Contributions
Abstract: 236
Type: Free Communications
Abstract Category: Pathology and pathogenesis of MS - Immunology
Introduction: Multiple sclerosis (MS) is an autoimmune disease of the central nervous system exhibiting profound and complex alterations of immune-regulatory networks. Even though MS etiology is complex, genetic susceptibility clearly plays a role, as supported by the fact that the concordance rate for MS in monozygotic (MZ) twins is about 25%.
Objective: Comparison of the immune phenotype of MZ MS-Twin (MST) versus Healthy-Co-Twin (HT).
Aims: Identification of MS-associated peripheral immune signaturesand assessment of the impact of the genetic background on immune cell profiles to gain insight in MS pathogenesis.
Methods: We examined cryoconserved PBMCs of 50 MZ twin pairs discordant for MS by conducting an extensive immune cell profiling via multi-colour flow cytometry followed by unbiased multi-clustering allowing for analysis of more than 20400 traits. As control cohorts we used PBMCs from sporadic healthy controls (HC) and treatment-naïve relapsing remitting MS patients (RRMS). Linear mixed models were used to adjust for twin dependencies and parameters like age, sex and disease status, which was used to differentially calculate correlations (R2) and estimation of the differences among all groups.
Results: Overall, comparison of peripheral cell composition among the twin groups (MST versus HT) via flow cytometry and unbiased clustering revealed a profound conformity of immune cell traits. Grouping into major innate and adaptive populations revealed significant correlations within MST and HT, although interestingly, for B cell populations the correlation was slightly diminished. Importantly, further mathematical modeling employing linear mixed models, considering age, sex, disease status as fixed, and twin affiliation as random effects, revealed a striking preponderance of the twin affiliation for explaining the majority of immune cell traits investigated (conditional R2= 0,69). However, due to the high degree of matching,we could reveal numerous populations within the B and T cell compartment as well as NK cells, whichwere differentially regulated in the MST compared to HT.
Conclusion: This immune profiling study in genetically identical twins with discordance for MS points towards a strong genetic determination of peripheral immune signatures, however, due to the high degree of matching it allows for identification of possible disease-specific immune cell traits, which might increase our understanding of MS-specific immune cell deviations.
Disclosure: Source of funding:
The study was funded by the Gemeinnützige Hertie Foundation. The National Twin cohort receives financial support for travel expenses of the twins (for study visits in Munich) by the German MS Foundation, regional and national division (DMSG Landesverband und Bundesverband Bayern) and the association “Therapieforschung für Multiple Sklerose Kranke”.
Disclosures:
Lisa Ann Gerdes has received speaker´s honoraria from Roche, Sanofi Genzyme and Merck Serono.
Claudia Janoschka received travel support from Novartis Pharma.
Bianca Mannig: nothing to disclose
Andreas Schulte-Mecklenbeck: nothing to disclose
Catharina C. Gross has received grants from the German Ministry for Education and Research, the German Research Foundation, and the European Union; received speaker honoraria and travel expenses for attending meetings from Biogen, Genzyme, Novartis Pharma and Bayer Health Care.
Maria Eveslage: nothing to disclose
Tania Kümpfel has received travel expenses and speaker honoraria from Bayer Healthcare, Teva Pharma, Merck, Novartis Pharma, Sanofi-Aventis/Genzyme, CLB Behring, Roche Pharma and Biogen as well as grant support from Bayer-Schering AG, Novartis and Chugai Pharma.
Heinz Wiendl received honoraria for acting as a member of Scientific Advisory Boards and steering committees for Biogen, Evgen, MedDay Pharmaceuticals, Merck Serono, Novartis, Roche Pharma AG, Sanofi-Genzyme, as well as speaker honoraria and travel support from Alexion, Biogen, Cognomed, F. Hoffmann-La Roche Ltd., Gemeinnützige Hertie-Stiftung, Merck Serono, Novartis, Roche Pharma AG, Peervoice, Sanofi-Genzyme, Swiss Multiple Sclerosis Society, TEVA, and WebMD Global; he acted as a paid consultant for Abbvie, Actelion, Biogen, IGES, Novartis, Roche Pharma AG, Sanofi-Genzyme and GlaxoSmithKline GmbH; 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, Novartis, Interdisciplinary Center for Clinical Studies (IZKF) Muenster and RE Children's Foundation, Biogen, GlaxoSmithKline GmbH, Roche Pharma AG, Sanofi-Genzyme.
Reinhard Hohlfeld received research grants and/or speaker honoraria from Actelion, Genzyme-Sanofi, Novartis, Immunic, Roche.
