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

Romme Christensen J, Börnsen L, Ratzer R, Piehl F, Khademi M, Olsson T, Sørensen PS, Sellebjerg F - PLoS ONE (2013)

Bottom Line: 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.In conclusion, this study is the first to demonstrate the potential involvement of activated TFH-cells in MS.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, University of Copenhagen, Rigshospitalet, Copenhagen, Denmark. jeppe.romme.christensen@rh.regionh.dk

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.

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Gene expression studies of peripheral blood CD4+ and CD8+T-cells from multiple sclerosis patients and healthy controls.Mean plots show mean normalization ratios (NR) with error bars representing 95% confidence intervals. Parametric (ANOVA and post-hoc T-tests) or non-parametric (Kruskal-Wallis (KW) and Mann-Whitney (MW)) statistic tests were applied when suitable. (A) Gene expression analysis in CD4+T-cells shows increased expression of ICOS, IL21R and LTB in secondary progressive (SPMS) and primary progressive (PPMS) multiple sclerosis patients as compared to healthy controls (HC) and increased expression of IL21 and IFNG in SPMS patients compared to HCs. (B) Gene expression analysis in CD8+T-cells shows increased expression of GATA3, LTB and LTBR in SPMS and PPMS compared to HCs. HLX, TGFB, TNFA and TNFSF14 were increased in SPMS compared to HCs.
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pone-0057820-g003: Gene expression studies of peripheral blood CD4+ and CD8+T-cells from multiple sclerosis patients and healthy controls.Mean plots show mean normalization ratios (NR) with error bars representing 95% confidence intervals. Parametric (ANOVA and post-hoc T-tests) or non-parametric (Kruskal-Wallis (KW) and Mann-Whitney (MW)) statistic tests were applied when suitable. (A) Gene expression analysis in CD4+T-cells shows increased expression of ICOS, IL21R and LTB in secondary progressive (SPMS) and primary progressive (PPMS) multiple sclerosis patients as compared to healthy controls (HC) and increased expression of IL21 and IFNG in SPMS patients compared to HCs. (B) Gene expression analysis in CD8+T-cells shows increased expression of GATA3, LTB and LTBR in SPMS and PPMS compared to HCs. HLX, TGFB, TNFA and TNFSF14 were increased in SPMS compared to HCs.

Mentions: To substantiate the findings in the flow cytometry studies, we analyzed gene expression in purified CD4+T-cells, CD8+T-cells, B-cells, monocytes and dendritic cells (Table S3). Expression of ICOS, IL21 and IL21R (IL21-receptor) in CD4+T-cells from SPMS patients was increased, which is suggestive of increased activation of TFH-cells in SPMS (Figure 3A). In addition, SPMS patients had increased expression of IFNG in CD4+T-cells and of LTB (lymphotoxin-beta) in CD4+ and CD8+T-cells and of TNFA, LTBR (LTB-receptor), TNFSF14 (LIGHT), and the transcription factors HLX and GATA3 in CD8+T-cells. In PPMS patients there was higher expression of ICOS, IL21R and LTB in CD4+T-cells and of LTB, LTBR, TGFB1 (transforming growth factor-beta) and GATA3 in CD8+T-cells.


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

Romme Christensen J, Börnsen L, Ratzer R, Piehl F, Khademi M, Olsson T, Sørensen PS, Sellebjerg F - PLoS ONE (2013)

Gene expression studies of peripheral blood CD4+ and CD8+T-cells from multiple sclerosis patients and healthy controls.Mean plots show mean normalization ratios (NR) with error bars representing 95% confidence intervals. Parametric (ANOVA and post-hoc T-tests) or non-parametric (Kruskal-Wallis (KW) and Mann-Whitney (MW)) statistic tests were applied when suitable. (A) Gene expression analysis in CD4+T-cells shows increased expression of ICOS, IL21R and LTB in secondary progressive (SPMS) and primary progressive (PPMS) multiple sclerosis patients as compared to healthy controls (HC) and increased expression of IL21 and IFNG in SPMS patients compared to HCs. (B) Gene expression analysis in CD8+T-cells shows increased expression of GATA3, LTB and LTBR in SPMS and PPMS compared to HCs. HLX, TGFB, TNFA and TNFSF14 were increased in SPMS compared to HCs.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3585852&req=5

pone-0057820-g003: Gene expression studies of peripheral blood CD4+ and CD8+T-cells from multiple sclerosis patients and healthy controls.Mean plots show mean normalization ratios (NR) with error bars representing 95% confidence intervals. Parametric (ANOVA and post-hoc T-tests) or non-parametric (Kruskal-Wallis (KW) and Mann-Whitney (MW)) statistic tests were applied when suitable. (A) Gene expression analysis in CD4+T-cells shows increased expression of ICOS, IL21R and LTB in secondary progressive (SPMS) and primary progressive (PPMS) multiple sclerosis patients as compared to healthy controls (HC) and increased expression of IL21 and IFNG in SPMS patients compared to HCs. (B) Gene expression analysis in CD8+T-cells shows increased expression of GATA3, LTB and LTBR in SPMS and PPMS compared to HCs. HLX, TGFB, TNFA and TNFSF14 were increased in SPMS compared to HCs.
Mentions: To substantiate the findings in the flow cytometry studies, we analyzed gene expression in purified CD4+T-cells, CD8+T-cells, B-cells, monocytes and dendritic cells (Table S3). Expression of ICOS, IL21 and IL21R (IL21-receptor) in CD4+T-cells from SPMS patients was increased, which is suggestive of increased activation of TFH-cells in SPMS (Figure 3A). In addition, SPMS patients had increased expression of IFNG in CD4+T-cells and of LTB (lymphotoxin-beta) in CD4+ and CD8+T-cells and of TNFA, LTBR (LTB-receptor), TNFSF14 (LIGHT), and the transcription factors HLX and GATA3 in CD8+T-cells. In PPMS patients there was higher expression of ICOS, IL21R and LTB in CD4+T-cells and of LTB, LTBR, TGFB1 (transforming growth factor-beta) and GATA3 in CD8+T-cells.

Bottom Line: 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.In conclusion, this study is the first to demonstrate the potential involvement of activated TFH-cells in MS.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, University of Copenhagen, Rigshospitalet, Copenhagen, Denmark. jeppe.romme.christensen@rh.regionh.dk

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.

Show MeSH
Related in: MedlinePlus