Naive CD4 T-cell activation identifies MS patients having rapid transition to progressive MS

  • E. Z
  • L. F
  • M. H
 et al. 
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Abstract

Objective: Our objective was to determine whether altered naive CD4 T-cell biology contributes to development of disease progression in secondary progressive multiple sclerosis (SPMS). Methods: We compared the naive CD4 T-cell gene expression profiles of 19 patients with SPMS and 14 healthy controls (HCs) using a whole-genome microarray approach. We analyzed surface protein expression of critical genes by flow cytometry after T-cell receptor (TCR) stimulation of naive CD4 T cells isolated from HCs and patients with SPMS. Results: Hierarchical clustering segregated patients with SPMS into 2 subgroups: SP-1, which had a short duration of relapsing-remitting multiple sclerosis (MS), and SP-2, which had a long duration of relapsing-remitting MS. SP-1 patients upregulated numerous immune genes, including genes within TCR and toll-like receptor (TLR) signaling pathways. SP-2 patients showed immune gene downregulation in comparison with HCs. We identified an SP-1-specific transcriptional signature of 3 genes (TLR4, TLR2, and chemokine receptor 1), and these genes had higher surface protein expression in SP-1 than in SP-2. After TCR stimulation for 48 hours, only SP-1 showed a progressive linear increase in TLR2 and TLR4 protein expression. Conclusions: Differences in naive CD4 T-cell biology, notably of TCR and TLR signaling pathways, identified patients with MS with more rapid conversion to secondary progression, a critical determinant of long-term disability in MS.

Author-supplied keywords

  • *CD4+ T lymphocyte
  • *T lymphocyte activation
  • *disease course
  • *multiple sclerosis/dt [Drug Therapy]
  • CD28 antigen/ec [Endogenous Compound]
  • CD3 antigen/ec [Endogenous Compound]
  • CD4 antigen/ec [Endogenous Compound]
  • CD45RA antigen/ec [Endogenous Compound]
  • Expanded Disability Status Scale
  • T lymphocyte receptor/ec [Endogenous Compound]
  • adult
  • article
  • beta1a interferon/dt [Drug Therapy]
  • cell isolation
  • chemokine receptor CCR1/ec [Endogenous Compound]
  • clinical article
  • controlled study
  • cyclophosphamide/dt [Drug Therapy]
  • demyelinating disease
  • disease duration
  • down regulation
  • female
  • flow cytometry
  • gene expression
  • gene expression profiling
  • gene ontology
  • genetic association
  • genetic transcription
  • human
  • immunogenetics
  • immunosuppressive treatment
  • innate immunity
  • interferon beta serine/dt [Drug Therapy]
  • interferon regulatory factor 5/ec [Endogenous Comp
  • interferon regulatory factor 7/ec [Endogenous Comp
  • male
  • membrane protein/ec [Endogenous Compound]
  • memory T lymphocyte
  • messenger RNA/ec [Endogenous Compound]
  • methotrexate/dt [Drug Therapy]
  • microarray analysis
  • middle aged
  • mitogen activated protein kinase/ec [Endogenous Co
  • monocyte
  • myeloid differentiation factor 88/ec [Endogenous C
  • nerve degeneration
  • overlapping gene
  • priority journal
  • protein expression
  • real time polymerase chain reaction
  • signal transduction
  • toll like receptor 1/ec [Endogenous Compound]
  • toll like receptor 2/ec [Endogenous Compound]
  • toll like receptor 4/ec [Endogenous Compound]
  • toll like receptor 7/ec [Endogenous Compound]
  • upregulation

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Authors

  • Zastepa E.

  • Fitz-Gerald L.

  • Hallett M.

  • Antel J.

  • Bar-Or A.

  • Baranzini S.

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