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Brain Injury in SLE
404 The importance of FcγRIIA in antibody-mediated neurovascular thrombosis
  1. Audrée Laroche1,2,
  2. Micaël Carrier3,4,
  3. Denis Soulet5,
  4. Marc Bazin5,
  5. Tania Levesque1,2,
  6. Isabelle Allaeys1,2,
  7. Nicolas Vallières6,
  8. Matthias Gunzer7,8,
  9. Louis Flamand1,2,
  10. Steve Lacroix6,
  11. Marie-Ève Tremblay3,4,9,10,11,
  12. Paul R Fortin2,12 and
  13. Eric Boilard1,2
  1. 1Centre de Recherche du CHU de Québec – Université Laval, Département de microbiologie et immunologie, Canada
  2. 2Centre de Recherche ARThrite de l’Université Laval, Canada
  3. 3Neurosciences Axis, Centre de Recherche du CHU de Québec, Université Laval, Québec City, QC, Canada
  4. 4Division of Medical Sciences, University of Victoria, Victoria, BC, Canada
  5. 5Université Laval, Faculté de pharmacie, Université Laval, Québec City, QC, Canada
  6. 6Centre de Recherche du CHU de Québec – Université Laval, Département de médecine moléculaire, Canada
  7. 7Institute for Experimental Immunology and Imaging, University Hospital, University Duisburg-Essen, Germany
  8. 8Leibniz-Institut für Analytische Wissenschaften ISAS -e.V, Germany
  9. 9Neurology and Neurosurgery Department, McGill University, Montreal, QC, Canada
  10. 10Department of Molecular Medicine, Université Laval, Québec City, QC, Canada
  11. 11Department of Biochemistry and Molecular Biology, The University of British Columbia, Vancouver, BC, Canada
  12. 12Centre de Recherche du CHU de Québec – Université Laval, Département de médecine, Canada

Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disease that damages many organs and tissues. SLE is characterized by the production of autoantibodies and the presence of circulating immune complexes (ICs) in blood. Neuropsychiatric lupus erythematosus (NPSLE) refers to the neurological and psychiatric symptoms directly related to SLE. Alterations in the blood-brain barrier (BBB) and presence of IgG antibodies have been observed in the brain of individuals affected by NPSLE. ICs bind Fcγ receptors (FcγRs), which signaling can play a major role in inflammation and thrombotic events. FcγRIIA receptor is expressed by many immune cells, such as platelets and neutrophils in humans, but it is absent in mice. This explains in part why the interactions of platelets and neutrophils with the brain vasculature endothelium in response to ICs have never been investigated. In this study, we used nanoscale-resolution chip mapping scanning electron microscopy to study the brain vasculature of lupus-prone mice expressing the FcγRIIA transgene (NZB/NZWF1.FcγRIIATGN). We found neutrophils (figure 1A), platelets (figure 1 B-C) and immune complexes (figure 1C) adhered to the endothelium of the brain vasculature. To visualize and quantify at the cellular level the events taking place in the brain vasculature in response to systemic administration of surrogate ICs, we generated Ly6gCre+/-::Rosa26-TdT+/-::CD41-YFP+/- mice expressing the FcγRIIA transgene and fluorescence in neutrophils (red) and platelets (yellow). Using real-time videomicroscopy to capture high velocity events and an unbiased computer assisted analysis approach, we provide images and quantifications of the cellular responses downstream of FcγRIIA stimulation. We observed platelet aggregation and neutrophil adhesion to blood vessel walls in response to ICs, only in FcγRIIATGN mice. Moreover, stable and transient interactions between platelets and neutrophils were captured in real time. Taken together, the results highlight the importance of the FcγRIIA receptor in neutrophil adhesion to the BBB in response to ICs and suggest the potential implication of neutrophils and platelets in mediating alterations of the BBB in NPSLE. This study puts forward an imaging and quantifying approach in a quadruple transgenic mouse model that can be utilized for the study of the pathogenic roles of ICs disease.

Abstract 404 Figure 1
Abstract 404 Figure 1

Adhesion of platelets, neutrophils and immune complexes to the brain vasculature of lupus-prone mice expressing FcγRIIA transgene (NZB/NZWF1.FcγRIIATGN). Scanning electron micrograph providing examples of (A) neutrophil (pseudocoloured in red), (B) platelet (pseudocoloured in blue) and (C) platelet (pseudocoloured in blue) associated with IgG antibodies (arrows) adhered to the brain vasculature of NZB/NZWF1.FcγRIIATGN mice at 28 weeks of age, a stage of pathology when positive proteinuria and signs of nephritis are observed. Endothelial cells are pseudocoloured in yellow. Scale bars represent 5 µm.

http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/ .

http://dx.doi.org/10.1136/lupus-2022-lupus21century.16

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