Microglia-dependent synapse loss in type I interferon-mediated lupus
Authors: Abhishek Das
Peter H Lapchak
George C Tsokos
Cees E van der Poel
Jessy Presumey
Allison R Bialas
Michael C Carroll
Gabriel Victora
Luka Mesin
Ronald Herbst
Christian Mawrin
Journal: Nature (2017)
Discipline: Multidisciplinary
Keywords: Systemic lupus erythematosus; autoimmune disease; autoantibody deposition; neuropsychiatric symptoms; central nervous system
Affiliations: Program in Cellular and Molecular Medicine, Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, Massachusetts 02115, USA., Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA., Laboratory for Lymphocyte Dynamics, The Rockefeller University, New York City, New York, USA., Department of Neuropathology, University of Magdeburg, Magdeburg, Germany., Center for Behavioral Brain Sciences (CBBS), Otto-von-Guericke-University Magdeburg, Magdeburg, Germany., Department of Cancer Biology, MedImmune LLC, Gaithersburg, Maryland 20878, USA.

Abstract:  Systemic lupus erythematosus (SLE) is an incurable autoimmune disease characterized by autoantibody deposition in tissues such as kidney, skin and lungs. Notably, up to 75% of patients with SLE experience neuropsychiatric symptoms that range from anxiety, depression and cognitive impairment to seizures and, in rare cases, psychosis-collectively this is referred to as central nervous system (CNS) lupus. In some cases, certain autoantibodies, such as anti-NMDAR or anti-phospholipid antibodies, promote CNS lupus. However, in most patients, the mechanisms that underlie these symptoms are unknown. CNS lupus typically presents at lupus diagnosis or within the first year, suggesting that early factors contributing to peripheral autoimmunity may promote CNS lupus symptoms. Here we report behavioural phenotypes and synapse loss in lupus-prone mice that are prevented by blocking type I interferon (IFN) signalling. Furthermore, we show that type I IFN stimulates microglia to become reactive and engulf neuronal and synaptic material in lupus-prone mice. These findings and our observation of increased type I IFN signalling in post-mortem hippocampal brain sections from patients with SLE may instruct the evaluation of ongoing clinical trials of anifrolumab, a type I IFN-receptor antagonist. Moreover, identification of IFN-driven microglia-dependent synapse loss, along with microglia transcriptome data, connects CNS lupus with other CNS diseases and provides an explanation for the neurological symptoms observed in some patients with SLE. 

Retracted: Yes

PubPeer comments:
 2020 retraction. https: www.nature.com articles s41586-020-1949-x In follow-up experiments to this Letter, we have been unable to replicate key aspects of the original results. Most importantly, the findings from behaviour studies and sequencing of microglia isolated from 564Igi autoimmune mice as shown in Figs. 1a, b, d and 3a, b are not substantiated upon further analysis of the original data. The authors therefore wish to retract the Letter. We deeply regret this error and apologize to our scientific colleagues. , 
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 Lots of the fold changes in original data donu2019t normalize to 1 in control condition. , 
 Lots of the fold changes in original data donu2019t normalize to 1 in control condition. ![](http: )![file] ![file] ![file] , 
 #4 In the second chart you have highlighted, the fold changes have been log2 transformed, thus 1 becomes 0, and 1 represents a 2-fold increase. , 
 Good catch thank you. However fold change issue still exists as that means that all genes should be at 0 for WT but several are not. , 
 Also significant issues with suspiciously similar values in source data and source data not matching graphed data. Similar to other issues raised here: https: pubpeer.com publications 4D618B72AA04EA0D52452C1DA668CD ![](http: ) ![file] ![file] ![file] ![file] , 
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