Contributions
Abstract: P1742
Type: Poster Sessions
Abstract Category: N/A
Background: Disturbed function of brain endothelial cells (ECs) resulting in impaired integrity of the blood brain barrier is an early hallmark of distinct neurological diseases. Susac syndrome (SuS) is a rare chronic neuro-inflammatory disease with an unknown etiology affecting microvascular ECs of central nervous system (CNS) microvessels leading to a clinical triad of encephalopathy, branch retinal artery occlusions, and sensorineural hearing loss.
Methods: 41 patients with definite SuS were included in this study to elucidate the mechanism underlying the endotheliopathy. In-depth functional immune-profiling of blood and cerebrospinal fluid (CSF) was combined with high throughput T-cell receptor (TCR) sequencing and a pathological study of brain biopsies. Furthermore, we developed a mouse model in which the influenza hemagglutinin (HA) is expressed as a neo-antigen in brain and retina ECs to mimick CD8 T-cell-mediated antigen-specific attack against CNS endothelium.
Results: We identified CD8 T cells as key players in the endotheliopathy underlying the development of SuS. SuS was associated with a strong accumulation and oligoclonal expansion of cytotoxic CD8 T cells (CTLs) in the periphery and CNS. Granzyme B and perforin expressing CTLs were found in CNS microvessels in close proximity to ECs, where they may cause vascular injury. Mimicking the CD8-mediated antigen-specific attack against CNS endothelium in a mouse model presenting striking similarities to SuS corroborated our findings that CTLs can indeed cause vascular CNS injury by targeting ECs in an antigen-dependent process. CD8-mediated endotheliopathy could be effectively blocked in this pre-clinical model by inhibiting adhesion and trafficking of CTLs using an anti-alpha4 integrin monoclonal antibody (mAb). Strikingly, treating 4 SuS patients with natalizumab, a humanized anti-alpha4 integrin mAb, resulted in attenuation of inflammatory activity.
Conclusions: Taken together, this study determined CD8 T-cell-mediated endotheliopathy as a novel pathomechanism in SuS that is associated with neuro-inflammation and might also play an important role in other inflammatory or infectious diseases of the CNS.
Disclosure: This work was supported by the European Susac Consortium (EuSaC), the German Research Foundation grant (DFG) GR3946_3/1 “Susac syndrome (SuS) as a paradigm of a CD8 T-cell mediated endotheliopathy” (to CCG and IK), the IMF grant KL 111421 “The pathophysiological role and clinical impact of the immune system in Susac syndrome (SuS)” (to IK and CCG); the Collaborative Research Centre CRC TR128 “Initiating/Effector versus Regulatory Mechanisms in Multiple Sclerosis - Progress towards Tackling the Disease” (projects A09 to HW and CCG, B01 to NS, and Z2 to HW and TK); SFB1009 Breaking Barriers (project A03 to HW and LK); the Federal Ministry of Education and Research funded Disease Related Competence Network for Multiple Sclerosis (KKNMS, project FKZ01FI1603A to HW, LK, and CCG); the intramural Cell in Motion (CiM) cluster of excellence bridging fund to UB. The design and study of the mouse model was supported by Inserm, CNRS, Toulouse University and by grants from the French MS society (ARSEP), The Foundation pour la Recherche Médicale (FRM), the French Research Agency (ANR T-cell Mig), ERA-NET NEURON (Meltra-BBB), the Institut Universitaire de France, and the German Research Foundation (DFG, SCHW 416/5-2 to MS).
