Pioneering discovery and therapeutics at the brain-vascular-immune interface, 2024, Katerina Akassoglou et al

Abstract
The brain-vascular-immune interface has emerged as a dynamic player in brain physiology and disease. We propose integrating vascular risk factors with genetic susceptibility as the nexus for the discovery of mechanisms and therapies for neuroinflammation, neurodegeneration, and neurorepair across polygenic neurologic diseases.

Main text
Brain-body communication governed by the immune and vascular systems has revolutionized our understanding of brain physiology, aging, and neurological diseases. Unanticipated cellular and molecular mechanisms and newly appreciated anatomical sites have been identified at the brain borders.

The integration of immune and vascular signals during brain homeostasis and disease remains an area of active investigation. Reciprocal interactions between the vascular and immune systems occur as immune mechanisms can alter vascular homeostasis, while blood and vascular signals can also instigate robust pathogenic immune programs in the brain.

Despite the discovery of new associations of immune and vascular genes with disease risk, these genetic variations are rare and cannot alone predict the onset and progression of neurological diseases, which are typically polygenic and sporadic.

In this Commentary, we discuss emerging mechanisms controlling brain-body communication at the neurovascular interface and highlight blood-induced inflammation as a common thread driving pathogenesis in diseases with diverse etiologies and genetic predispositions, including autoimmune, infectious, and neurodegenerative diseases as well as neurodevelopmental disorders. We propose integrating genetic susceptibility with immune triggers and vascular comorbidities as the nexus for the discovery of underlying mechanisms and new therapeutic targets. Finally, we conclude that interdisciplinary research integrating breakthrough technologies at the interface of immune and vascular systems will usher in a new era for discovery and therapies for neurological diseases.

Integrating genetic susceptibility with vascular risk factors
Polygenic neurological diseases with modest heritability, such as multiple sclerosis (MS) and Alzheimer’s disease (AD), generally involve gene variants associated with increased disease risk and multifaceted gene-environment interactions.

Low-risk and low-penetrance immune and vascular genetic loci have emerged among the most significant genetic associations with neurological diseases. These genetic loci are often common among other diseases and cannot predict who will develop the disease. For example, despite the discovery of over 250 genes associated with immune dysregulation in MS, the onset, disease course, and response to treatment remain unpredictable. In identical twins, the risk of developing MS increases by only ∼30% despite the same genetic risk between the healthy twin and the one with MS, suggesting that these genetic variations may not be causal and that an additional trigger is required for the development of the disease.

In late-onset AD, several of the low-risk loci identified in microglia are rare, occurring in less than 1% of patients. Higher-penetrance genes like APOE4 significantly increase risk, but AD can also develop in individuals without the APOE4 polymorphism. The vast majority of cases for many neurodegenerative diseases are sporadic, as they occur without family history or causal association to specific genetic variants, such as in AD, Parkinson’s disease, and amyotrophic lateral sclerosis.

Neurodevelopmental disorders with complex etiologies, such as autism, are governed by a multitude of genetic mutations and environmental triggers leading to a broad spectrum of differences in brain function. These findings support a model where a general risk is inherited, but additional epigenetic determinants and environmental exposures ultimately dictate the onset, severity, and progression of disease
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Conclusions
Neurovascular brain immunology has heralded the advent of multidisciplinary research integrating immunology and neuroscience with vascular biology and hematology to study the blood-brain-immune interface. Leveraging advances in genomics, imaging, and machine learning, this emerging field is poised to revolutionize our understanding of brain physiology and disease with paradigm-shifting discoveries at an unprecedented pace.

Rigorous preclinical studies and the development of experimental models of disease-relevant pathways and environmental exposures could be critical for dissecting neurovascular mechanisms in disease. Unraveling the causality of immune and vascular genes, epigenetic changes, and environmental triggers associated with disease onset and progression holds great promise for developing new therapies. Ultimately, integration of polygenic risk scores with environmental disease accelerators and clinical variables will be fundamental for ushering in a new era of precision immune and vascular therapies for CNS diseases.

In the coming decade, scientific breakthroughs at the blood-brain-immune interface will emerge from interdisciplinary collaborative networks of immunologists, neuroscientists, hematologists, geneticists, computer scientists, physicists, bioengineers, drug developers, and clinical researchers. These partnerships across academia, industry, foundations, and venture will catalyze innovation in drug discovery and transform medical practice for neurological diseases.