A breakthrough study by a research team has identified a specific antibody target implicated in neuropsychiatric symptoms of lupus. These symptoms, including cognitive impairment, mood disorders, seizures, headaches and psychosis, are among the most prevalent manifestations of the disease and occur in as many as 80% of adults and 95% of children with lupus. The Lupus Foundation of America estimates that more than 1.5 million Americans and 5 million people worldwide suffer from some form of lupus, with 90% of cases affecting women. The study was published today in the Journal of Neuroscience.

The study identified antibodies that are directed at regulatory brain cytoplasmic RNAs (BC ribonucleic acid) that are unique to lupus patients. The 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 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.

In layman's terms, these antibodies disrupt these regulators of protein synthesis that allow synapses in the brain to control how they receive, store and recall information. Because these antibodies are unique in the brains of lupus patients, the study suggests that this is at the root of neuropsychiatric symptoms seen in these patients.

"Prior to this study, we poorly understood why lupus affects the brain in the way in which it does and causes neurocognitive symptoms," said Principle Investigator. "Because we could not treat the cause, the only alternative was for physicians to treat the symptoms with anti-inflammatory drugs, immunosuppressives and other therapies, depending on the how the brain was being affected."

According to the senior author, the discovery gives new insight into both how and why many lupus patients suffer from these symptoms, and, just as important, may well provide the basic understanding necessary for scientists to pursue effective treatments.

"Now that we appear to have an understanding of what is causing at least some of these neuropsychiatric affects, we can turn our attention to finding treatments that target the disease process itself and will block or repress these antibodies from causing the molecular disruptions."

"Women of color are three times more likely to be diagnosed with lupus and are much more likely to develop the disease at a younger age. Additionally, when diagnosed, women of color often have more serious complications and significantly higher death rates," said another author.

https://www.downstate.edu/news_releases/2019/08-12-2019.html

https://www.jneurosci.org/content/early/2019/08/12/JNEUROSCI.1657-18.2019