CCG received speaker honoraria and travel expenses for attending meetings from Biogen, Euroimmun, Genzyme, Novartis Pharma GmbH, and Bayer Health Care, none related to this study. Her work is funded by the German Ministry for Education and Research (BMBF; 01GI1603A), the German Research Foundation (DFG; GR3946/3-1 and SFB/Transregio 128 A09), the European Union (Horizon2020, RESTORE), and the IMF (KL 111421). IK received travel expenses for attending meetings from Pfizer and CSL Behring. JB´s work is funded by the Austrian Science Fund (FWF: P26936-B27). TK received speaker honoraria from Novartis and Excemed.MR received speaker honoraria from Novartis, Bayer Vital GmbH and Ipsen and travel reimbursement from Bayer Schering, Biogen Idec, Merz, Genzyme, Teva and Merck, none related to this study. JD received research support by Bayer and Novartis, travel support by Bayer, Novartis, Biogen, Merck Serono, and honoraria for lectures and advisory by Bayer, Novartis, Biogen, Merck Serono, Roche, Sanofi Genzyme. BW received research support from German Ministry of Education and Research, Dietmar Hopp Foundation, Klaus Tschira Foundation, Sanofi Genzyme, Merck Serono, Novartis, and speaker honoraria and/or travel support from Bayer Healthcare, Biogen, Merck Serono, Novartis, Sanofi Genzyme, TEVA outside the submitted work. NS received travel support from Novartis and Sanofi-Genzyme. LK received compensation for serving on scientific advisory boards for Genzyme and Novartis; speaker honoraria and travel support from Novartis, Merck Serono, and CSL Behring; and research support from Novartis and Biogen. SGM has received honoraria for lecturing, travel expenses for attending meetings and financial research support from Almirall, Amicus Therapeutics Germany, Bayer Health Care, Biogen, Diamed, Genzyme, MedDay Pharmaceuticals, Merck Serono, Novartis, Novo Nordisk, ONO Pharma, Roche, Sanofi-Aventis, Chugai Pharma, QuintilesIMS and Teva. GMB received speaker honoraria and travel support for attending meetings from Abbvie, Genzyme, Gilead and Pfizer. HW received honoraria for scientific advisory boards/steering committees fromBiogen, Evgen, MedDay Pharmaceuticals, Merck Serono, Novartis, Roche Pharma AG, and Sanofi-Genzyme. He received speaker honoraria and travel support for attending meetings from Alexion,Biogen,Cognomed, F. Hoffmann-La Roche Ltd., Gemeinnützige Hertie-Stiftung, Merck Serono, Novartis, Roche Pharma AG, Sanofi-Genzyme, TEVA, and WebMD Globa. HW received compensation as a consultant from Abbvie, Actelion, Biogen, IGES, Novartis, Roche, Sanofi-Genzyme, and the Swiss Multiple Sclerosis Society. He also received research support from the German Ministry for Education and Research (BMBF), Deutsche Forschungsgesellschaft (DFG), Else Kröner Fresenius Foundation, Fresenius Foundation, Hertie Foundation, NRW Ministry of Education and Research, Interdisciplinary Center for Clinical Studies (IZKF) Muenster and RE Children's Foundation, Biogen GmbH, GlaxoSmithKline GmbH, Roche Pharma AG, Sanofi-Genzyme. RL received grant support from Pierre Fabre, GlaxoSmithKline, and Diaccurate. He received speaker or scientific board honoraria fromBiogen, Servier, Novartis, and Sanofi-Genzyme. RL is currently receiving grants from GlaxoSmithKline, Cancer Research Institute, French Cancer research foundation (ARC), Rare Diseases Foundation, and National Institute of Cancer (INCa).CM, UB, LY, JB, AT, HP, ASM, SH, TSH, MS, WB, EB, and KD have no financial disclosures.
Abstract: P1742
Type: Poster Sessions
Abstract Category: N/A
Background: Disturbed function of brain endothelial cells (ECs) resulting in impaired integrity of the blood brain barrier is an early hallmark of distinct neurological diseases. Susac syndrome (SuS) is a rare chronic neuro-inflammatory disease with an unknown etiology affecting microvascular ECs of central nervous system (CNS) microvessels leading to a clinical triad of encephalopathy, branch retinal artery occlusions, and sensorineural hearing loss.
Methods: 41 patients with definite SuS were included in this study to elucidate the mechanism underlying the endotheliopathy. In-depth functional immune-profiling of blood and cerebrospinal fluid (CSF) was combined with high throughput T-cell receptor (TCR) sequencing and a pathological study of brain biopsies. Furthermore, we developed a mouse model in which the influenza hemagglutinin (HA) is expressed as a neo-antigen in brain and retina ECs to mimick CD8 T-cell-mediated antigen-specific attack against CNS endothelium.
Results: We identified CD8 T cells as key players in the endotheliopathy underlying the development of SuS. SuS was associated with a strong accumulation and oligoclonal expansion of cytotoxic CD8 T cells (CTLs) in the periphery and CNS. Granzyme B and perforin expressing CTLs were found in CNS microvessels in close proximity to ECs, where they may cause vascular injury. Mimicking the CD8-mediated antigen-specific attack against CNS endothelium in a mouse model presenting striking similarities to SuS corroborated our findings that CTLs can indeed cause vascular CNS injury by targeting ECs in an antigen-dependent process. CD8-mediated endotheliopathy could be effectively blocked in this pre-clinical model by inhibiting adhesion and trafficking of CTLs using an anti-alpha4 integrin monoclonal antibody (mAb). Strikingly, treating 4 SuS patients with natalizumab, a humanized anti-alpha4 integrin mAb, resulted in attenuation of inflammatory activity.
Conclusions: Taken together, this study determined CD8 T-cell-mediated endotheliopathy as a novel pathomechanism in SuS that is associated with neuro-inflammation and might also play an important role in other inflammatory or infectious diseases of the CNS.
