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Sweet and low—autoantibodies deny oligodendrocytes their sugar fix

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Science Immunology  05 Jun 2020:
Vol. 5, Issue 48, eabd0546
DOI: 10.1126/sciimmunol.abd0546

Abstract

Pathogenic autoantibodies causing encephalopathy modify the expression of the glucose transporter in oligodendrocytes.

In the book Brain on Fire, author Susannah Cahalan describes her hospitalization for presumed psychosis and potential violent behavior. Initial diagnoses focused on a primary psychiatric disturbance. However, pathology was deemed immune-based. Autoantibodies targeting the N-methyl-D-aspartate receptor (NMDAR) were causing encephalopathy. These autoantibodies target the GluN1 subunit, causing receptor internalization in neurons, leading to encephalitis and psychiatric symptomatology. Reduced NMDAR expression results in glutamatergic dysregulation, causing an inhibitory response. This deficit in neuronal signaling affects both pre- and post-synaptic Ca+2 neurotransmission, shifting synaptic plasticity and excitation.

Imaging studies of NMDAR encephalitis patients demonstrate that myelinated white matter integrity can be compromised, thus questioning whether NMDAR involvement extends beyond neurons. The myelin sheath, made by oligodendrocytes, protects neuronal axons and supports the metabolic function of neurons by supplying lactate. Oligodendrocytes express the glucose transporter GLUT1, a key component for neuronal glycolytic support. Matute et. al. investigated whether the pathogenic capacity of NMDAR autoantibodies includes targeting of oligodendrocytes. Cerebrospinal fluid (CSF) of patients with anti-NMDAR encephalitis harboring autoantibodies was tested with cultured oligodendrocytes to measure decreased Ca+2 response to NMDA. They first showed that NMDA activates robust expression of GLUT1 on oligodendrocytes in a NMDAR-dependent manner. They then showed that the addition of patient, but not control CSF, inhibited the GLUT1 expression. These findings indicate that the pathogenic mechanisms of NMADR autoantibodies are diverse and that they affect a number of cell types.

NMDAR-mediated encephalitis and other autoimmune encephalidities were previously thought to be psychiatric disorders; however, we now understand that many are autoimmune-focused, thus shifting this paradigm and calling to question other primary psychiatric entities and their pathologic etiology. The inflammatory and immunologic characterization of psychiatric disorders is well underway, with schizophrenia among the most widely studied. As such, the term “autoimmune psychosis” has gained popularity, as acute psychosis is frequently accompanied by neurological symptomatology. This raises suspicion for whether these etiologies might be parainfectious, autoimmune, inflammatory, and/or paraneoplastic despite lack of autoantibody identification. The ongoing identification and mechanistic characterization of these autoantibodies promises to better focus treatment and shift the understanding of acute psychiatric illness.

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