Neuropsychiatric Lupus in B6.Nba2 Mice-A New Model to Study Behavioral Defects Associated with SLE
Abstract
A significant subset of patients (up to 80%) diagnosed with systemic lupus erythematosus (SLE) suffers from neuropsychiatric (NP) manifestations such as headache, fatigue, cognitive dysfunction, psychosis, and seizures. It has estimated that symptoms associated with a diagnosis of neuropsychiatric lupus (NPSLE) accounts for a cost of more than $30,000 per patient each year in the United States alone. No specific treatment is available for NPSLE patients, who are commonly treated only symptomatically, with standard immunosuppressive agents alone, which have unsafe numeral side-effect profiles, or in combination with anti-psychotic or anti-depressive agents commonly used for management of symptoms in non-SLE neurological diseases. Thus, investigations into the etiology of NPSLE with the goal of identifying new therapeutic targets are necessary. Recent studies in spontaneous mouse strains of SLE known to develop NPSLE-like manifestations have started to shed light on the underlying biology driving disease in lupus-prone mice. Although these studies have elegantly showed an association between elevated levels of type I interferons and the development of anxiety and cognitive dysfunction, the exact mechanism remains elusive. For example, the complex genetic background of these mice makes genetic studies time-consuming due to the extensive mouse breeding required and thus often not feasible. Thus new appropriate animal models are needed to further investigate and establish the involvement of key biological factors in driving disease development. We have recently discovered that the B6.Nba2 mouse model of SLE develops severe anxiety; a hallmark of NPSLE-like disease in lupus-prone mice. The B6.Nba2 mice offers a clear advantage in mouse NPSLE research as the strain exists on the most common non-autoimmune mouse genetic background (B6) making most gene-manipulated mouse models available for easy analysis. B6.Nba2 mice develop an SLE-like disease characterized by an overactive immune system, significant autoantibody production and kidney inflammation. Furthermore, this model depend on type I interferon, similarly the NZBWF1 models. As a concept, we propose here to establish the complete spontaneous NPSLE phenotype of B6.Nba2 mice. To do so, we will employ a number of behavioral analyses of our mouse model to establish the core deficiencies in this model. These will include repeat analyses of tests for anxiety and mobility, and the addition of more specific tests to evaluate if the mice exhibit depression and cognitive dysfunction. At the end of testing, we will visualize basic brain structures, brain resident and inflammatory cells, and cytokine levels in spinal fluid from the mice and correlate these parameters with behavioral results and the presence of standard SLE-like symptoms (serum autoantibodies, renal inflammation and IgG-immune complex deposition, immune cell hyper-activation profiles). Importantly, we will use both male and female mice for these studies to evaluate gene-hormone interactions in NPSLE. This is particularly important, as SLE-like disease in B6.Nba2 mice show a female predominance, similarly to human SLE patients. In order to generate preliminary data investigating the type I interferons in NPSLE-like disease in B6.Nba2 mice, we will also study mice in which the type I interferon receptor is depleted in specific cell subsets located either in the brain or in the immune system, to determine how type I interferons may play a role in driving NPSLE. The proposed studies fall under the specific Focus Area: “Understand how the underlying genetic components and gene-environment interactions of lupus relate to clinical disease characteristics using functional genomic studies” and will provide support for the establishment of a much needed new mouse model of NPSLE, in which genetic manipulation is easily achievable. Given the promising data on type I interferon receptor blockade in SLE patients and the potent
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910760
Entities
People
- Trine Jorgensen
Organizations
- Cleveland Clinic
- United States Army