mechanisms to modulate neurovascular unit cells as a therapeutic modality for several CNS disorders with an emphasis on MS⁵. The authors describe the structure, organization, and functions of cells that make up the neurovascular unit, which includes endothelial cells, pericytes, astrocytes, microglia, and neurons. They then provide a cell-by-cell account of how these neurovascular unit cells are modulated by neuroinflammatory processes during disease. Understanding how cells that are part of the neurovascular unit function during various disease states to change the integrity of the blood-brain barrier may provide new insights into improving drug delivery to the CNS.

A fundamental aspect of immune surveillance is detecting and eliminating invading pathogens that can have potentially detrimental consequences to the health and integrity of the CNS. In the next review article, Dr. Shinohara and colleagues discuss the increasing importance of anti-fungal immunity due to the expanding prevalence of immunocompromising therapies and conditions⁶. To better understand the targetable molecules and pathways to combat CNS mycosis, the authors discuss mechanisms of fungal CNS invasion, the ability of resident and non-resident CNS cells to detect fungi, and highlight potential therapeutic targets.

Another very timely review by Dr. Bergmann and colleagues highlights other pathogens that have the potential to inflict permanent CNS damage: DNA and RNA viruses⁷. Although viral infections of the CNS are rare, treatment options are severely limited and often neurological sequelae are permanent and present a lifelong threat to hosts. B cells produce cerebrospinal fluid (CSF)-localized anti-viral antibodies; however, their pathogenic versus protective functions during viral infection are poorly understood. Here, the authors present a comprehensive discussion of viral and autoimmunity models to study intrathecal B cell immunity and the implications for human disease.

The SARS-CoV-2 global pandemic has put the importance of immunology research in the limelight like never before. While the field has come together to make astounding progress in both vaccine development as well as in the characterization of the immune response to this emerging pathogen, our knowledge of why some individuals develop long-lasting neurological symptoms post-infection still remains poorly understood. This has spurred renewed interest into how peripheral infections and systemic inflammation can impinge on neurological health. In the piece contributed by Petri and colleagues to this issue, they highlight recent insights into the neurological disease sequelae that can ensue as a result of SARS-CoV-2 infection⁸. In particular, they provide an authoritative review of existing knowledge regarding how SARS-CoV-2 infection affects olfactory neuroepithelium health and leads to anosmia in patients.

Following infection of the CNS, there are a number of alterations to immunity that are controlled by epigenetic modifications. Dr. Kielian and Zachary Van Roy give a comprehensive account of the specific epigenetic changes that unfold in immune cell populations during CNS infection and further summarize how these epigenetic modifications can impact immune cell activation and function⁹. The authors conclude by discussing the resolution of infection, highlighting the burgeoning field of immunometabolism, tools to further study epigenetics, and clinical implications. A deeper understanding of how epigenetic alterations shape the immune landscape during CNS pathogen invasion can have significant therapeutic implications for a number of infections that pose a significant threat to the CNS.

The study of neurodegenerative disease has emerged as arguably one of the most pressing biomedical research areas of our time. Neurodegenerative disorders, which include Alzheimer’s disease, ALS, and Parkinson’s disease, are devastating neurological conditions that are broadly characterized by neuronal cell death, neuroinflammation, and progressive loss of proper neurological function. Care for these conditions puts a tremendous financial and societal strain on our health care systems. With life expectancies and population sizes continuing to increase across the globe, there is mounting concern over the impact that neurodegenerative disease care may have on our medical and financial systems. Despite being extremely prevalent and debilitating in nature, we still, unfortunately, lack effective treatments to target the root causes of many neurodegenerative diseases. However, there is growing optimism over the promise that targeting the immune system may have in combating neurodegenerative disorders. Considerable progress in recent years has been made in defining how various arms of the immune system contribute to the neuronal cell death that underlies neurodegenerative disease progression. This was the focus of the article crafted by Dr. Chiu and colleagues for this special issue. In their piece, they provide an impressive and expansive overview of our current knowledge surrounding the involvement of various programmed cell death pathways in ALS¹⁰. In the closing of their review article, they also discuss the therapeutic potential of targeting cell death pathways and neuroinflammation as treatment strategies for ALS.

T cells have also been identified to be major drivers of neuronal demise in various neurological disease settings including MS. In the next article of the series, Dr. Alvarez and colleagues offer new insights into how CNS-intrinsic signals reshape T cell function in the context of demyelinating neuroinflammatory diseases such as MS¹¹. Many previous MS reviews have focused on how T cells impact CNS-resident cells. In contrast, the review by Alvarez and colleagues flips the script and provides a fresh take on how the CNS microenvironment, and astrocytes, in particular, modulate encephalitogenic T cell responses. Improved understanding of the bidirectional crosstalk between peripherally-derived immune cells and CNS-resident cells will be key to the development of improved strategies to treat MS and many other forms of neurological disease.

