Therapeutic Inhibition of the Complement System in Diseases of the Central Nervous System.

Sarah M Carpanini,Bryan Paul Morgan,Megan Torvell

doi:10.3389/fimmu.2019.00362

Sarah M Carpanini, Bryan Paul Morgan + Show 1 more

Open Access

https://doi.org/10.3389/fimmu.2019.00362

Copy DOI

Abstract

The complement system plays critical roles in development, homeostasis, and regeneration in the central nervous system (CNS) throughout life; however, complement dysregulation in the CNS can lead to damage and disease. Complement proteins, regulators, and receptors are widely expressed throughout the CNS and, in many cases, are upregulated in disease. Genetic and epidemiological studies, cerebrospinal fluid (CSF) and plasma biomarker measurements and pathological analysis of post-mortem tissues have all implicated complement in multiple CNS diseases including multiple sclerosis (MS), neuromyelitis optica (NMO), neurotrauma, stroke, amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). Given this body of evidence implicating complement in diverse brain diseases, manipulating complement in the brain is an attractive prospect; however, the blood-brain barrier (BBB), critical to protect the brain from potentially harmful agents in the circulation, is also impermeable to current complement-targeting therapeutics, making drug design much more challenging. For example, antibody therapeutics administered systemically are essentially excluded from the brain. Recent protocols have utilized “Trojan horse” techniques to transport therapeutics across the BBB or used osmotic shock or ultrasound to temporarily disrupt the BBB. Most research to date exploring the impact of complement inhibition on CNS diseases has been in animal models, and some of these studies have generated convincing data; for example, in models of MS, NMO, and stroke. There have been a few recent clinical trials of available anti-complement drugs in CNS diseases associated with BBB impairment, for example the use of the anti-C5 monoclonal antibody (mAb) eculizumab in NMO, but for most CNS diseases there have been no human trials of anti-complement therapies. Here we will review the evidence implicating complement in diverse CNS disorders, from acute, such as traumatic brain or spine injury, to chronic, including demyelinating, neuroinflammatory, and neurodegenerative diseases. We will discuss the particular problems of drug access into the CNS and explore ways in which anti-complement therapies might be tailored for CNS disease.

Highlights

The Central Nervous System (CNS) as a Distinct EnvironmentThe CNS was, for a long time, considered an immunologically privileged organ because the brain and spinal cord are protected from circulating inflammagens by the blood-brain barrier (BBB)
The healthy BBB forms early in development and restricts the infiltration of circulating immune cells into the brain parenchyma; the dominant immune cells of the brain are the resident macrophage population—microglia (Figure 1B). This self-renewing [4], yolk sac-derived population develops within the CNS [5,6,7] and differs in many respects from macrophage populations found in the periphery [8,9,10]
mannose-binding lectin (MBL)−/− mice were protected from neurological injury following Traumatic Brain Injury (TBI) [70]; in contrast, another reported that MBL−/− mice showed increased levels of degenerating neurons in the hippocampus CA3 region and impaired performance in nonspatial learning tasks [71]

Summary

INTRODUCTION

The CNS was, for a long time, considered an immunologically privileged organ because the brain and spinal cord are protected from circulating inflammagens by the BBB. TBI can cause diffuse or focal damage to the brain tissue and blood vessels depending on the type of injury Subsequent to this primary injury, the BBB becomes compromised and there is a huge influx of cells, inflammatory mediators and plasma proteins, including complement proteins, that drive the delayed secondary inflammation, which is the major determinant of clinical outcome and recovery and survival [44]. MBL−/− mice were protected from neurological injury following TBI [70]; in contrast, another reported that MBL−/− mice showed increased levels of degenerating neurons in the hippocampus CA3 region and impaired performance in nonspatial learning tasks [71] Despite several such inconsistencies, the studies to date suggest that deficiencies of individual complement proteins of the classical, alternative or terminal pathway improves outcome after TBI.

C1q C3 C4 C5aR1

CONCLUDING REMARKS