Session Title: SLE – Clinical Poster I: Epidemiology & Pathogenesis – ARP
Session Type: Poster Session (Sunday)
Session Time: 9:00AM-11:00AM
Background/Purpose: In systemic lupus erythematosus (SLE), autoantibodies are often directed against nucleic acids or their binding proteins. Regulatory Brain-specific Cytoplasmic (BC) RNAs operate as translational regulators at neuronal synapses. BC RNAs are transported to synapto-dendritic sites of function by heterogeneous nuclear ribonucleoprotein A2 (hnRNP A2). Dysregulation of BC RNA control has been associated with cognitive impairment and epilepsy. Here we hypothesize that transport-specifying structural motifs in BC RNAs can become targets of autoimmune reactivity in neuropsychiatric SLE.
Methods: We collected sera from 69 patients diagnosed with SLE. Sera from non-SLE human (n = 38) subjects were collected as follows: healthy subjects (HS), patients with rheumatoid arthritis (RA), and patients with multiple sclerosis (MS). IgG was purified from sera using Protein A/G and Protein G spin columns (Nab Spin Kit, Thermo Fisher Scientific). BC RNA transcripts were generated by in vitro transcription (Promega). RNA-protein interactions were analyzed by electrophoretic mobility shift assays (EMSAs). Microinjection transport analysis was performed with sympathetic neurons in primary. BALB/c mice were used for in situ hybridization. Quantitative and statistical analysis was performed with Prism (Graphpad) and SPSS Statistics.
Results: Autoantibodies against BC RNAs (anti-BC abs) were detected in a subset of lupus patient sera. Strength of SLE anti-BC autoimmune reactivity and occurrence of neuropsychiatric manifestations correlated strongly (Spearman’s rs = 0.89, P < 0.0001, n = 69). Anti-BC abs were not detected in sera from RA or MS patients or in sera from HS. RNA transport experiments were performed as follows. Following preincubation with IgGs, radiolabeled BC RNAs were injected into sympathetic neurons in primary culture. Preincubation with SLE IgG SLE, but not with non-SLE IgG, significantly reduced dendritic delivery of BC RNAs (one-way ANOVA, P < 0.0001). In a second set of experiments, we bath-applied IgGs to sympathetic neurons in culture prior to microinjection of BC RNAs. Bath application of SLE IgG, but not of non-SLE IgG, resulted in significantly reduced dendritic targeting of BC RNAs (P < 0.0001). In vivo experiments showed that SLE IgG, but not non-SLE IgG, prevented endogenous BC1 RNA from localizing to pyramidal cell dendrites in hippocampal CA1 (Dunnett’s test stratum pyramidale vs. strata oriens and radiatum: P < 0.0001). SLE anti-BC abs were specifically directed at BC RNA structural motifs that serve as dendritic targeting elements (DTEs). Interaction of SLE anti-BC abs with such motifs caused displacement of RNA transport factor hnRNP A2 from BC RNAs. As a result, SLE anti-BC abs significantly reduced BC RNA dendritic targeting.
Conclusion: Our findings demonstrate that lupus anti-BC abs effectively compete with hnRNP A2 for DTE access and significantly diminish BC RNA delivery to synapto-dendritic destination sites. Lack of BC RNA causes phenotypic abnormalities including cognitive impairment and epileptogenic responses. The combined data indicate a role of anti-BC RNA autoimmunity in SLE and its neuropsychiatric manifestations.
To cite this abstract in AMA style:MUSLIMOV I, IACOANGELI A, EOM T, RUIZ A, LEE M, STEPHENSON S, Ginzler E. Neuronal BC RNAs: Systemic Lupus Erythematosus Autoantibodies Cause Dendritic Transport Impairments [abstract]. Arthritis Rheumatol. 2019; 71 (suppl 10). https://acrabstracts.org/abstract/neuronal-bc-rnas-systemic-lupus-erythematosus-autoantibodies-cause-dendritic-transport-impairments/. Accessed April 13, 2021.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/neuronal-bc-rnas-systemic-lupus-erythematosus-autoantibodies-cause-dendritic-transport-impairments/