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Neuronal BC RNA Transport Impairments Caused by Systemic Lupus Erythematosus Autoantibodies
- Source :
- The Journal of Neuroscience. 39:7759-7777
- Publication Year :
- 2019
- Publisher :
- Society for Neuroscience, 2019.
-
Abstract
- The etiology of the autoimmune disorder systemic lupus erythematosus (SLE) remains poorly understood. In neuropsychiatric SLE (NPSLE), autoimmune responses against neural self-antigens find expression in neurological and cognitive alterations. SLE autoantibodies often target nucleic acids, including RNAs and specifically RNA domains with higher-order structural content. We report that autoantibodies directed against neuronal regulatory brain cytoplasmic (BC) RNAs were generated in a subset of SLE patients. By contrast, anti-BC RNA autoantibodies (anti-BC abs) were not detected in sera from patients with autoimmune diseases other than SLE (e.g., rheumatoid arthritis or multiple sclerosis) or in sera from healthy subjects with no evidence of disease. SLE anti-BC abs belong to the IgG class of immunoglobulins and target both primate BC200 RNA and rodent BC1 RNA. They are specifically directed at architectural motifs in BC RNA 5′ stem–loop domains that serve as dendritic targeting elements (DTEs). SLE anti-BC abs effectively compete with RNA transport factor heterogeneous nuclear ribonucleoprotein A2 (hnRNP A2) for DTE access and significantly diminish BC RNA delivery to synapto-dendritic sites of function.In vivoexperiments with male BALB/c mice indicate that, upon lipopolysaccharide-induced opening of the blood–brain barrier, SLE anti-BC abs are taken up by CNS neurons where they significantly impede localization of endogenous BC1 RNA to synapto-dendritic domains. Lack of BC1 RNA causes phenotypic abnormalities including epileptogenic responses and cognitive dysfunction. The combined data indicate a role for anti-BC RNA autoimmunity in SLE and its neuropsychiatric manifestations.SIGNIFICANCE STATEMENTAlthough clinical manifestations of neuropsychiatric lupus are well recognized, the underlying molecular–cellular alterations have been difficult to determine. We report that sera of a subset of lupus patients contain autoantibodies directed at regulatory brain cytoplasmic (BC) RNAs. These antibodies, which we call anti-BC abs, target the BC RNA 5′ domain noncanonical motif structures that specify dendritic delivery. Lupus anti-BC abs effectively compete with RNA transport factor heterogeneous nuclear ribonucleoprotein A2 (hnRNP A2) for access to BC RNAs. As a result, hnRNP A2 is displaced, and BC RNAs are impaired in their ability to reach synapto-dendritic sites of function. The results reveal an unexpected link between BC RNA autoantibody recognition and dendritic RNA targeting. Cellular RNA dysregulation may thus be a contributing factor in the pathogenesis of neuropsychiatric lupus.
- Subjects :
- Male
0301 basic medicine
RNA transport
Biology
medicine.disease_cause
Autoantigens
RNA Transport
Autoimmunity
Mice
03 medical and health sciences
0302 clinical medicine
RNA, Small Cytoplasmic
medicine
Animals
Humans
Lupus Erythematosus, Systemic
Research Articles
Autoantibodies
Neurons
Mice, Inbred BALB C
Systemic lupus erythematosus
General Neuroscience
Multiple sclerosis
Autoantibody
Brain
RNA
medicine.disease
030104 developmental biology
Immunology
Nucleic acid
biology.protein
Female
Antibody
030217 neurology & neurosurgery
Subjects
Details
- ISSN :
- 15292401 and 02706474
- Volume :
- 39
- Database :
- OpenAIRE
- Journal :
- The Journal of Neuroscience
- Accession number :
- edsair.doi.dedup.....83b44733e7d48f90fdd84646599b5bc4
- Full Text :
- https://doi.org/10.1523/jneurosci.1657-18.2019