Hello from the Other Side: How Autoantibodies Circumvent the Blood–Brain Barrier in Autoimmune Encephalitis

Abstract

Antibodies against neuronal receptors and synaptic proteins are associated with autoimmune encephalitides (AE) that produce movement and psychiatric disorders. In order to exert their pathological effects on neural circuits, autoantibodies against central nervous system (CNS) targets must gain access to the brain and spinal cord by crossing the blood–brain barrier (BBB), a tightly regulated gateway formed by endothelial cells lining CNS blood vessels. To date, the pathogenic mechanisms that underlie autoantibody-triggered encephalitic syndromes are poorly understood, and how autoantibodies breach the barrier remains obscure for almost all AE syndromes. The relative importance of cellular versus humoral immune mechanisms for disease pathogenesis also remains largely unexplored. Here, we review the proposed triggers for various autoimmune encephalopathies and their animal models, as well as basic structural features of the BBB and how they differ among various CNS regions, a feature that likely underlies some regional aspects of autoimmune encephalitis pathogenesis. We then discuss the routes that antibodies and immune cells employ to enter the CNS and their implications for AE. Finally, we explore future therapeutic strategies that may either preserve or restore barrier function and thereby limit immune cell and autoantibody infiltration into the CNS. Recent mechanistic insights into CNS autoantibody entry indicate promising future directions for therapeutic intervention beyond current, short-lived therapies that eliminate circulating autoantibodies.

In vivo CRISPRa decreases seizures and rescues cognitive deficits in a rodent model of epilepsy

“…Although in this study a non-mammalian nuclease has been used, which can evoke an immune response in the primate CNS (Samaranch et al, 2014), CNS disorders attributable to antibodies against nuclear neuronal proteins are rare, and rare forms of autoimmune encephalitis generally involve membrane proteins (Platt et al, 2017). The doxycycline transactivator protein could also potentially evoke an immune response, although new inducible systems are in consideration for clinical translation (Das et al, 2016;Kundert et al, 2019).…”

Evaluation of the Cunningham Panel™ in pediatric autoimmune neuropsychiatric disorder associated with streptococcal infection (PANDAS) and pediatric acute-onset neuropsychiatric syndrome (PANS): Changes in antineuronal antibody titers parallel changes in patient symptoms

“…Other clinical reports have been published showing effective utilization of immunomodulatory treatment for autoimmune encephalitis based upon the presence of antineuronal antibodies directed against NMDA receptor (Dalmau et al, 2017), voltage-gated potassium channel-complex (VGKC) (Vincent et al, 2011), leucine-rich glioma inactivated-1 (LGI1), astrocyte aquaporin-4 (AQP4) (Zekeridou and Lennon, 2015), glutamic acid decarboxylase (GAD65), gamma-aminobutyric acid-B receptor (GABAB), and others (Mader et al, 2017;Platt et al, 2017;Mohammad and Dale, 2018;Lancaster, 2016;Dale et al, 2017). It is plausible there could be additional antineuronal antibody targets that lead to symptoms of autoimmune encephalitis.…”

Caveolin1 Is Required for Th1 Cell Infiltration, but Not Tight Junction Remodeling, at the Blood-Brain Barrier in Autoimmune Neuroinflammation

“…During CNS autoimmune diseases, leukocytes migrate across several pathways to reach the CNS parenchyma. These include a vascular route through the blood-brain barrier (BBB)/blood-spinal cord barrier (BSCB), the blood-cerebrospinal fluid route through an epithelial barrier present in the choroid plexus and the meningeal lymphatic route on the surface of the brain (Daneman and Engelhardt, 2017; Louveau et al, 2017; Platt et al, 2017). The BBB is characterized by impermeable tight junctions (TJ) and reduced transcellular transcytosis (Lampugnani et al, 2015; Reese and Karnovsky, 1967).…”