Until recently, the prevailing wisdom was that immune signaling is broadly deleterious to brain health. However, this paradigm has been torn down over the last years through a series of work clearly showing that the immune system plays beneficial roles in regulating brain homeostasis, cognition, and behavior. The unexpected involvement of immune cells and signaling pathways in CNS homeostasis, cognition, and behavior was spotlighted in two separate review articles contributed by Drs. Coulibaly and Filiano^12,13. Dr. Coulibaly discusses how peripherally-derived neutrophils can impact cognition and behavior in various contexts¹². In this article, Dr. Coulibaly also provides a valuable overview of the behavioral tests that can be leveraged by scientists to probe specific behavioral domains in experimental animal models. In the article by Dr. Filiano and colleagues, they put forth compelling theories to explain how IFN-γ/STAT1 signaling in neurons can paradoxically lead to both pathology and behavioral regulation¹³. More specifically, they postulate that differential IFN-γ/STAT1 activation and signaling in neurons molecularly underlie these divergent downstream outcomes. Mapping out the intricacies of neuronal IFN-γ/STAT1 signaling is of particular significance considering that this pathway has been centrally implicated in multiple neurodegenerative disorders as well as in the regulation of social behavior.

One of the fields of neuroimmunology that has grown the fastest over the last decade concerns how the immune system shapes brain development. Ever increasing evidence demonstrates that immune signaling is required for healthy brain maturation. Most notably, the innate immune system, and microglia, in particular, have emerged as key sculptors of brain circuitry and maturation¹⁴. While controlled immune activation is a prerequisite of healthy brain development, aberrant regulation of these immune responses during gestation can lead to altered CNS maturation and the development of behavioral abnormalities¹⁵. Indeed, dysregulated activation of the immune system during gestation has been increasingly linked to neurodevelopmental disorders such as autism spectrum disorder and schizophrenia¹⁶. This burgeoning area of neuroimmunology was the focus of the review article contributed by Antonson and colleagues in this special issue¹⁷. In their article, they draw special attention to the role that the gut-brain-microglia axis plays in neurodevelopmental disorders. They also stress the need for improved animal models to better recapitulate the complexity of human immune responses. More specifically, the majority of studies in this field to date have relied on the use of simple mimetics (e.g., polyinosinic:polycytidylic acid and lipopolysaccharide) that do not fully recapitulate the kinetics and intricacies of the immune response to live pathogens.

As previously mentioned, effective therapeutic strategies that target the root causes of disease do not exist for most neurological ailments. Another major challenge in the treatment of neurological diseases, especially those involving neurodegeneration, is that we lack sensitive diagnostics to detect early signs of disease pathogenesis. Most notably, by the time that most patients present with neurological symptoms, it is already too late, and irreversible damage has already occurred to the brain. Therefore, there is also a tremendous need to establish biomarkers that can aid in the early diagnosis of neurological diseases. The recent identification of the role of immune dysfunction in most major neurological diseases has led to great hope that immunomodulatory therapies will hold promise in the treatment and earlier diagnosis of neurological conditions. One specific immune molecule that has recently garnered significant interest as a potential therapeutic target and biomarker for CNS diseases is Osteopontin. This was the focus of the article contributed by Dr. Brown and colleagues in this special issue¹⁸. Here they highlighted the fascinating biochemistry of this multifunctional protein and discussed current evidence of its involvement in multiple brain conditions including CNS injury, NeuroHIV infection, and stroke, just to name a few. Overall, they provide a persuasive argument as to why Osteopontin is an especially attractive therapeutic target for a spectrum of neurological disorders.

Our understanding of neuroimmunology has been significantly expanded in recent years by the ever-increasing collaborations between immunologists and neuroscientists, but also by the incorporation of additional disciplines including, but certainly not limited to, microbiology, genetics, and vascular biology. The reviews in this collection represent the broad range of expertise that have made neuroimmunology such a diverse and fruitful field with the potential to have a meaningful impact on human disease.

Figure 1. The many facets of neuroimmunology during health and disease.

Neuroimmunology encompasses a broad and ever-expanding discipline that centers on the interactions between cells of the immune and central nervous systems. This crosstalk is critical for proper CNS development, surveillance, clearance of pathogens, and the resolution of inflammation. During aberrant inflammatory processes and neurodegeneration, local immune cell activation can lead to bystander tissue damage and devastating clinical consequences. While novel therapeutic modalities to treat these neuroinflammatory diseases are needed, the blood-brain barrier presents a unique challenge to therapeutic development and CNS targeting and is an ongoing area of investigation.