In patients with a clinical diagnosis of schizophrenia, the prevalence of known NSAbs is still rather low (approximately 4%), but this group of patients is extremely important to identify as other therapy options may be effective for these cases 22. The diagnosis of schizophrenia is currently based on a broad set of symptoms after exclusion of other known treatable diseases with similar clinical presentation. Antibodies against VGKC may confer a clinical picture with psychotic symptoms, movement disorder, amnesia, and seizures 20, 21. Antibodies to extracellular epitopes of NMDARs and the voltage gated potassium channel complex (VGKC), specifically to epitopes of CASPR2 and LGI1, have been the subject of numerous studies 15, 18, 19. However, a recent study has shown that GluN1 antibodies, independent of medical condition and immunoglobulin (Ig) class, are functional resulting in decreased GluN1 surface expression 16.Īdditional studies have shown that antibodies toward the NMDAR are also linked to psychiatric symptoms in neuropsychiatric systemic lupus erythematosus, where cross-reactivity between anti-DNA antibodies and the GluN2A subunit was reported 17. The diagnosis of NMDAR encephalitis is currently based on the presence of GluN1 antibodies in the cerebrospinal fluid (CSF) of patients. Where early work focused on patients with severe neurological conditions such as epilepsy 14, it is now clear that early stages of the disease may present a heterogeneous mix of psychiatric symptoms, such as anxiety, personality changes, and psychotic symptoms, including hallucinations and delusions 15. NSAbs are implicated in diseases such as limbic encephalitis including N-methyl- d-aspartate (NMDA) receptor encephalitis 11, 12 where they bind to extracellular epitopes of NMDA receptors (NMDARs) causing a dysfunction, leading to psychosis and other neurological phenotypes in these patients 13. It is of importance to be able to identify whether psychiatric patients suffer from NSAb-associated diseases since it will have a fundamental impact on the future for precision diagnosis and treatment as these patients usually respond well to immunotherapies 10. Diseases caused by autoantibodies binding to proteins in the central nervous system (CNS) are known as neuronal surface antibody (NSAb)-mediated diseases. The identification of brain reactive autoantibodies with potential pathological relevance in cases presenting with primarily psychiatric symptoms such as psychosis has opened a whole new research field 7, 8, 9. The concept that some cases of severe mental disorders such as schizophrenia might be caused by a chronic low-grade neuroinflammation was postulated by Bechter in the mild encephalitis hypothesis 6. Additional studies have indicated increased levels of cytokines such as interleukin-1 (IL-1) and IL-6, as well as transforming growth factor-β, in schizophrenia patients during acute psychotic episodes with decreasing levels during treatment, while levels of interferon-γ, tumor necrosis factor-α, IL-12, and soluble IL-2 receptor remained elevated irrespective of clinical treatment 4, 5. In recent years, several studies have reported high autoantibody titers in patients with schizophrenia 1, 2, 3. By further validating GluN2D and additional potential autoantigens, we will seek insights into how these are associated with severe mental illnesses. In a separate cohort with serum samples from 395 young adults with a wider spectrum of psychiatric disorders, higher levels of serum autoantibodies targeting GluN2D were found when compared to 102 control individuals. Among the detected autoantigens, higher IgG reactivity in subjects with schizophrenia, as compared to psychiatrically healthy subjects, was found against the glutamate ionotropic receptor NMDA type subunit 2D (anti-GluN2D). Tissue-based analysis of IgG reactivities using antigen suspension bead arrays was performed in a multiplex and parallel fashion for all 125 subjects. Based on these results of ours and other previous studies of autoantibodies related to psychosis, we selected 226 fragments with an average length of 80 amino acids, representing 127 unique proteins. Selected brain tissue lysates were first explored for IgG reactivity on planar microarrays composed of 11,520 protein fragments representing 10,820 unique proteins. This study applies an untargeted and a targeted affinity proteomics approach to explore and characterize the autoantibody repertoire in brain tissues from 73 subjects diagnosed with schizophrenia and 52 control subjects with no psychiatric or neurological disorders. In recent years, studies have shown higher prevalence of autoantibodies in patients with schizophrenia compared to healthy individuals.
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