Th17 are still in the mind or many.

T

IL-17A is associated with the breakdown of the blood-brain barrier in relapsing-remitting multiple sclerosis.Setiadi AF, Abbas AR, Jeet S, Wong K, Bischof A, Peng I, Lee J, Bremer M, Eggers EL, DeVoss J, Staton T, Herman A, von Büdingen HC, Townsend MJ. J Neuroimmunol. 2019;332:147-154.

IL-17 has been implicated in the pathogenesis of multiple sclerosis (MS). Here, we show that blockade of IL-17A, but not IL-17F, attenuated experimental autoimmune encephalomyelitis (EAE). We further show that IL-17A levels were elevated in the CSF of relapsing-remitting MS (RRMS) patients and that they correlated with the CSF/serum albumin quotient (Qalb), a measure of blood-brain barrier (BBB) dysfunction. We then demonstrated that the combination of IL-17A and IL-6 reduced the expression of tight junction (TJ)-associated genes and disrupted monolayer integrity in the BBB cell line hCMEC/D3. However, unlike IL-17A, IL-6 in the CSF from RRMS patients did not correlate with Qalb. These data highlight the potential importance of targeting IL-17A in preserving BBB integrity in RRMS.

We shouldn’t give up on the TH17 idea. TH17 produce interleukin 17 and there are many different variants of this. This study tels us that IL-17A and not IL-17F is the interesting one…I guess this is not that surprising as this is what the knockout mice has told us that IL-17A is important.

If we look at the effect however. I say is this as good as it gets as many current DMT would have eliminated EAE if used in the same way. OK the treated animals get a limp tail but they still are getting disease and so woud be seen as a relapse and a failure in human studies. The mice were only checked every 3 days and so the results are probably quite un-reliable as a lot can happen in 3 days

The paper suggests that IL-17 is involved in affecting blood brain barrier problems…However the past trial only got rid of enhancing lesions by less beta interferon (about 65%), so not in the same league as B cell depletion at about 95%. You can have a read as it is open access.

Meanwhile other people are saying that B cell products in the brain are the problem

Association of Intrathecal Immunoglobulin G Synthesis With Disability Worsening in Multiple Sclerosis.Gasperi C, Salmen A, Antony G, Bayas A, Heesen C, Kümpfel T, Linker RA, Paul F, Stangel M, Tackenberg B, Bergh FT, Warnke C, Weber F, Wiendl H, Wildemann B, Zettl UK, Ziemann U, Zipp F, Tumani H, Gold R, Hemmer B; German Competence Network of Multiple Sclerosis. JAMA Neurol. 2019 Apr 29. doi: 10.1001/jamaneurol.2019.0905. [Epub ahead of print]PMID: 31034002

IMPORTANCE: Reliable biomarkers associated with disability worsening in multiple sclerosis (MS) are still needed.

OBJECTIVE: To determine a possible association of intrathecal IgG synthesis and early disability worsening as measured by Expanded Disability Status Scale (EDSS) scoring in patients with relapsing-remitting MS or clinically isolated syndrome.

DESIGN, SETTING, AND PARTICIPANTS: Cerebrospinal fluid measurements and clinical data from the observational longitudinal German national multiple sclerosis cohort were analyzed. Patients were recruited between August 2010 and November 2015 from 18 centers. Data analysis was completed from August 2018 to December 2018.

EXPOSURE:

Patients were offered standard immunotherapies per national treatment guidelines.

MAIN OUTCOMES AND MEASURES: A possible association between intrathecal IgG synthesis and risk of EDSS worsening 4 years after study inclusion was tested as the primary end point by multivariable binomial regression analysis. Kaplan-Meier analysis with a log-rank test was used to assess the association of intrathecal IgG synthesis with the time to EDSS worsening. Associations between intrathecal IgM or IgA synthesis and other cerebrospinal fluid parameters and EDSS worsening were analyzed as exploratory end points. Data collection began before the hypotheses were formulated.

