Update on the pathogenesis of central nervous system lupus

Propose of reviewNeuropsychiatric systemic lupus erythematosus (NPSLE) is an emerging frontier in lupus care encompassing a wide spectrum of clinical manifestations. Its pathogenesis remains poorly understood because of the complexity of pathophysiologic mechanisms involved and limited access to tissue. We highlight recent advances in the pathophysiology of neuropsychiatric lupus.Recent findingsDisruption of blood-brain barrier (BBB) facilitating entrance of neurotoxic antibodies into the central nervous system (CNS), neuroinflammation and cerebral ischemia are the key mechanisms. Disruption of the BBB may occur not only at the traditional BBB, but also at the blood-cerebrospinal fluid barrier. Certain autoantibodies, such as anti-N-methyl-d-aspartate receptors, antiribosomal P and antiphospholipid antibodies may cause injury in subsets of patients with diffuse neuropsychiatric disease. Activation of microglia via autoantibodies, interferon-a or other immune reactants, may amplify the inflammatory response and promote neuronal damage. New inflammatory pathways, such as TWEAK/Fn14, Bruton's tyrosine kinase, Nogo-a and ACE may represent additional potential targets of therapy. Novel neuroimaging techniques suggest alterations in brain perfusion and metabolism, increased concentration of neurometabolites, indicative of glial activation, vasculopathy and neuronal impairment.SummaryNPSLE encompasses a diverse phenotype with distinct pathogenic mechanisms, which could be targeted by novel therapies or repositioning of existing drugs. © 2019 Wolters Kluwer Health, Inc. All rights reserved

Gene expression and regulation in systemic lupus erythematosus

Background Systemic lupus erythematosus (SLE) is the prototypic systemic autoimmune disease. Genomewide (GW) association studies have identified more than 40 disease-associated loci, together accounting for only 10-20% of disease heritability. Gene expression represents the intermediate phenotype between DNA and disease phenotypic variation, and provides insights regarding genetic and epigenetic effects. We review data on gene expression and regulation in SLE by our group and other investigators. Materials and methods Systematic PubMed search for GW expression studies in SLE published since the year 2000. Results Deregulation of genes involved in type I interferon signaling is a consistent finding in the peripheral blood of active and severe SLE patients. Upregulation of granulocyte-specific transcripts especially in bone marrow mononuclear cells (BMMCs), and of myeloid lineage transcripts in lupus nephritis, provide evidence for pathogenic role of these cells. Gene network analysis in BMMCs identified central gene regulators which could represent therapeutic targets and a high similarity between SLE and non-Hodgkin lymphoma providing a molecular basis for the reported association of the two diseases. Gene expression abnormalities driven by deregulated expression of certain microRNAs in SLE contribute to interferon production, T- and B-cell hyperactivity, DNA hypomethylation, and defective tissue response to injury. Methylation arrays have revealed alterations in white blood cell DNA methylation in SLE suggesting an important role of epigenetics and the environment. Conclusions Gene expression studies have contributed to the characterization of pathogenic processes in SLE. Integrated approaches utilizing genetic variation, transcriptome and epigenome profiling will facilitate efforts towards a molecular-based disease taxonomy. © 2013 Stichting European Society for Clinical Investigation Journal Foundation