On our bookshelf is a monograph with a series of reviews from the 1950s edited by Marian Kies that provides a snapshot into the field of neuroinflammation some half a century ago. Kies discovered myelin basic protein in the 1950s and demonstrated that injection into rabbits induced what was called experimental allergic encephalitis, heralding the modern era of neuroimmunology. This issue of Seminars in Immunopathology now provides a state-of-the-art overview of where a field is, where it is going and how much has happened since T and B cells were discovered in 1965. We highlight recent advances in the field of neuroinflammation that has undergone incredible expansion over the past decade as we have better recognized the role of inflammation in neurologic diseases focusing on neuroimmune interactions in health and disease.

We now understand that there are fundamental contributions from cells of the innate immune system (e.g., microglia and macrophages) to many neurological diseases. As such, the field of neuroimmunology stands on the shoulders of the scientists who laid the framework for the innate immune system—giants like Ilya Mechnikov and Charles Janeway and continued in the work of Ruslan Medzhitov and others. Mechnikov discovered phagocytosis and made fundamental links between leukocyte migration and phagocytosis with host defense and tissue homeostasis. He also recognized links between the gut and microbiome and host immunity, all in the late 1800s. Fast forward almost 100 years, when Charlie Janeway laid the theoretical framework for the functioning of the innate immune system, the roles of pattern recognition receptors, and the links between innate immunity and the induction of the adaptive responses. Janeway and Medzhitov then continued this work in the discovery of human Toll-like receptor 4 and Medzhitov continues to advance our understanding of macrophages in tissue homeostasis and conceptual frameworks to understanding leukocyte and stromal cell interactions that control tissue fate during inflammation. The advances of these scientists and many others have provided the foundations for studies on neuroimmune interactions in homeostasis, aging, neurodegeneration, stroke, neuro-HIV, macular degeneration, and other diseases discussed in this issue.

One emerging theme over the past decade is the renewed interest in neuroimmune-microbiota interactions, i.e., the role of the gut microbiome in shaping systemic immune responses and particularly in the brain. This is of particular interest with recent data from several laboratories suggesting the T cells in the brain derive from the gut. Nguyen and Palm provide a comprehensive review of the historical context of gut-brain interactions and a framework for future research in diverse neurological diseases.1 Spilijar et al. discuss how differentiation, transcriptional regulation, and metabolic factors determine the function of CD4+ T cell subsets in CNS autoimmunity.2 They examine the critical role of metabolic reprogramming for activation and proliferation of T cells to meet bioenergetic demands. The authors focus on the critical T helper (Th)17/T regulatory (Treg) cell balance that can either promote or dampen autoimmune responses in the CNS and thus affect disease outcome. Future experiments will explore how the gut influences the metabolism of T cells in the CNS.

As a better understanding of relapsing clinical autoimmune demyelinating disease has been revealed, it has become clear that multiple sclerosis is a distinct disease from neuromyelitis optica (NMO) where autoantibodies reactive to a water channel protein aquaporin 4 (AQP4) is detected in patients that plays a key role in the disease’s pathology. Chihara et al. discuss the identification of possible targets of therapy, including complement pathway and interleukin-6 (IL-6) receptor signaling and highlight recent clinical trials showing the efficacy of antibodies specific for complement C5, IL-6 receptor, and CD19+ B cells in prevention of NMO spectrum disorder relapses.3

Critical roles for immunity have emerged in diseases previously not recognized as having an immune component. Narcolepsy, a disease characterized by excessive daytime sleepiness and cataplexy, is one example. Latorre et al. review the strong HLA gene polymorphisms found in GWAS studies of narcolepsy and the emerging data on autoreactive T cells against the hypothalamic hypocretin/orexin-producing neurons that regulate sleep.4 It has recently been recognized that inflammation plays a role in outcome after cerebrovascular diseases like ischemic stroke. DeLong et al. in this issue examine the initiation and resolution of the inflammatory responses after stroke with the complex impacts of leukocytes and microglia on outcomes.5

The most common neurodegenerative diseases of the elderly are Alzheimer’s disease (AD) and Parkinson’s disease (PD), both now recognized to have strong immune contributions to the pathophysiology. While both have different genetic components, aging is the strongest risk factor. There is a growing appreciation of the role the immune system plays in these neurodegenerative diseases. The review by Heavener et al. explored the intersection of aging and the immune system in AD and PD.6 While inflammation has a role in both diseases, recent data suggests that a subset of patients with PD may have an autoimmune disease where pathological α-synuclein propagates from the gut to the brain. The review by Zhu et al. describe immune responses in the pathogenesis of Parkinson’s disease where the innate immune responses triggered by microglia can cause neuronal death and disease progression.7 The review also examines the role that T cells infiltrating the brains of Parkinson’s disease patients and the role of α-synuclein reactive T cells. Macular degeneration is a neurodegenerative disease of the retina and one of the most common causes of blindness in the world. Dhodapkar et al. provide a review of the emerging role of microglia in the pathophysiology, highlighting glial-immune-neuron crosstalk leading to neuronal damage in this neurodegenerative disease.8 Another important topic around immune responses in the CNS is the concept of immune privilege. The review by Yoshida et al. explore the role of co-inhibitory receptors in limiting immune responses in the brain.9 Marx et al. explore the role of the immune system in glioblastoma and discuss the major pathways that inhibit T cell-mediated immunity against glioblastoma, with an emphasis on receptor–ligand systems by which glioma cells and recruited myeloid cells inhibit T cell function and the related challenges where glioblastomas tend to be poorly infiltrated by T cells caused by inhibitory molecular pathways.10 A conceptual framework for the development of immunotherapies is proposed.

In contrast to cancer and glioblastoma, Killingsworth et al. outline the neuropathogenesis of CNS viral infection by HIV from initial HIV entry into the CNS to chronic infection.11 The review explores how chronic HIV infection is maintained in the CNS and how the virus remains in a latent “hidden” state in diverse cells in the brain leading to sustained pathological inflammatory responses. This can lead to persist of HIV and associate with ongoing neuropathology including CD8+ T-lymphocyte-mediated encephalitis.

Finally, the realization that the immune system is involved with more than microbial responses and is deeply involved in organ homeostasis has greatly impacted our understanding of human physiology and biology. In both early neurodevelopment and adult neurogenesis, the ability to phagocytose unnecessary or dysfunctional cells is inextricably linked to the normal function of the brain. Mercau et al. review the molecularly triggered cell death pathways in the brain and the mechanisms of sensing and clearing dead cells in both homeostasis and disease.12 The observation that administration of type-I interferons can be clinically associated with depression and discovery that loss of interferon (IFN)γ cytokine secreting T cells can lead to alteration in rodent behavior and the role of microglia in synaptic pruning further suggesting a critical role of the CNS innate immune system in neural homeostasis.

In summary, deep mechanistic investigation of human diseases can provide unique insights into basic biologic processes. For example, the discovery that IFNγ secreting T cells are present in normal CNS9, discovered during investigation of multiple sclerosis, raises the fascinating idea that both the adaptive and innate immune system are integrally involved in neurodevelopment. Moreover, future investigations exploring the gut–immune–brain interactions may provide new insight into CNS inflammatory disease and physiologic processes in the brain.