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      A20/ TNFAIP3 heterozygosity predisposes to behavioral symptoms in a mouse model for neuropsychiatric lupus

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          Abstract

          Background

          Neuropsychiatric lupus (NPSLE) refers to the neurological and psychiatric manifestations that are commonly observed in patients with systemic lupus erythematosus (SLE). An important question regarding the pathogenesis of NPSLE is whether the symptoms are caused primarily by CNS-intrinsic mechanisms or develop as a consequence of systemic autoimmunity. Currently used spontaneous mouse models for SLE have already contributed significantly to unraveling how systemic immunity affects the CNS. However, they are less suited when interested in CNS primary mechanisms. In addition, none of these models are based on genes that are associated with SLE. In this study, we evaluate the influence of A20, a well-known susceptibility locus for SLE, on behavior and CNS-associated changes in inflammatory markers. Furthermore, given the importance of environmental triggers for disease onset and progression, the influence of an acute immunological challenge was evaluated.

          Methods

          Female and male A20 heterozygous mice (A20 +/−) and wildtype littermates were tested in an extensive behavioral battery. This was done at the age of 10±2weeks and 24 ​± ​2 weeks to evaluate the impact of aging. To investigate the contribution of an acute immunological challenge, LPS was injected intracerebroventricularly at the age of 10±2weeks followed by behavioral analysis. Underlying molecular mechanisms were evaluated in gene expression assays on hippocampus and cortex. White blood cell count and blood-brain barrier permeability were analyzed to determine whether peripheral inflammation is a relevant factor.

          Results

          A20 heterozygosity predisposes to cognitive symptoms that were observed at the age of 10 ​± ​2 weeks and 24 ​± ​2 weeks. Young A20 +/− males and females showed a subtle cognitive phenotype (10±2weeks) with distinct neuroinflammatory phenotypes. Aging was associated with clear neuroinflammation in female A20 +/− mice only. The genetic predisposition in combination with an environmental stimulus exacerbates the behavioral impairments related to anxiety, cognitive dysfunction and sensorimotor gating. This was predominantly observed in females. Furthermore, signs of neuroinflammation were solely observed in female A20 +/− mice. All above observations were made in the absence of peripheral inflammation and of changes in blood-brain barrier permeability, thus consistent with the CNS-primary hypothesis.

          Conclusions

          We show that A20 heterozygosity is a predisposing factor for NPSLE. Further mechanistic insight and possible therapeutic interventions can be studied in this mouse model that recapitulates several key hallmarks of the disease.

          Highlights

          • A novel mouse model for neuropsychiatric lupus was established.

          • Loss of 1 copy of A20/TNFAIP3 leads to neuroinflammation and cognitive symptoms.

          • Female-specific neuroinflammation was seen with age.

          • An environmental stimulus worsens the behavioral impairments.

          • The results show that the brain is the primary affected site.

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          Most cited references104

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          Sex differences in immune responses

          Males and females differ in their immunological responses to foreign and self-antigens and show distinctions in innate and adaptive immune responses. Certain immunological sex differences are present throughout life, whereas others are only apparent after puberty and before reproductive senescence, suggesting that both genes and hormones are involved. Furthermore, early environmental exposures influence the microbiome and have sex-dependent effects on immune function. Importantly, these sex-based immunological differences contribute to variations in the incidence of autoimmune diseases and malignancies, susceptibility to infectious diseases and responses to vaccines in males and females. Here, we discuss these differences and emphasize that sex is a biological variable that should be considered in immunological studies.
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            Analyzing real-time PCR data by the comparative C(T) method.

            Two different methods of presenting quantitative gene expression exist: absolute and relative quantification. Absolute quantification calculates the copy number of the gene usually by relating the PCR signal to a standard curve. Relative gene expression presents the data of the gene of interest relative to some calibrator or internal control gene. A widely used method to present relative gene expression is the comparative C(T) method also referred to as the 2 (-DeltaDeltaC(T)) method. This protocol provides an overview of the comparative C(T) method for quantitative gene expression studies. Also presented here are various examples to present quantitative gene expression data using this method.
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              An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex.

              The major cell classes of the brain differ in their developmental processes, metabolism, signaling, and function. To better understand the functions and interactions of the cell types that comprise these classes, we acutely purified representative populations of neurons, astrocytes, oligodendrocyte precursor cells, newly formed oligodendrocytes, myelinating oligodendrocytes, microglia, endothelial cells, and pericytes from mouse cerebral cortex. We generated a transcriptome database for these eight cell types by RNA sequencing and used a sensitive algorithm to detect alternative splicing events in each cell type. Bioinformatic analyses identified thousands of new cell type-enriched genes and splicing isoforms that will provide novel markers for cell identification, tools for genetic manipulation, and insights into the biology of the brain. For example, our data provide clues as to how neurons and astrocytes differ in their ability to dynamically regulate glycolytic flux and lactate generation attributable to unique splicing of PKM2, the gene encoding the glycolytic enzyme pyruvate kinase. This dataset will provide a powerful new resource for understanding the development and function of the brain. To ensure the widespread distribution of these datasets, we have created a user-friendly website (http://web.stanford.edu/group/barres_lab/brain_rnaseq.html) that provides a platform for analyzing and comparing transciption and alternative splicing profiles for various cell classes in the brain. Copyright © 2014 the authors 0270-6474/14/3411929-19$15.00/0.
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                Author and article information

                Contributors
                Journal
                Brain Behav Immun Health
                Brain Behav Immun Health
                Brain, Behavior, & Immunity - Health
                Elsevier
                2666-3546
                14 December 2019
                February 2020
                14 December 2019
                : 2
                : 100018
                Affiliations
                [a ]Laboratory of Behavioral and Developmental Genetics, Department of Human Genetics, KU Leuven, Leuven, Belgium
                [b ]VIB-UGent Center for Inflammation Research, Gent, Belgium
                [c ]Department of Biomedical Molecular Biology, Ghent University, Gent, Belgium
                [d ]Laboratory of Biological Psychology, KU Leuven, Leuven, Belgium
                Author notes
                []Corresponding author. patrick.callaerts@ 123456kuleuven.be
                [∗∗ ]Corresponding author. zsuzsanna.vegh@ 123456kuleuven.be
                Article
                S2666-3546(19)30018-3 100018
                10.1016/j.bbih.2019.100018
                8474646
                ca2c5cf6-20f6-4478-a854-87a55a6e03d6
                © 2019 The Authors

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 8 October 2019
                : 28 November 2019
                : 4 December 2019
                Categories
                Full Length Article

                neuropsychiatric lupus,a20/tnfaip3,behavior,neuroinflammation,genetic predisposition,environmental trigger,female predominance

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