Disclosure: This work was supported by the European Susac Consortium (EuSaC), the German Research Foundation grant (DFG) GR3946_3/1 “Susac syndrome (SuS) as a paradigm of a CD8 T-cell mediated endotheliopathy” (to CCG and IK), the IMF grant KL 111421 “The pathophysiological role and clinical impact of the immune system in Susac syndrome (SuS)” (to IK and CCG); the Collaborative Research Centre CRC TR128 “Initiating/Effector versus Regulatory Mechanisms in Multiple Sclerosis - Progress towards Tackling the Disease” (projects A09 to HW and CCG, B01 to NS, and Z2 to HW and TK); SFB1009 Breaking Barriers (project A03 to HW and LK); the Federal Ministry of Education and Research funded Disease Related Competence Network for Multiple Sclerosis (KKNMS, project FKZ01FI1603A to HW, LK, and CCG); the intramural Cell in Motion (CiM) cluster of excellence bridging fund to UB. The design and study of the mouse model was supported by Inserm, CNRS, Toulouse University and by grants from the French MS society (ARSEP), The Foundation pour la Recherche Médicale (FRM), the French Research Agency (ANR T-cell Mig), ERA-NET NEURON (Meltra-BBB), the Institut Universitaire de France, and the German Research Foundation (DFG, SCHW 416/5-2 to MS).
CCG received speaker honoraria and travel expenses for attending meetings from Biogen, Euroimmun, Genzyme, Novartis Pharma GmbH, and Bayer Health Care, none related to this study. Her work is funded by the German Ministry for Education and Research (BMBF; 01GI1603A), the German Research Foundation (DFG; GR3946/3-1 and SFB/Transregio 128 A09), the European Union (Horizon2020, RESTORE), and the IMF (KL 111421). IK received travel expenses for attending meetings from Pfizer and CSL Behring. JB´s work is funded by the Austrian Science Fund (FWF: P26936-B27). TK received speaker honoraria from Novartis and Excemed.MR received speaker honoraria from Novartis, Bayer Vital GmbH and Ipsen and travel reimbursement from Bayer Schering, Biogen Idec, Merz, Genzyme, Teva and Merck, none related to this study. JD received research support by Bayer and Novartis, travel support by Bayer, Novartis, Biogen, Merck Serono, and honoraria for lectures and advisory by Bayer, Novartis, Biogen, Merck Serono, Roche, Sanofi Genzyme. BW received research support from German Ministry of Education and Research, Dietmar Hopp Foundation, Klaus Tschira Foundation, Sanofi Genzyme, Merck Serono, Novartis, and speaker honoraria and/or travel support from Bayer Healthcare, Biogen, Merck Serono, Novartis, Sanofi Genzyme, TEVA outside the submitted work. NS received travel support from Novartis and Sanofi-Genzyme. LK received compensation for serving on scientific advisory boards for Genzyme and Novartis; speaker honoraria and travel support from Novartis, Merck Serono, and CSL Behring; and research support from Novartis and Biogen. SGM has received honoraria for lecturing, travel expenses for attending meetings and financial research support from Almirall, Amicus Therapeutics Germany, Bayer Health Care, Biogen, Diamed, Genzyme, MedDay Pharmaceuticals, Merck Serono, Novartis, Novo Nordisk, ONO Pharma, Roche, Sanofi-Aventis, Chugai Pharma, QuintilesIMS and Teva. GMB received speaker honoraria and travel support for attending meetings from Abbvie, Genzyme, Gilead and Pfizer. HW received honoraria for scientific advisory boards/steering committees fromBiogen, Evgen, MedDay Pharmaceuticals, Merck Serono, Novartis, Roche Pharma AG, and Sanofi-Genzyme. He received speaker honoraria and travel support for attending meetings from Alexion,Biogen,Cognomed, F. Hoffmann-La Roche Ltd., Gemeinnützige Hertie-Stiftung, Merck Serono, Novartis, Roche Pharma AG, Sanofi-Genzyme, TEVA, and WebMD Globa. HW received compensation as a consultant from Abbvie, Actelion, Biogen, IGES, Novartis, Roche, Sanofi-Genzyme, and the Swiss Multiple Sclerosis Society. He also received research support from the German Ministry for Education and Research (BMBF), Deutsche Forschungsgesellschaft (DFG), Else Kröner Fresenius Foundation, Fresenius Foundation, Hertie Foundation, NRW Ministry of Education and Research, Interdisciplinary Center for Clinical Studies (IZKF) Muenster and RE Children's Foundation, Biogen GmbH, GlaxoSmithKline GmbH, Roche Pharma AG, Sanofi-Genzyme. RL received grant support from Pierre Fabre, GlaxoSmithKline, and Diaccurate. He received speaker or scientific board honoraria fromBiogen, Servier, Novartis, and Sanofi-Genzyme. RL is currently receiving grants from GlaxoSmithKline, Cancer Research Institute, French Cancer research foundation (ARC), Rare Diseases Foundation, and National Institute of Cancer (INCa).CM, UB, LY, JB, AT, HP, ASM, SH, TSH, MS, WB, EB, and KD have no financial disclosures.