Dynamic Response Genes in CD4+ T Cells Reveal a Network of Interactive Proteins that Classifies Disease Activity in Multiple Sclerosis.
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.
Department of Clinical and Experimental Medicine, Linköping University, 581 83 Linköping, Sweden.
Sandra
S
Hellberg
Department of Clinical and Experimental Medicine, Linköping University, 581 83 Linköping, Sweden. Electronic address: daniel.eklund@liu.se.
Daniel
D
Eklund
The Centre for Individualised Medicine, Department of Clinical and Experimental Medicine, Linköping University, 581 83 Linköping, Sweden.
Danuta R
DR
Gawel
The Centre for Individualised Medicine, Department of Clinical and Experimental Medicine, Linköping University, 581 83 Linköping, Sweden; Bioinformatics, Department of Physics, Chemistry and Biology, Linköping University, 581 83 Linköping, Sweden.
Mattias
M
Köpsén
The Centre for Individualised Medicine, Department of Clinical and Experimental Medicine, Linköping University, 581 83 Linköping, Sweden.
Huan
H
Zhang
The Centre for Individualised Medicine, Department of Clinical and Experimental Medicine, Linköping University, 581 83 Linköping, Sweden.
Colm E
CE
Nestor
Neuroimmunology Unit, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, 171 77 Linköping, Sweden.
Ingrid
I
Kockum
Neuroimmunology Unit, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, 171 77 Linköping, Sweden.
Tomas
T
Olsson
Department of Rheumatology and Department of Clinical and Experimental Medicine, Linköping University, 581 83 Linköping, Sweden.
Thomas
T
Skogh
Department of Rheumatology and Department of Clinical and Experimental Medicine, Linköping University, 581 83 Linköping, Sweden.
Alf
A
Kastbom
Department of Rheumatology and Department of Clinical and Experimental Medicine, Linköping University, 581 83 Linköping, Sweden.
Christopher
C
Sjöwall
Department of Neurology and Department of Clinical and Experimental Medicine, Linköping University, 581 83 Linköping, Sweden.
Magnus
M
Vrethem
Department of Neurology and Department of Clinical and Experimental Medicine, Linköping University, 581 83 Linköping, Sweden.
Irene
I
Håkansson
The Centre for Individualised Medicine, Department of Clinical and Experimental Medicine, Linköping University, 581 83 Linköping, Sweden.
Mikael
M
Benson
Department of Clinical and Experimental Medicine, Linköping University, 581 83 Linköping, Sweden.
Maria C
MC
Jenmalm
Bioinformatics, Department of Physics, Chemistry and Biology, Linköping University, 581 83 Linköping, Sweden. Electronic address: mika.gustafsson@liu.se.
Mika
M
Gustafsson
Department of Clinical Immunology and Transfusion Medicine and Department of Clinical and Experimental Medicine, Linköping University, 581 83 Linköping, Sweden.
Jan
J
Ernerudh
D000328:Adult; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D016022:Case-Control Studies; D002556:Cerebrospinal Fluid Proteins / Q000378:metabolism; D002633:Chemotaxis / Q000235:genetics; D015331:Cohort Studies; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D055106:Genome-Wide Association Study; D006801:Humans; D008213:Lymphocyte Activation / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000134:cerebrospinal fluid / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D011379:Prognosis; D060066:Protein Interaction Maps / Q000235:genetics*; D055815:Young Adult
D002556:Cerebrospinal Fluid Proteins