Luisa Klotz received compensation for serving on scientific advisory boards (Genzyme, Novartis Pharma); speaker honoraria and travel support (CSL Behring, Merck Serono, Roche, Novartis Pharma); research support (Biogen, Novartis Pharma)
Abstract: 236
Type: Free Communications
Abstract Category: Pathology and pathogenesis of MS - Immunology
Introduction: Multiple sclerosis (MS) is an autoimmune disease of the central nervous system exhibiting profound and complex alterations of immune-regulatory networks. Even though MS etiology is complex, genetic susceptibility clearly plays a role, as supported by the fact that the concordance rate for MS in monozygotic (MZ) twins is about 25%.
Objective: Comparison of the immune phenotype of MZ MS-Twin (MST) versus Healthy-Co-Twin (HT).
Aims: Identification of MS-associated peripheral immune signaturesand assessment of the impact of the genetic background on immune cell profiles to gain insight in MS pathogenesis.
Methods: We examined cryoconserved PBMCs of 50 MZ twin pairs discordant for MS by conducting an extensive immune cell profiling via multi-colour flow cytometry followed by unbiased multi-clustering allowing for analysis of more than 20400 traits. As control cohorts we used PBMCs from sporadic healthy controls (HC) and treatment-naïve relapsing remitting MS patients (RRMS). Linear mixed models were used to adjust for twin dependencies and parameters like age, sex and disease status, which was used to differentially calculate correlations (R2) and estimation of the differences among all groups.
Results: Overall, comparison of peripheral cell composition among the twin groups (MST versus HT) via flow cytometry and unbiased clustering revealed a profound conformity of immune cell traits. Grouping into major innate and adaptive populations revealed significant correlations within MST and HT, although interestingly, for B cell populations the correlation was slightly diminished. Importantly, further mathematical modeling employing linear mixed models, considering age, sex, disease status as fixed, and twin affiliation as random effects, revealed a striking preponderance of the twin affiliation for explaining the majority of immune cell traits investigated (conditional R2= 0,69). However, due to the high degree of matching,we could reveal numerous populations within the B and T cell compartment as well as NK cells, whichwere differentially regulated in the MST compared to HT.
Conclusion: This immune profiling study in genetically identical twins with discordance for MS points towards a strong genetic determination of peripheral immune signatures, however, due to the high degree of matching it allows for identification of possible disease-specific immune cell traits, which might increase our understanding of MS-specific immune cell deviations.
Disclosure: Source of funding:
The study was funded by the Gemeinnützige Hertie Foundation. The National Twin cohort receives financial support for travel expenses of the twins (for study visits in Munich) by the German MS Foundation, regional and national division (DMSG Landesverband und Bundesverband Bayern) and the association “Therapieforschung für Multiple Sklerose Kranke”.
Disclosures:
Lisa Ann Gerdes has received speaker´s honoraria from Roche, Sanofi Genzyme and Merck Serono.
Claudia Janoschka received travel support from Novartis Pharma.
Bianca Mannig: nothing to disclose
Andreas Schulte-Mecklenbeck: nothing to disclose
Catharina C. Gross has received grants from the German Ministry for Education and Research, the German Research Foundation, and the European Union; received speaker honoraria and travel expenses for attending meetings from Biogen, Genzyme, Novartis Pharma and Bayer Health Care.
Maria Eveslage: nothing to disclose
Tania Kümpfel has received travel expenses and speaker honoraria from Bayer Healthcare, Teva Pharma, Merck, Novartis Pharma, Sanofi-Aventis/Genzyme, CLB Behring, Roche Pharma and Biogen as well as grant support from Bayer-Schering AG, Novartis and Chugai Pharma.
Heinz Wiendl received honoraria for acting as a member of Scientific Advisory Boards and steering committees for Biogen, Evgen, MedDay Pharmaceuticals, Merck Serono, Novartis, Roche Pharma AG, Sanofi-Genzyme, as well as speaker honoraria and travel support from Alexion, Biogen, Cognomed, F. Hoffmann-La Roche Ltd., Gemeinnützige Hertie-Stiftung, Merck Serono, Novartis, Roche Pharma AG, Peervoice, Sanofi-Genzyme, Swiss Multiple Sclerosis Society, TEVA, and WebMD Global; he acted as a paid consultant for Abbvie, Actelion, Biogen, IGES, Novartis, Roche Pharma AG, Sanofi-Genzyme and GlaxoSmithKline GmbH; 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, Novartis, Interdisciplinary Center for Clinical Studies (IZKF) Muenster and RE Children's Foundation, Biogen, GlaxoSmithKline GmbH, Roche Pharma AG, Sanofi-Genzyme.
Reinhard Hohlfeld received research grants and/or speaker honoraria from Actelion, Genzyme-Sanofi, Novartis, Immunic, Roche.
Luisa Klotz received compensation for serving on scientific advisory boards (Genzyme, Novartis Pharma); speaker honoraria and travel support (CSL Behring, Merck Serono, Roche, Novartis Pharma); research support (Biogen, Novartis Pharma)