Dynamic Response Genes in CD4+ T Cells Reveal a Network of Interactive Proteins that Classifies Disease Activity in Multiple Sclerosis
Sandra Hellberg,
Daniel Eklund,
Danuta R. Gawel,
Mattias Köpsén,
Huan Zhang,
Colm E. Nestor,
Ingrid Kockum,
Tomas Olsson,
Thomas Skogh,
Alf Kastbom,
Christopher Sjöwall,
Magnus Vrethem,
Irene Håkansson,
Mikael Benson,
Maria C. Jenmalm,
Mika Gustafsson,
Jan Ernerudh
Affiliations
Sandra Hellberg
Department of Clinical and Experimental Medicine, Linköping University, 581 83 Linköping, Sweden
Daniel Eklund
Department of Clinical and Experimental Medicine, Linköping University, 581 83 Linköping, Sweden
Danuta R. Gawel
The Centre for Individualised Medicine, Department of Clinical and Experimental Medicine, Linköping University, 581 83 Linköping, Sweden
Mattias Köpsén
The Centre for Individualised Medicine, Department of Clinical and Experimental Medicine, Linköping University, 581 83 Linköping, Sweden
Huan Zhang
The Centre for Individualised Medicine, Department of Clinical and Experimental Medicine, Linköping University, 581 83 Linköping, Sweden
Colm E. Nestor
The Centre for Individualised Medicine, Department of Clinical and Experimental Medicine, Linköping University, 581 83 Linköping, Sweden
Ingrid Kockum
Neuroimmunology Unit, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, 171 77 Linköping, Sweden
Tomas Olsson
Neuroimmunology Unit, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, 171 77 Linköping, Sweden
Thomas Skogh
Department of Rheumatology and Department of Clinical and Experimental Medicine, Linköping University, 581 83 Linköping, Sweden
Alf Kastbom
Department of Rheumatology and Department of Clinical and Experimental Medicine, Linköping University, 581 83 Linköping, Sweden
Christopher Sjöwall
Department of Rheumatology and Department of Clinical and Experimental Medicine, Linköping University, 581 83 Linköping, Sweden
Magnus Vrethem
Department of Neurology and Department of Clinical and Experimental Medicine, Linköping University, 581 83 Linköping, Sweden
Irene Håkansson
Department of Neurology and Department of Clinical and Experimental Medicine, Linköping University, 581 83 Linköping, Sweden
Mikael Benson
The Centre for Individualised Medicine, Department of Clinical and Experimental Medicine, Linköping University, 581 83 Linköping, Sweden
Maria C. Jenmalm
Department of Clinical and Experimental Medicine, Linköping University, 581 83 Linköping, Sweden
Mika Gustafsson
Bioinformatics, Department of Physics, Chemistry and Biology, Linköping University, 581 83 Linköping, Sweden
Jan Ernerudh
Department of Clinical Immunology and Transfusion Medicine and Department of Clinical and Experimental Medicine, Linköping University, 581 83 Linköping, Sweden
Multiple sclerosis (MS) is a chronic inflammatory disease of the CNS and has a varying disease course as well as variable response to treatment. Biomarkers may therefore aid personalized treatment. We tested whether in vitro activation of MS patient-derived CD4+ T cells could reveal potential biomarkers. The dynamic gene expression response to activation was dysregulated in patient-derived CD4+ T cells. By integrating our findings with genome-wide association studies, we constructed a highly connected MS gene module, disclosing cell activation and chemotaxis as central components. Changes in several module genes were associated with differences in protein levels, which were measurable in cerebrospinal fluid and were used to classify patients from control individuals. In addition, these measurements could predict disease activity after 2 years and distinguish low and high responders to treatment in two additional, independent cohorts. While further validation is needed in larger cohorts prior to clinical implementation, we have uncovered a set of potentially promising biomarkers.
