Immunology seminars

Shimon Sakaguchi, Mary E. Brunkow and Fred Ramsdell explain how peripheral immune tolerance prevents the immune system from attacking the body. Sakaguchi follows the identification of regulatory T cells, the CD25 marker, and the relationship between central tolerance and active suppression of self-reactive cells. He considers how changing regulatory T-cell activity could support cancer treatment and transplantation. Brunkow describes genetic investigation of scurfy mice, identification of FOXP3, and the connection between mutations in this gene and human IPEX syndrome. The work establishes a molecular basis for the development and function of regulatory T cells. Ramsdell traces the move from these basic discoveries toward therapeutic strategies, including engineering a patient’s regulatory T cells to target inflammation in rheumatoid arthritis. He discusses early clinical investigation and the ambition of restoring immune balance; these approaches are presented as developing treatments rather than established cures.

Immune-mediated mechanisms are increasingly recognised as a cause of epilepsy even in the absence of an immune response against a specifical neuronal antigen. In some cases, these autoimmune processes are clearly pathogenic, for example acute seizures in autoimmune encephalitis, whereas in others this is less clear, for example autoimmune-associated epilepsy. Recent research has provided novel insights into the clinical, paraclinical and immunopathogenetic mechanisms in these conditions. I will provide an overview of clinical and paraclinical features of immune-associated seizures. Furthermore, I will describe specific immunopathogenic examples implicating lymphoid follicular autoimmunisation and intrathecal B cells in these conditions. These insights into immunopathogenesis may help to explain the role of current and immunotherapies in these conditions.

The neurovascular unit (NVU) consists of cerebral blood vessels, neurons, astrocytes, microglia, and pericytes. It plays a vital role in regulating blood flow and ensuring the proper functioning of neural circuits. Among other, this is made possible by the blood-brain barrier (BBB), which acts as both a physical and functional barrier. Previous studies have shown that dysfunction of the BBB is common in most neurological disorders and is associated with neural dysfunction. Our studies have demonstrated that BBB dysfunction results in the transformation of astrocytes through transforming growth factor beta (TGFβ) signaling. This leads to activation of the innate neuroinflammatory system, changes in the extracellular matrix, and pathological plasticity. These changes ultimately result in dysfunction of the cortical circuit, lower seizure threshold, and spontaneous seizures. Blocking TGFβ signaling and its associated pro-inflammatory pathway can prevent this cascade of events, reduces neuroinflammation, repairs BBB dysfunction, and prevents post-injury epilepsy, as shown in experimental rodents. To further understand and assess BBB integrity in human epilepsy, we developed a novel imaging technique that quantitatively measures BBB permeability. Our findings have confirmed that BBB dysfunction is common in patients with drug-resistant epilepsy and can assist in identifying the ictal-onset zone prior to surgery. Current clinical studies are ongoing to explore the potential of targeting BBB dysfunction as a novel treatment approach and investigate its role in drug resistance, the spread of seizures, and comorbidities associated with epilepsy.

Katalin Karikó and Drew Weissman explain the scientific development of messenger RNA as a therapeutic platform. Their lectures address why laboratory-produced RNA can trigger inflammatory responses and how modification of its nucleosides changes immune recognition and improves protein production. The programme connects those molecular findings with the practical challenges of making RNA stable and delivering it into cells, including lipid-nanoparticle formulations. It follows the development of modified mRNA from a difficult experimental material to a foundation for vaccines and other therapeutic strategies. The lectures cover both the discovery of the relevant RNA biology and the engineering needed to make that biology useful for inducing desired proteins and immune responses.

Epileptogenesis is a gradual and dynamic process leading to difficult-to-treat seizures. Several cellular, molecular, and pathophysiologic mechanisms, including the activation of inflammatory processes. The use of human brain tissue represents a crucial strategy to advance our understanding of the underlying neuropathology and the molecular and cellular basis of epilepsy and related cognitive and behavioral comorbidities, The mounting evidence obtained during the past decade has emphasized the critical role of inflammation in the pathophysiological processes implicated in a large spectrum of genetic and acquired forms of focal epilepsies. Dissecting the cellular and molecular mediators of the pathological immune responses and their convergent and divergent mechanisms, is a major requisite for delineating their role in the establishment of epileptogenic networks. The role of small regulatory molecules involved in the regulation of specific pro- and anti-inflammatory pathways and the crosstalk between neuroinflammation and oxidative stress will be addressed. The observations supporting the activation of both innate and adaptive immune responses in human focal epilepsy will be discussed and elaborated, highlighting specific inflammatory pathways as potential targets for antiepileptic, disease-modifying therapeutic strategies.

Caroline Williams-Gray is a Principal Research Associate in the Department of Clinical Neurosciences, University of Cambridge, and an honorary consultant neurologist specializing in Parkinson’s disease and movement disorders. She leads a translational research group investigating the clinical and biological heterogeneity of PD, with the ultimate goal of developing more targeted therapies for different Parkinson’s subtypes. Her recent work has focused on the theory that the immune system plays a significant role in mediating the heterogeneity of PD and its progression. Her lab is investigating this using blood and CSF -based immune markers, PET neuroimaging and neuropathology in stratified PD cohorts; and she is leading the first randomized controlled trial repurposing a peripheral immunosuppressive drug (azathioprine) to slow the progression of PD.

https://doi.org/10.1016/j.immuni.2022.10.005

https://www.cnsbordercellatlas.org/

https://doi.org/10.1016/j.neuron.2022.10.020

Genome-wide association studies and functional genomics studies have linked specific cell types, genes, and pathways to Alzheimer’s disease (AD) risk. In particular, AD risk alleles primarily affect the abundance or structure, and thus the activity, of genes expressed in macrophages, strongly implicating microglia (the brain-resident macrophages) in the etiology of AD. These genes converge on pathways (endocytosis/phagocytosis, cholesterol metabolism, and immune response) with critical roles in core macrophage functions such as efferocytosis. Here, we review these pathways, highlighting relevant genes identified in the latest AD genetics and genomics studies, and describe how they may contribute to AD pathogenesis. Investigating the functional impact of AD-associated variants and genes in microglia is essential for elucidating disease risk mechanisms and developing effective therapeutic approaches." https://doi.org/10.1016/j.neuron.2022.10.015

Recent studies have begun to reveal critical roles for the brain’s professional phagocytes, microglia, and their receptors in the control of neurotoxic amyloid beta (Aβ) and myelin debris accumulation in neurodegenerative disease. However, the critical intracellular molecules that orchestrate neuroprotective functions of microglia remain poorly understood. In our studies, we find that targeted deletion of SYK in microglia leads to exacerbated Aβ deposition, aggravated neuropathology, and cognitive defects in the 5xFAD mouse model of Alzheimer’s disease (AD). Disruption of SYK signaling in this AD model was further shown to impede the development of disease-associated microglia (DAM), alter AKT/GSK3β-signaling, and restrict Aβ phagocytosis by microglia. Conversely, receptor-mediated activation of SYK limits Aβ load. We also found that SYK critically regulates microglial phagocytosis and DAM acquisition in demyelinating disease. Collectively, these results broaden our understanding of the key innate immune signaling molecules that instruct beneficial microglial functions in response to neurotoxic material." https://doi.org/10.1016/j.cell.2022.09.030