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.

Keywords: NMDA receptor; Sydenham’s chorea; autoantibodies; autoimmune encephalitis; basal ganglia encephalitis; blood–brain barrier; dopamine receptor; pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections.

Figure 1

Comparison of mouse pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS)/Sydenham’s chorea (SC) models. (A) Schematic representing the initiation of the intranasal model, where mice receive live bacteria intranasally once a week for 5 weeks prior to sacrifice. (B) Subcutaneous GAS exposure involves adjuvant and antigen exposure three times, every 2 weeks, following an initial boost with intravenous pertussis toxin. (C) Comparison of immune, neural, and behavioral outcomes after each route of GAS exposure. Investigators have used either subcutaneous or intranasal routes to induce an immune response against S. pyogenes [Group A Streptococcus (GAS)] in efforts to understand the mechanisms underlying the behavioral and motor symptoms characteristic of PANDAS and SC patients. The former route necessitates opening the blood–brain barrier (BBB) artificially using B. pertussis toxin, whereas the latter features intranasal inhalation of live bacteria to trigger a Th17 response in nasal tissue that is directly communicated to the brain along the olfactory nerve.

Figure 2

T cells originating in the nose infiltrate the brain parenchyma. In a mouse model for pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections, T cells first arise in the nasal-associated lymphoid tissue and olfactory epithelium at the site of a latent S. pyogenes infection. These cells then respond to chemotactic cues release by olfactory ensheathing glia to accompany sensory axons into the brain. Once there, infiltrating T cells release inflammatory cytokines and chemokines, damaging synapses within olfactory glomeruli and breaking down tight junctions of olfactory bulb capillaries. These T cells may then move centrally, against the rostral migratory stream and toward the SVZ, and exit through the ventricles, or continue following the projections of olfactory mitral/tufted neurons.

Figure 3

Antibody and immune cell access to the brain parenchyma via four distinct routes. (A) Systemic cytokines break down tight junctions (TJs) within the brain–cerebrospinal fluid barrier to allow central nervous system (CNS) access of antibodies or immune cells. (B) Olfactory ensheathing glia facilitate transport of IgGs or immune cells along sensory axons exiting the olfactory mucosa. (C) Inflammatory cytokines in the bloodstream damage TJs between endothelial cells, thus allowing antibodies or immune cells (T or B cells) to enter the CNS. (D) F_c receptor directionality reverses, shuttling IgG from vessels into brain parenchyma as in systemic lupus erythematosus.