Abstract
The etiology of psychotic disorders is still unknown, but in a subgroup of patients symptoms might be caused by an autoimmune reaction. In this study, we tested patterns of autoimmune reactivity against potentially novel hippocampal antigens. Serum of a cohort of 621 individuals with psychotic disorders and 257 controls were first tested for reactivity on neuropil of rat brain sections. Brain reactive sera (67 diseased, 27 healthy) were further tested for antibody binding to glutamic acid decarboxylase (GAD) isotype 65 and 67 by cell-based assay (CBA). A sub-cohort of 199 individuals with psychotic disorders and 152 controls was tested for the prevalence of anti-nuclear antibodies (ANA) on HEp2-substrate as well as for reactivity to double-stranded DNA, ribosomal P (RPP), and cardiolipin (CL). Incubation of rat brain with serum resulted in unidentified hippocampal binding patterns in both diseased and control groups. Upon screening with GAD CBA, one of these patterns was identified as GAD65 in one individual with schizophrenia and also in one healthy individual. Two diseased and two healthy individuals had low antibody levels targeting GAD67 by CBA. Antibody reactivity on HEp-2-substrate was increased in patients with schizoaffective disorder, but only in 3 patients did antibody testing hint at a possible diagnosis of systemic lupus erythematosus. Although reactivity of serum to intracellular antigens might be increased in patients with psychotic disorder, no specific targets could be identified. GAD antibodies are very rare and do not seem increased in serum of patients with psychotic disorders.
Highlights
Much attention has been drawn to the role of autoantibodies targeting neuronal surface antigens (NSAbs) in the brain of patients with autoimmune encephalitis who often present with psychosis
Enzyme Linked Immunosorbent Assay (ELISA) or line immune assays (LIAs) were performed to test for the presence of extractable nuclear antigens (ENA), dsDNA, CL and Ribosomal P protein (RPP) autoantibodies. To this end an ELISA plate was pre-coated with the respective antigen(s): ENA (collectively detects, in one well, total ENAs against dsDNA, nDNA, histones, SS-A(Ro), SS-B(La), Sm, Sm/RNP, Scl-70, Jo-1, and centrometric antigens, ImmuLisaTM Enhanced anti-nuclear antibodies (ANA) Screen ELISA, catalog # 5175), dsDNA (ImmuLisaTM Double stranded DNA antibody Enhanced ELISA, #5120), RPP (IMMULisa Ribosomal P, # 4133), or CL (ImmuLisaTM Cardiolipin IgG, IgA and IgM antibody(ACA) Enhanced ELISAs, #5118G, #5118A and #5118M)
As glutamic acid decarboxylase (GAD) is an antigen that is related to neurological syndromes with gamma amino-butyric acid (GABA) disturbances, we extended our antigen-specific screening of all sera that were graded 1–3 and with cell-based assay (CBA) testing for GAD65 and GAD67 reactivity
Summary
Much attention has been drawn to the role of autoantibodies targeting neuronal surface antigens (NSAbs) in the brain of patients with autoimmune encephalitis who often present with psychosis. One of the proteins targeted is the N-methyl-D-aspartate receptor (NMDAR) causing patients to develop characteristic neurologic and psychiatric symptoms (Dalmau et al, 2011). It is clinically important that these diseases respond very well to immunosuppressive treatment indicating that any neuronal damage might be largely reversible (Graus et al, 2016; Varley et al, 2017; Zandi et al, 2014). Autoantibodies against NMDAR and five other neuronal surface antigens in patients with a broad diagnostic spectrum of psychotic disorders were found to be absent after careful cross-validation to eliminate false positives (de Witte et al, 2015; Hoffmann et al, 2019)
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