Systemic inflammation in progressive multiple sclerosis involves follicular T-helper, Th17- and activated B-cells and correlates with progression

PLoS One. 2013;8(3):e57820. doi: 10.1371/journal.pone.0057820. Epub 2013 Mar 1.

Abstract

Pathology studies of progressive multiple sclerosis (MS) indicate a major role of inflammation including Th17-cells and meningeal inflammation with ectopic lymphoid follicles, B-cells and plasma cells, the latter indicating a possible role of the newly identified subset of follicular T-helper (TFH) cells. Although previous studies reported increased systemic inflammation in progressive MS it remains unclear whether systemic inflammation contributes to disease progression and intrathecal inflammation. This study aimed to investigate systemic inflammation in progressive MS and its relationship with disease progression, using flow cytometry and gene expression analysis of CD4(+) and CD8(+)T-cells, B-cells, monocytes and dendritic cells. Furthermore, gene expression of cerebrospinal fluid cells was studied. Flow cytometry studies revealed increased frequencies of ICOS(+)TFH-cells in peripheral blood from relapsing-remitting (RRMS) and secondary progressive (SPMS) MS patients. All MS subtypes had decreased frequencies of Th1 TFH-cells, while primary progressive (PPMS) MS patients had increased frequency of Th17 TFH-cells. The Th17-subset, interleukin-23-receptor(+)CD4(+)T-cells, was significantly increased in PPMS and SPMS. In the analysis of B-cells, we found a significant increase of plasmablasts and DC-SIGN(+) and CD83(+)B-cells in SPMS. ICOS(+)TFH-cells and DC-SIGN(+)B-cells correlated with disease progression in SPMS patients. Gene expression analysis of peripheral blood cell subsets substantiated the flow cytometry findings by demonstrating increased expression of IL21, IL21R and ICOS in CD4(+)T-cells in progressive MS. Cerebrospinal fluid cells from RRMS and progressive MS (pooled SPMS and PPMS patients) had increased expression of TFH-cell and plasmablast markers. In conclusion, this study is the first to demonstrate the potential involvement of activated TFH-cells in MS. The increased frequencies of Th17-cells, activated TFH- and B-cells parallel findings from pathology studies which, along with the correlation between activated TFH- and B-cells and disease progression, suggest a pathogenic role of systemic inflammation in progressive MS. These observations may have implications for the treatment of progressive MS.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • B-Lymphocytes / metabolism
  • B-Lymphocytes / pathology*
  • Cell Adhesion Molecules / cerebrospinal fluid
  • Cell Adhesion Molecules / genetics
  • Dendritic Cells / metabolism
  • Dendritic Cells / pathology
  • Disease Progression
  • Female
  • Flow Cytometry
  • Gene Expression
  • Humans
  • Inducible T-Cell Co-Stimulator Protein / genetics
  • Inducible T-Cell Co-Stimulator Protein / metabolism
  • Inflammation / cerebrospinal fluid
  • Inflammation / genetics
  • Inflammation / pathology
  • Interleukin-21 Receptor alpha Subunit / genetics
  • Interleukin-21 Receptor alpha Subunit / metabolism
  • Interleukin-23 / cerebrospinal fluid
  • Interleukin-23 / genetics
  • Interleukins / cerebrospinal fluid
  • Interleukins / genetics
  • Lectins, C-Type / genetics
  • Lymphocyte Activation
  • Male
  • Middle Aged
  • Monocytes / metabolism
  • Monocytes / pathology
  • Multiple Sclerosis, Chronic Progressive / cerebrospinal fluid*
  • Multiple Sclerosis, Chronic Progressive / genetics
  • Multiple Sclerosis, Chronic Progressive / pathology*
  • Receptors, Cell Surface / genetics
  • Receptors, Interleukin / genetics
  • Receptors, Interleukin / metabolism
  • Th17 Cells / metabolism
  • Th17 Cells / pathology*

Substances

  • Cell Adhesion Molecules
  • DC-specific ICAM-3 grabbing nonintegrin
  • ICOS protein, human
  • IL21R protein, human
  • IL23R protein, human
  • Inducible T-Cell Co-Stimulator Protein
  • Interleukin-21 Receptor alpha Subunit
  • Interleukin-23
  • Interleukins
  • Lectins, C-Type
  • Receptors, Cell Surface
  • Receptors, Interleukin
  • interleukin-21

Grant support

This work was supported by the Danish Council for Independent Research (grant 271-06-0246), the Danish Council for Strategic Research (grant 2142-08-0039), the Danish MS Society, the Warwara Larsen Foundation, the Johnsen Foundation, Brdr. Rønje Holding, Jeppe Juel Memorial Legacy and research grants from Biogen Idec. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.