Neuronal BC RNA Transport Impairments Caused by Systemic Lupus Erythematosus Autoantibodies

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 5Ј 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 vivo experiments 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.

Brain Cytoplasmic RNAs in Neurons: From Biosynthesis to Function

“…Muslimov and colleagues recently reported that the mislocalization of BC RNAs is also associated with SLE [38]. Researchers confirmed the production of antibodies that recognize BC200 RNA in SLE patients and named them anti-BC abs.…”

“…In 2019, a study by Muslimov et al confirmed that the dendritic localization of BC200 RNA was severely impaired in the autoimmune disease systemic lupus erythematosus (SLE) [38]. They further detected specific antibodies against BC200 RNA in the serum of SLE patients and found that the antibody competitively inhibited binding to hnRNP A2.…”

“…This gene is derived from a monomeric Alu element and the transcript has a poly A region similar to BC1 RNA, but the overall sequences are very different [31,36]. However, research over the past three decades has confirmed that BC1 and BC200 RNA are functional analogues that perform the same function in each neuron through key common motifs including the GA kink motif, the poly A region, and the C-loop motif ( Figure 2) [32,[37][38][39].…”

hnRNP A/B Proteins: An Encyclopedic Assessment of Their Roles in Homeostasis and Disease

“…In animal models for both MS and RA, antibodies to A1 and A2/B1, respectively, exacerbate disease. Autoantibodies, including those targeting A1 and A2/B1, have been shown to be internalized within cells of the central nervous system and interact with their intracellular protein targets [ 217 , 218 , 219 ]. MS autoantibodies to A1 in neurons primarily target its M9 nuclear localization sequence [ 210 ], localizing with SGs and trapping A1 in the cytoplasm, and ultimately preventing it from carrying out essential nuclear functions and resulting in neuronal cell death.…”

The noncoding RNA BC200 associates with polysomes to positively regulate mRNA translation in tumor cells

“…BC200 (Brain cytoplasmic RNA 1, BCYRN1) is a 200-nt anthropoid primate-specific monomeric Alu RNA that is abundantly expressed in the brain ( 6 , 7 , 8 , 9 ). In a similar manner to its rodent counterpart BC1, BC200 is postulated to regulate localized translation in neuronal dendrites ( 10 , 11 ). BC1 is a 143-nt transcribed ID element, a type of SINE found in variable numbers of copies among rodent species ( 12 ).…”