The Role of Brain-Reactive Autoantibodies in Brain Pathology and Cognitive Impairment

Abstract

Antibodies to different brain proteins have been recently found to be associated with an increasing number of different autoimmune diseases. They need to penetrate the blood-brain barrier (BBB) in order to bind antigens within the central nervous system (CNS). They can target either neuronal or non-neuronal antigen and result in damage either by themselves or in synergy with other inflammatory mediators. Antibodies can lead to acute brain pathology, which may be reversible; alternatively, they may trigger irreversible damage that persists even though the antibodies are no longer present. In this review, we will describe two different autoimmune conditions and the role of their antibodies in causing brain pathology. In systemic lupus erythematosus (SLE), patients can have double stranded DNA antibodies that cross react with the neuronal N-methyl-d-aspartate receptor (NMDAR), which have been recently linked to neurocognitive dysfunction. In neuromyelitis optica (NMO), antibodies to astrocytic aquaporin-4 (AQP4) are diagnostic of disease. There is emerging evidence that pathogenic T cells also play an important role for the disease pathogenesis in NMO since they infiltrate in the CNS. In order to enable appropriate and less invasive treatment for antibody-mediated diseases, we need to understand the mechanisms of antibody-mediated pathology, the acute and chronic effects of antibody exposure, if the antibodies are produced intrathecally or systemically, their target antigen, and what triggers their production. Emerging data also show that in utero exposure to some brain-reactive antibodies, such as those found in SLE, can cause neurodevelopmental impairment since they can penetrate the embryonic BBB. If the antibody exposure occurs at a critical time of development, this can result in irreversible damage of the offspring that persists throughout adulthood.

Keywords: autoantibodies; blood–brain barrier; brain; cognition; maternal antibodies; neuromyelitis optica; systemic lupus erythematosus.

Figure 1

Upon penetration of anti-DNA/anti-NMDA receptor antibodies (DNRAbs) into the central nervous system through the impaired blood–brain barrier, the antibodies trigger two different pathomechanisms dependent on the antibody concentration. At high concentrations (continuous line), the antibodies lead to mitochondrial stress and leads to neuronal apoptosis through receptors containing GluN2A. If the neuronal loss occurs in the hippocampus, the antibody binding results in spatial memory impairment and cognitive dysfunction. Binding of antibodies in the amygdala affects the stress response. At lower concentrations (dotted line), antibody binding results in altered synaptic function.

Figure 2

Upon penetration of aquaporin-4 (AQP4) antibodies to the central nervous system, possibly through the help of pathogenic T cells, AQP4 antibodies can lead to astrocyte impairment either through complement-dependent cellular cytotoxicity (CDCC), antibody-dependent cytotoxicity (ADCC), or through downregulation of AQP4. Inflammation might occur prior to or secondary to antibody penetration. Ultimately, oliogdendrocytes are affected resulting in demyelination and neuronal loss.