RESULTS: Of all 1376 patients in the German Competence Network of Multiple Sclerosis cohort, 703 patients were excluded owing to missing cerebrospinal fluid or EDSS data. Of the 673 included patients, 459 (68.2%) were women. The mean (SD) age at baseline was 34 (10) years. Intrathecal IgG synthesis was associated with a higher risk of EDSS worsening after 4 years (odds ratio, 2.02 [95% CI, 1.15-3.58]; P = .01), independent of the occurrence of relapses and disease-modifying therapy. Additionally, intrathecal IgG synthesis was associated with earlier EDSS worsening; 4 years after study entry, worsening occurred in 28.4% (95% CI, 22.7%-34.1%) and 18.1% (95% CI, 12.4%-23.9%) of patients with and without intrathecal IgG synthesis, respectively. No association of other routine cerebrospinal fluid parameters with EDSS worsening was found.

CONCLUSIONS AND RELEVANCE: Patients with new diagnoses of relapsing-remitting multiple sclerosis or clinically isolated syndrome with intrathecal IgG synthesis had a higher risk of and shorter time to EDSS worsening across a 4-year period of follow-up. Intrathecal IgG synthesis is a potentially useful marker for disability worsening in patients with multiple sclerosis and may be useful for early treatment decisions.

So another person says we need to get rid of the B cell response in the brain. ProfG an NDG are working on it

B cell depletion

About the author

MouseDoctor

3 comments

  • Mouse your ´re the man

    So question :

    Does this pass the” smack in your eyes test”?

    “worsening occurred in 28.4% (95% CI, 22.7%-34.1%) and 18.1% (95% CI, 12.4%-23.9%) of patients with and without intrathecal IgG synthesis, respectively”

    Guess what 18.1% of patients (122) did´nt had Ocbs and STILL progressed ( the diference is 10,3% for the ocbs positive patients) …In the next 4 years

    Should our treatment target in MS include the intrathecal plasma cell response?

    https://www.msard-journal.com/article/S2211-0348(18)30569-8/fulltext

    “we hypothesise that OCBs are likely to be pathogenic in
    MS.”

    Professor Giovannoni

    If they are what you going to say to those 122 patiients (18.1%) that had -ocbs and had progressed in 4 years????

    The abstract does´nt mention the number ocb + and ocb- as a whole that is very important

    In 4 years 360 patients DID NOT progressed where they ocb+ or ocb – ?

    It would be useful to see those that are ocb + and did not progressed

    I dont have acess to the paper(not yet)

    Ps: Of those people there are more 2 that are ocb –

    The Wheelchair Kamikaze
    August 1, 2018 at 8:50 am

    A Nonny Moose – For what it’s worth, I am also OCB negative and have had a progressively worsening disease path ever since diagnosis (actually from before diagnosis). I believe Dr. G has stated that he thinks OCB negative patients may not have ms.

    https://multiple-sclerosis-research.org/2018/07/oligoclonal-bands-what-are-they-doing/

  • “We conclude that the demographic and topographic characteristics are low-impact prognostic factors, the presence of oligoclonal bands is a medium-impact prognostic factor, and the number of lesions on brain magnetic resonance is a high-impact prognostic factor.

    Defining high, medium and low impact
    prognostic factors for developing multiple
    sclerosis

    10.1093/brain/awv105

  • Optimal Response to Dimethyl Fumarate is Mediated by a Reduction of Th17.1 cells after 3 Months of Treatment
    Results:The beneficial effect of DMF was associated with a specific depletion of memory CD4+ and CD8+ T lymphocytes and B cells. Importantly, only NEDA patients showed: i) a shift from a pro- to an anti-inflammatory profile, with an increase of Th2 cells and a decrease of Th17.1 lymphocytes; ii) an induction of transitional B cells; and iii) an increase of regulatory CD56bright NK cells. Conclusions:The optimal response to DMF is mediated by a shift to anti-inflammatory and immunoregulatory profile, showing Th17.1 lymphocytes as a potential early biomarker of treatment response.
    http://indexsmart.mirasmart.com/AAN2019/PDFfiles/AAN2019-003271.pdf

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