Identification of multiple sclerosis endophenotypes by high dimensional blood signatures associated with distinct disease trajectories
Catharina C Gross1, Andreas Schulte-Mecklenbeck1, Olga V Steinberg1, Timo Wirth1, Sarah Lauks1, Sergio E Baranzini2, Stefan Bittner3, Judith Bellmann-Strobl4, Nora Bünger1, Eva Eilers1, Maria Eveslage5, Vinzenz Fleischer3, Barbara Gisevius6, Sergiu Groppa3, Jürgen Haas7, Martin Kerschensteiner8, Lucienne Kirstein1, Catharina Korsukewitz1, Lisa Lohmann1, Jan Lünemann9, Felix Lüssi3, Gerd Meyer zu Hörste1, Jeremias Motte6, Tobias Ruck10, Nicholas Schwab1, Sven G Meuth10, Friedemann Paul11, Brigitte Wildemann12, Tania Kümpfel8, Ralf Gold6, Frauke Zipp3, Luisa Klotz1, Heinz Wiendl1
1University Hospital Münster, 2University of California San Francisco, 3University Medical Center of the Johannes Gutenberg University Mainz, 4Max Delbrueck Center for Molecular Medicine and Charité Universitätsmedizin Berlin, 5University of Münster, 6University Hospital Bochum, 7University of Heidelberg, 8Ludwig Maximilians University of Munich, 9University and University Hospital of Münster, 10Heinrich-Heine-University Düsseldorf, 11Charite Universitatsmedizin in Berlin, 12University Hospital Heidelberg
Objective:
To identify immune-response signatures in the blood of multiple sclerosis (MS) patients predictive for clinical disease trajectories and supporting personalized treatment decisions based on pathobiological principles.
Background:
MS is a neuro-immunological disease representing with a broad spectrum of clinical manifestations and disease progression. To date it is still controversially discussed, whether discrete immune-response signatures in the blood represent inflammatory disease characteristics versus signs of early neurodegeneration with prognostic and therapeutic consequences.
Design/Methods:
In this multicentric prospective study, we employed high-dimensional flow cytometry and targeted proteomics to a discovery cohort of 378 treatment-naïve early (£ 2years from disease onset) MS patients from the NationMS cohort with comprehensive clinical and paraclinical data. Resulting data were analyzed applying state-of-the-art computational biology. Results were reproduced in a validation cohort of 78 MS patients.
Results:
We identified MS as a disease of disturbed immune-regulatory networks that can be detected in the blood. Early MS consists of four immunological endophenotypes associated with different HLA-backgrounds suggestive for discrete immunological pathways in disease pathogenesis. Immunological endophenotypes were mirrored by specific clinical and paraclinical disease trajectories exhibiting inflammatory disease characteristics versus signs of early neurodegeneration. Distinct immune-therapeutic principles differed in their capacity to normalize immune-response signatures associated with each endophenotype, exemplified by the limited effect of interferon-beta on immune-response signatures in patients with the inflammatory endophenotype, which was accompanied by increased clinical and imaging features of diseases progression in these patients.
Conclusions:
Ascertaining immune-response signatures in the blood of MS patients is an innovative clinical tool for predicting longitudinal outcomes and guiding personalized treatment decisions based on pathobiological principles.