B cell Cytokines in MS brain, may support B cell follicles.

More on B cells.

No interested?…Why Not?

Interested?…Read on!

Stein J, Xu Q, Jackson KC, Romm E, Wuest SC, Kosa P, Wu T, Bielekova B.Intrathecal B Cells in MS Have Significantly Greater Lymphangiogenic Potential Compared to B Cells Derived From Non-MS Subjects.Front Neurol. 2018;9:554. 

Although B cell depletion is an effective therapy of multiple sclerosis (MS), the pathogenic functions of B cells in MS remain incompletely understood. We asked whether cerebrospinal fluid (CSF) B cells in MS secrete different cytokines than control-subject B cells and whether cytokine secretion affects MS phenotype. 

We blindly studied CSF B cells after their immortalization by Epstein-Barr Virus (EBV) in prospectively-collected MS patients and control subjects with other inflammatory-(OIND) or non-inflammatory neurological diseases (NIND) and healthy volunteers (HV). The pilot cohort (n = 80) was analyzed using intracellular cytokine staining (n = 101 B cell lines [BCL] derived from 35 out of 80 subjects). We validated differences in cytokine production in newly-generated CSF BCL (n = 207 BCL derived from subsequent 112 prospectively-recruited subjects representing validation cohort), using ELISA enhanced by objective, flow-cytometry-based B cell counting. After unblinding the pilot cohort, the immortalization efficiency was almost 5 times higher in MS patients compared to controls (p< 0.001). MS subjects’ BCLs produced significantly more vascular endothelial growth factor (VEGF) compared to control BCLs. Progressive MS patients BCLs produced significantly more tumor necrosis factor (TNF)-α and lymphotoxin (LT)-α than BCL from relapsing-remitting MS (RRMS) patients. In the validation cohort, we observed lower secretion of IL-1β in RRMS patients, compared to all other diagnostic categories. The validation cohort validated enhanced VEGF-C production by BCL from RRMS patients and higher TNF-α and LT-α secretion by BCL from progressive MS. No significant differences among diagnostic categories were observed in secretion of IL-6 or GM-CSF. However, B cell secretion of IL-1β, TNF-α, and GM-CSF correlated significantly with the rate of accumulation of disability measured by MS disease severity scale (MS-DSS). 
Finally, all three cytokines (VEGF-C, TNF-α, and LT-α) with increased secretion in different stages of MS enhance lymphangiogenesis, suggesting that intrathecal B cells directly facilitate the formation of tertiary lymphoid follicles, thus compartmentalizing inflammation to the central nervous system.

In this study they found that B cells from people with MS were much more susceptible to infection with EBV and transformation of the B cell. Although the reasons for this was not investigated, it could be that the genetics of people with MS make them more susceptible to infection, or perhaps more susceptible to be activated once infected. There are differences in infection with different HLA-DR variants in some studies and this would be consistent with a hypothesis that EBV may confer better immune responsiveness to infection, which would support co-evolution theory of virus and humans by ProfG 

In this study the majority of CSF B cells (87.2%) were memory B cells, including CD27-/IgD- memory tissue-based B cells, expressing CD80 and CD86 cell activation markers TNF-α and LT-α were strongly co-expressed by the same B cells.

It is therefore of interest that lymphotoxin also known as tumour necrosis factor beta, is an integral cytokine that is involved in the formation of B cell follicles (place where memory B cells and antibody-forming cells are generated). Another interesting feature is that tumour necrosis factor is a major survival factor for antibody producing plasma cells. 

Interestingly, whilst anti-TNF inhibits arthrits and other autoimmune diseases and gets rid of B cell follicles. In contrast in MS it does not and may make MS worse. Is this because TNF promotes memory B cells, which we know promotes relapsing MS.  However the antibody (anti-TNF) is not going to get into the CNS and so it won’t touch the plasma cell component in the CNS. 

Is this why it failed to inhibit MS?  

Based on studies in arthritis, TNF alpha can promote the production of interleukin-1 and vascular cell growth factor, so maybe in this study they just looking at the same biological process from different ways as they are interlinked.

However, the problem of this unbiased, blinded look-see approach, is that you may not see the wood for the trees

What you find probably does not reflect what is being secreted, but reflects the cell types present and the cytokine contents of those cells. This may have nothing to do with the bias of cytokines being secreted.

So these approaches are totally biased to detect the contents of cells. Therefore if the CNS contains mainly memory B cells, you are going to detect the cytokines within memory B cells. 

There was limited CD24 detected as there were probably few B cells with presumed regulatory function. Does that mean less IL-10, as was found here. If they found loads of IL-10 they would have said regulation, regulation, regulation! 

However, IL-10 is a B cell growth and differentiation factor just as IL-4 is a B cell growth factor and was found to correlate with the immature (transitional) cells. Are these regulatory and produce Th2 cells or do these Bcells use IL-4 to grow? 

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  • Wild guess that b cells of ms patients produce negative effects compared to controls and progressive ms b cells produce more negative effects then RRMS. What is really needed are anti-EBV therapies.

    Every year brings more documentation on ms being combination of EBV
    and genetic alleles.

    "the speculation that the increased blood viral loads seen in our patients are the consequence of a suboptimal control of EBV replication/reactivation by HLA-B*07+ restricted CD8+ T cell. Notably, HLA-B*07 antigen was recently shown to only weakly present viral epitopes to cytotoxic T lymphocytes"

  • For me, the fact that they did the study blinded gives a level of comfort. I favor the hypothesis that the difference in transformation efficiency is a reflection of the number and types of cells in the MSers compared to the non-MSers.

    The influence of the genetic background on susceptibility for EBV infection is a testable hypothesis: Try to transform the B cells from the CNS of people who have MS-susceptibility alleles. You could also compare MSers with Non-MSers, but make sure they have the same HLA genetic background.

    • Number of Types relate to infection efficency…Good call, I think this is sensible guess, they should have immunophenotyped and sorted them so that they were dealing with the same subtype.

      Infections and HLA. Good call too but I am sure it is more than just HLA-

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