8.2 HEALTHY AND IL NMDAR1 AUTOANTIBODY CARRIERS: FUNCTIONAL CONSEQUENCES DEPEND ON BLOOD-BRAIN-BARRIER INTEGRITY. (9th April 2019)

• Record Type: Journal Article
• Authors: Ehrenreich, Hannelore
• Is Part Of: Schizophrenia bulletin. Volume 45(2019)Supplement 2
• Page Start: S100
• Page End: S100
• Publication Date: 2019-04-09
• Subjects: Schizophrenia -- Periodicals; Schizophrenia -- Research -- Periodicals; 616.898005
• DOI: 10.1093/schbul/sbz022.029
• Languages: English
• ISSNs: 0586-7614

Abstract

Abstract: Background: Autoantibodies (AB) of the IgG class against N-methyl-D-aspartate-receptor subunit-NR1 (NMDAR1) were first described in anti-NMDAR encephalitis and seen as disease indicators. Recent work on together >5000 individuals challenged this exclusive view by showing age-dependently up to >20% NMDAR1-AB seroprevalence with comparable immunoglobulin (Ig) class and titer distribution, as well as epitopes across health and disease. This presentation will demonstrate that both experimental and clinical studies support the decisive role of the blood-brain-barrier (BBB) regarding functional consequences. Methods: Among others, sera of human NMDAR1-AB carriers (IgM, IgA, IgG), healthy or diagnosed with psychiatric diseases, hypertension, diabetes, or anti-NMDAR encephalitis were investigated regarding NMDAR1-AB epitopes. Other mammalian species were screened for serum NMDAR1-AB. For functionality screening, internalization assays upon NMDAR1-AB exposure were performed using human IPSC-derived cortical neurons. Active immunization of mice against 4 peptides of the extracellular NMDAR1 domain should help elucidate mechanisms of encephalitogenesis. Results: Only in situations of BBB disturbance, appreciable symptoms of NMDAR1 antagonism (ketamine-like effects) can be measured in NMDAR1-AB seropositive individuals. All NMDAR1-AB positive human sera, regardless of source (ill or healthy donor) and Ig class, provoked NMDAR1 internalization in human neurons and reduction of glutamate-evoked currents in NR1-1b/NR2-A-expressing Xenopus oocytes. They displayed frequently polyclonal epitope recognition in extracellular or intracellular NMDAR1 domains and some additionally in NR2-A. Notably, NMDAR1-AB belong to the normal autoimmune repertoire of dogs, cats, rats, mice, baboons and rhesus macaques, and are also functional in the NMDAR1-internalization assay. The age-dependence of seroprevalence is lost in non-human primates in captivity and human migrants, raising the intriguing possibility that chronic life stress may be related to NMDAR1-AB formation, predominantly of the IgA-class. Upon immunization against NMDAR1, the endogenously formed NMDAR1-AB (IgG) provoke psychosis-like symptoms under MK-801 challenge in ApoE-/- mice, characterized by an open BBB, but not in their ApoE+/+ littermates. Importantly, even upon BBB disruption, NMDAR1-AB do not induce any sign of brain inflammation on their own. Conclusions: All circulating NMDAR1-autoantibodies have pathogenic potential regarding the whole spectrum of neuronal NMDAR-mediated effects upon access to the brain in situations of increased BBB permeability. Even high titers of NMDAR1-AB of the IgG-class do not cause brain inflammation on their own.