Is the B cell idea broken?....Sort of Th17 and Th1 are the problem.

The B cell hypothesis gains momentum with the Pharma Industry, but do our academic colleagues know better and it really is the TH17 cell at the top of the pyramid.
Both Th1 and Th17 cells use distinct transmigration routes to enter the CNS. In experimental autoimmune encephalomyelitis, Th1 cells preferentially migrate into the spinal cord, while Th17 cells mainly infiltrate the brain. This is facilitated by their differential expression of pro-inflammatory cytokines, chemokine receptors and integrins 

Interleukin-17 (IL-17) and C-C chemokine receptor 6 (CCR6) are key determinants for Th17 transmigration across the blood–brain barrier

The surface expression of another chemokine receptor, CXCR3, defines Th17 cells with Th1-like which are called Th17.1

In people with CIS that convert to MS there are less TH17.1 cells in the blood.  "The, Th1-like Th17 effector memory cells to non-effector memory ratios in CIS blood inversely correlated to anti-EBNA1 IgG titres (P = 0.013; Fig. 1C). So more link with EBV. Great I say but I must admit this a "neurology correlation" a P value as long as your arm but something that would mean nothing in predicting the influence on an individual. It fails the "smack you in the eye test" and you can draw a line of correlation where ever you like as there is nothing obvious:-(.

Reduction of Th1-like Th17 effector cells in the blood of CIS patients with short time to CDMS. CIS patients were selected based on blood sampling within 4 months after diagnosis and time between CIS and CDMS. ‘CIS-CDMS’ patients were diagnosed with CDMS within 1 year (n = 16; filled bars), while ‘CIS-CIS’ patients were not diagnosed with CDMS for at least 5 years (n = 16; shaded bars). CD4+ T cells in the blood were compared for (A) Th1 (CCR6−CXCR3+), Th17 (CCR6+CXCR3−) and Th1-like Th17 (CCR6+CXCR3+) cell distribution, as well as (B) effector memory (EM; CCR7−CD45RA−) to central memory (CM; CCR7+CD45RA−) cell ratios within each of these subsets, as determined by flow cytometry. Th1-like Th17 effector to central memory cell ratios were correlated to reported predictors of early CIS to CDMS transition, anti-EBNA1 IgG blood titre (C) and fatigue severity scale (FSS; D). *P < 0.05; **P < 0.01.

The cells are gone from the blood because they are in the brain.

These TH17.1 cells however produce interferon gamma and granulocycte macrophage colony stimulating factor but not much IL-17. Is this why anti-IL17A dind't do much in MS?

However, why didn't anti-IL-12/IL-23 as these cells have receptor for IL-23R? This issue was not addressed, yet response to therapy is important is determining what is important and what is not.

Actually, inhibition of IL-12/IL-23 is great at eliminating the induction of disease in mice but to be honest this activity didn't inhibit relapse in mice, so why would you expect it to work in relapsing MS?

The use of both CCR6 and CXCR3 as discriminating markers for Th17 cells does not only reflect their pro-inflammatory state, but also their capability to migrate into local inflammatory sites. 

So should we consider chemokine therapy to get rid of these cells?

In this study theeveal that IFN-γ-/GM-CSF-producing (CCR6+,CXCR3+), but not IL-17-producing (CCR6+CXCR3-) Th17 effector cells are key regulators of multiple sclerosis onset. A Th1-like Th17 subpopulation termed Th17.1  (CCR6+CXCR3+,CCR4-) is selectively targeted by natalizumab in patients with multiple sclerosis who remained free of clinical relapses.

The paper ends " The prominent association of Th1-like Th17 cells, in particular Th17.1, with multiple sclerosis activity suggests the possibility for more specific T cell-targeted therapies, and pleads for further assessment of the use of natalizumab earlier in the disease course of multiple sclerosis"

If DrK got his wish and everyone at diagnosis/presentation was put on natalizumab to stop disease activity whilst time is taken to do clinical work-up and drug selection, this would happen.

So is the B cell idea dead and this is proof that the B cell hypothesis is incorrect. We don't know, as they did not report on what happened with memory B cells so maybe an oppertunity lost. Maybe they measured memory B cells and this failed to show anything interesting maybe they are reporting fantastic results as we read.

van Langelaar J, van der Vuurst de Vries RM, Janssen M, Wierenga-Wolf AF, Spilt IM, Siepman TA, Dankers W, Verjans GMGM, de Vries HE, Lubberts E, Hintzen RQ, van Luijn MM. T helper 17.1 cells associate with multiple sclerosis disease activity: perspectives for early intervention. Brain. 2018 Apr 5. doi: 10.1093/brain/awy069. [Epub ahead of print]

Interleukin-17-expressing CD4+ T helper 17 (Th17) cells are considered as critical regulators of multiple sclerosis disease activity. However, depending on the species and pro-inflammatory milieu, Th17 cells are functionally heterogeneous, consisting of subpopulations that differentially produce interleukin-17, interferon-gamma and granulocyte macrophage colony-stimulating factor. In the current study, we studied distinct effector phenotypes of human Th17 cells and their correlation with disease activity in multiple sclerosis patients. T helper memory populations single- and double-positive for C-C chemokine receptor 6 (CCR6) and CXC chemokine receptor 3 (CXCR3) were functionally assessed in blood and/or cerebrospinal fluid from a total of 59 patients with clinically isolated syndrome, 35 untreated patients and 24 natalizumab-treated patients with relapsing-remitting multiple sclerosis, and nine patients with end-stage multiple sclerosis. Within the clinically isolated syndrome group, 23 patients had a second attack within 1 year and 26 patients did not experience subsequent attacks during a follow-up of >5 years. Low frequencies of T helper 1 (Th1)-like Th17 (CCR6+CXCR3+), and not Th17 (CCR6+CXCR3-) effector memory populations in blood strongly associated with a rapid diagnosis of clinically definite multiple sclerosis. In cerebrospinal fluid of clinically isolated syndrome and relapsing-remitting multiple sclerosispatients, Th1-like Th17 effector memory cells were abundant and showed increased production of interferon-gamma and granulocyte macrophage colony-stimulating factor compared to paired CCR6+ and CCR6-CD8+ T cell populations and their blood equivalents after short-term culturing. Their local enrichment was confirmed ex vivo using cerebrospinal fluid and brain single-cell suspensions. Across all pro-inflammatory T helper cells analysed in relapsing-remitting multiple sclerosis blood, Th1-like Th17 subpopulation T helper 17.1 (Th17.1; CCR6+CXCR3+CCR4-) expressed the highest very late antigen-4 levels and selectively accumulated in natalizumab-treated patients who remained free of clinical relapses. This was not found in patients who experienced relapses during natalizumab treatment. The enhanced potential of Th17.1 cells to infiltrate the central nervous system was supported by their predominance in cerebrospinal fluid of early multiple sclerosis patients and their preferential transmigration across human brain endothelial layers. These findings reveal a dominant contribution of Th1-like Th17 subpopulations, in particular Th17.1 cells, to clinical disease activity and provide a strong rationale for more specific and earlier use of T cell-targeted therapy in multiple sclerosis.