Rebound after treatment withdrawal says the important cells for relapse are…yep you got it!

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ProfG always said the rebound that occurs after natalizumab was going to be one of the best ways to work out what are the important disease drivers in MS. Natalizumab is a brake for pathogenic cells entering the brain, Remove the brake and cells go in and trigger disease activation. Sadly by the time of thinking about this, strategies to stop rebound were developed and as we would switch treatement before we were going to see rebound, and so we couldn’t do a natalizilumab-induced rebound study. The next oppertunity came with fingolimod, but again an opportunity was missed. Fingolimod is eliminated slowly and so rebound may not occur as quickly as could occur with ozanimod and siponimod.

How quickly will you switch if ozanimod fails with the view to stop rebound. Indeed with any migration inhibitor it is worth thinking about “what next” before you start. There are a number of new Sphingosine-1-phosphate modulator arriving and these may carry a risk of rebound disease activity when you stop taking them and transition onto something else. There is a window of opportunity to work out what is driving the relapse if rebound happens. T cells? B cells? or both T and B cells? With siponimod in the EU, there is no alternative to switch too. So what cells will be entering. In this study it seems it was guess what?….. Th17 T cells? No, it was antigen-experienced memory B cells. Do you feel that a pattern is emerging? Maybe the penny is droppping, because in this study they did not look at T cells. So whilst the Big-swingers (opinion leaders) keep on their T cell crusades as they have massive labs to feed, the “readers” are starting to focus elsewhere.

The Choroid Plexus Is Permissive for a Preactivated Antigen-Experienced Memory B-Cell Subset in Multiple Sclerosis.Haas J, Rudolph H, Costa L, Faller S, Libicher S, Würthwein C, Jarius S, Ishikawa H, Stump-Guthier C, Tenenbaum T, Schwerk C, Schroten H, Wildemann B.Front Immunol. 2021 Jan 26;11:618544. doi

The role of B cells in multiple sclerosis (MS) is increasingly recognized. B cells undergo compartmentalized redistribution in blood and cerebrospinal fluid (CSF) during active MS, whereby memory B cells accumulate in the CSF. While B-cell trafficking across the blood-brain barrier has been intensely investigated, cellular diapedesis through the blood-CSF barrier (BCSFB) is incompletely understood. To investigate how B cells interact with the choroid plexus to transmigrate into the CSF we isolated circulating B cells from healthy donors (HC) and MS patients, utilized an inverted cell culture filter system of human choroid plexus papilloma (HIBCPP) cells to determine transmigration rates of B-cell subsets, immunofluorescence, and electron microscopy to analyze migration routes, and qRT-PCR to determine cytokines/chemokines mediating B-cell diapedesis. We also screened the transcriptome of intrathecal B cells from MS patients. We found, that spontaneous transmigration of HC- and MS-derived B cells was scant, yet increased significantly in response to B-cell specific chemokines CXCL-12/CXCL-13, was further boosted upon pre-activation and occurred via paracellular and transcellular pathways. Migrating cells exhibited upregulation of several genes involved in B-cell activation/migration and enhanced expression of chemokine receptors CXCR4/CXCR5, and were predominantly of isotype class switched memory phenotype. This antigen-experienced migratory subset displayed more pronounced chemotactic activities in MS than in HC and was retrieved in intrathecal B cells from patients with active MS. Trafficking of class-switched memory B cells was downscaled in a small cohort of natalizumab-exposed MS patients and the proportions of these phenotypes were reduced in peripheral blood yet were enriched intrathecally in patients who experienced recurrence of disease activity after withdrawal of natalizumab. Our findings highlight the relevance of the BCSFB as important gate for the entry of potentially harmful activated B cells into the CSF

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3990679/

The choroid plexus or plica choroidea, is a plexus of cells that arises from the tela choroidea in each of the ventricles of the brain. The choroid plexus produces most of the cerebrospinal fluid (CSF) of the central nervous system.CSF is produced and secreted by the regions of choroid plexus. The choroid plexus consists of modified ependymal cells surrounding a core of capillaries and loose connective tissue. Here they suggest again it is a gateway for cells and if we look back in the literature it has been suggested that suggested to serve as a gateway for encephalitogenic cells entering the CNS via CCL20-CCR6 interactions between Th17 cells and Choroid plexus-derived CCL20. It is also a gateway for macrophage-type cells. You do get MS-lesions accumulating in the ventricles and their are alternative ideas of why this occurs. Quick call the Doctors CCSVIers have infiltrated my brain, however it is clear cells get into the CNS not through such gates.

Is the T cell tide changing. I think so and this can only occur if the referees of papers have an open mind. It is amazing the number of times that one is forced to mention T cells by the referees, yet turn it the other way on a T cell paper and B cells never get mentioned.

However, as you are drip-fed the story and some will say like “water torture”, opinions change. The big swingers will have a “eureka” moment and convince us all that they have invented the B cell wheel. However it is weight of evidence that is important and happy that this is all boosting our H-index .

Baker D, Marta M, Pryce G, Giovannoni G, Schmierer K. Memory B Cells are Major Targets for Effective Immunotherapy in Relapsing Multiple Sclerosis. EBioMedicine (2017) 16:41–50

If evidence that counters our ideas occur let us know if we dont review it because if they are right we will change our ideas and move one. But on this one I have a feeling you may get that drip, drip, drip for some time :-).

Why is it important to do this? Well I think it helps to explain your treatments better and if you know where to focus you can make the treatments better and safer.

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MouseDoctor

2 comments

Leave a Reply to Steve Cancel reply

  • What’s stopping them from checking both T & B cells? I feel we’ve reached the stage where we could also test a dozen of arbitrary things in parallel.

  • “With siponimod in the EU, there is no alternative to switch too “.
    Why is switching to another, like a CD20 therapy, not possible?

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