Thursday, 14 March 2013

Research: Th17 and Progressive MS


Background: 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 (T) cells. Although previous studies reported increased systemic inflammation in progressive MS it remains unclear whether systemic inflammation contributes to disease progression and intrathecal inflammation. 


Aims & methods: 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 CD8T-cells, B-cells, monocytes and dendritic cells. Furthermore, gene expression of cerebrospinal fluid cells was studied. 

Results: Flow cytometry studies revealed increased frequencies of ICOST-cells in peripheral blood from relapsing-remitting (RRMS) and secondary progressive (SPMS) MS patients. All MS subtypes had decreased frequencies of Th1 T-cells, while primary progressive (PPMS) MS patients had increased frequency of Th17 T-cells. The Th17-subset, interleukin-23-receptor CD4T-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 CD83B-cells in SPMS. ICOST-cells and DC-SIGNB-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 , and in CD4 T-cells in progressive MS. Cerebrospinal fluid cells from RRMS and progressive MS (pooled SPMS and PPMS patients) had increased expression of T-cell and plasmablast markers. 

Conclusions: In conclusion, this study is the first to demonstrate the potential involvement of activated T-cells in MS. The increased frequencies of Th17-cells, activated T- and B-cells parallel findings from pathology studies which, along with the correlation between activated T- 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.


What causes progressive MS is still not clear. The failure of T cell therapy to have a major influence on progressive MS, has questioned the role of this part of the immune system in progression. However many people think that the problem with MS is all simply a problem of the immune system. This study looks at the blood of relapsing and progressive MSers. They find an increased occurrance of Th17 cells in primary and  secondary progressive MS. Is this causal or an epiphenomenon?  The best way to find out is get rid of them and see if it impacts progressive MS. Many cells in the blood will be passengers for the day, whether they are reflective of the disease causing cells requires further study.

6 comments:

  1. Th17 have been proven to have a causal relation during relapses in the relapsing-remitting form. Now Th17 are also present in the SP form, and nevertheless no (or very little) inflamation can be seen in SPMS patients MRIs. How is it possible that T-cells do not cross the BB Barrier during the progressive phase, if the same peripheral T cells appear to be present in excess as during the relapses?

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  2. Where is the proven causal role data in MS I must have missed it...please send a link

    There is little T cell inflammation but there is glial inflammation in SPMS and I suspect that T cells do indeed cross the BBB but in low numbers

    Best wishes

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  3. You know, I'm still unclear about the role of plasma
    blasts in progressive MS. The monococlonal antibodies being trialled in PPMS are CD20, but isn't it CD19 antibodies that treat wayward plasmablasts? Therefore, why are we pursuing CD20?

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    Replies
    1. Both CD19 and CD20 are being pursued

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    2. Anon: Are you new to the blog? Check out the following post: http://multiple-sclerosis-research.blogspot.co.uk/2012/11/anti-cd19-and-multiple-sclerosis.html

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    3. Why on earth are CD19 trials only open to RRMSers when the drug will actually, if successful, benefit the much underserved PPMS community? Once again this illustrates the inefficiency of medical trials because even if the results are good when trials end in 2016, it will take another three years to repeat trials in PPMSers.

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