Eloy Cuadrado1, Adeline Vanderver2, Kristy J Brown2, Annie Sandza2, Asako Takanohashi2, Machiel H Jansen3, Jasper Anink4, Brian Herron5, Simona Orcesi6, Ivana Olivieri6, Gillian I Rice7, Eleonora Aronica8, Pierre Lebon9, Yanick J Crow7, Elly M Hol10, Taco W Kuijpers3. 1. Astrocyte Biology & Neurodegeneration, Netherlands Institute for Neuroscience, an Institute of the Royal Netherlands Academy of Arts and Sciences, Amsterdam, The Netherlands Department of Experimental Immunology, Academic Medical Center, University of Amsterdam (UvA), Amsterdam, The Netherlands. 2. Center for Genetic Medicine Research, Children's National Medical Center, Washington DC, USA. 3. Department of Experimental Immunology, Academic Medical Center, University of Amsterdam (UvA), Amsterdam, The Netherlands. 4. Department of (Neuro)Pathology, SEIN-Stichting Epilepsie Instellingen Nederland, Academic Medical Center, University of Amsterdam (UvA), Amsterdam, The Netherlands. 5. Department of Neuropathology, Royal Victoria Hospital, Belfast, UK. 6. Child Neurology and Psychiatry Unit, C. Mondino National Neurological Institute, Pavia, Italy. 7. Manchester Centre for Genomic Medicine, University of Manchester, Manchester Academic Health Sciences Centre (MAHSC), Manchester, UK. 8. Department of (Neuro)Pathology, SEIN-Stichting Epilepsie Instellingen Nederland, Academic Medical Center, University of Amsterdam (UvA), Amsterdam, The Netherlands Swammerdam Institute for Life Sciences, Center for Neuroscience, University of Amsterdam, Amsterdam, The Netherlands. 9. Hôpital Cochin, Université Paris Descartes, Service de Virologie, Paris, France. 10. Astrocyte Biology & Neurodegeneration, Netherlands Institute for Neuroscience, an Institute of the Royal Netherlands Academy of Arts and Sciences, Amsterdam, The Netherlands Swammerdam Institute for Life Sciences, Center for Neuroscience, University of Amsterdam, Amsterdam, The Netherlands Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands.
Abstract
OBJECTIVES: Aicardi-Goutières syndrome (AGS) is an autoimmune disorder that shares similarities with systemic lupus erythematous. AGS inflammatory responses specially target the cerebral white matter. However, it remains uncertain why the brain is the most affected organ, and little is known about the presence of autoantibodies in AGS. Here, we aim to profile specific autoantibodies in AGS and to determine whether these autoantibodies target cerebral epitopes. METHODS: Using a multiplex microarray, we assessed the spectrum of serum autoantibodies in 56 genetically confirmed patients with AGS. We investigated the presence of immunoglobulins in AGS brain specimens using immunohistochemistry and studied the reactivity of sera against brain epitopes with proteomics. RESULTS: Serum from patients exhibited high levels of IgGs against nuclear antigens (gP210, Nup62, PCNA, Ro/SSA, Sm/RNP complex, SS-A/SS-B), components of the basement membrane (entactin, laminin), fibrinogen IV and gliadin. Upon testing whether antibodies in AGS could be found in the central nervous system, IgGs were identified to target in vivo endothelial cells in vivo and astrocytes in brain sections of deceased patients with AGS. Using a proteomics approach, we were able to confirm that IgGs in serum samples from AGS patients bind epitopes present in the cerebral white matter. CONCLUSIONS: Patients with AGS produce a broad spectrum of autoantibodies unique from other autoimmune diseases. Some of these autoantibodies target endothelial cells and astrocytes in the brain of the affected patients, perhaps explaining the prominence of neurological disease in the AGS phenotype. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
OBJECTIVES: Aicardi-Goutières syndrome (AGS) is an autoimmune disorder that shares similarities with systemic lupus erythematous. AGS inflammatory responses specially target the cerebral white matter. However, it remains uncertain why the brain is the most affected organ, and little is known about the presence of autoantibodies in AGS. Here, we aim to profile specific autoantibodies in AGS and to determine whether these autoantibodies target cerebral epitopes. METHODS: Using a multiplex microarray, we assessed the spectrum of serum autoantibodies in 56 genetically confirmed patients with AGS. We investigated the presence of immunoglobulins in AGS brain specimens using immunohistochemistry and studied the reactivity of sera against brain epitopes with proteomics. RESULTS: Serum from patients exhibited high levels of IgGs against nuclear antigens (gP210, Nup62, PCNA, Ro/SSA, Sm/RNP complex, SS-A/SS-B), components of the basement membrane (entactin, laminin), fibrinogen IV and gliadin. Upon testing whether antibodies in AGS could be found in the central nervous system, IgGs were identified to target in vivo endothelial cells in vivo and astrocytes in brain sections of deceased patients with AGS. Using a proteomics approach, we were able to confirm that IgGs in serum samples from AGSpatients bind epitopes present in the cerebral white matter. CONCLUSIONS:Patients with AGS produce a broad spectrum of autoantibodies unique from other autoimmune diseases. Some of these autoantibodies target endothelial cells and astrocytes in the brain of the affected patients, perhaps explaining the prominence of neurological disease in the AGS phenotype. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
Authors: John T Crowl; Elizabeth E Gray; Kathleen Pestal; Hannah E Volkman; Daniel B Stetson Journal: Annu Rev Immunol Date: 2017-01-30 Impact factor: 28.527
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