Times are Changing. People are getting B cell tinted glasses to try and explain MS


Our favourite saying has been saying “Its behind you” because when you dont know where you are looking you might not look in the right place….and the big bag cat with a club is behind you compared to the cute little kitties in fronto fo you. In the time of street light science we have been looking at the T cell….Drip, Drip, Drip and we have been making the case that something in the memory B cell pool is important and then you know where to look…It is now no longer really complex and you can focus. You may not focus right but at least you are not wasting your time focussing in the wrong place.

The “Streetlight Effect”: a metaphor for knowledge and ignorance – Axis,  Praxis

Pregnancy-induced effects on memory B-cell development in multiple sclerosis.Janssen M, Rijvers L, Koetzier SC, Wierenga-Wolf AF, Melief MJ, van Langelaar J, Runia TF, de Groot CJM, Neuteboom R, Smolders J, van Luijn MM.Sci Rep. 2021 Jun 9;11(1):12126. In MS, pathogenic memory B cells infiltrate the brain and develop into antibody-secreting cells. Chemokine receptors not only define their brain-infiltrating capacity, but also assist in their maturation in germinal centers. How this corresponds to pregnancy, as a naturally occurring modifier of MS, is underexplored. Here, we aimed to study the impact of pregnancy on both ex vivo and in vitro B-cell differentiation in MS. The composition and outgrowth of peripheral B cells were compared between 19 MS pregnant patients and 12 healthy controls during the third trimester of pregnancy (low relapse risk) and postpartum (high relapse risk). Transitional, and not naive mature, B-cell frequencies were found to drop in the third trimester, which was most prominent in patients who experienced a pre-pregnancy relapse. Early after delivery, these frequencies raised again, while memory B -cell frequencies modestly declined. CXCR4 was downregulated and CXCR5, CXCR3 and CCR6 were upregulated on postpartum memory B cells, implying enhanced recruitment into germinal center light zones for interaction with T follicular helper (TFH) cells. Postpartum memory B cells of MS patients expressed higher levels of CCR6 and preferentially developed into plasma cells under TFH-like in vitro conditions. These findings imply that memory B- cell differentiation contributes to postpartum relapse risk in MS.

Now some people will say that antibodies are not the major issue for B cells in MS. its one explanation there are others. But it seems that memory cells get in the brain. In this paper they report CXCR3 and CCR6 are up regulated and this are chemokine receptors that allow cells to migrate up a gradient towards CXCR3 and CCR6 ligands (things that bind to receptors).. CXCR5 goes down so the B cells wont be attracted in lymphoid tissue and cells with CCR6 migrate towards CCL20, also known as macrophage inflammatory protein 3. CCL20 can be expressed in inflamed CNS…is this how memory B cells get in the brain. CCL20 variants may be a risk factor for MS. It will be part of the equation

In the other paper below they change the genetic environment of a B cell infected with EBV and it can now migrate into the central nervous system and one of the proteins make is osteopontin. This protein has been implicated in the pathology of MS and arthritis.

Trafficking of pathogenic B-cells to the CNS can drive CNS lymphoma and multiple sclerosis (MS). Here, we show that EBV+ B-cells can undergo an epigenetic switch conferring a neuroinvasive phenotype with upregulation of SPP1/Osteopontin, which when blocked reduces CNS penetrance.

While most EBV infections lead to the establishment of benign infection, EBV can also be the causative agent of a diverse spectrum of lymphoid and epithelial malignancies, including Burkitt’s and Hodgkin’s lymphomas. EBV-associated lymphoproliferative disease and primary central nervous system lymphoma (PCNSL) can occur during immunosuppression. In addition, a growing body of epidemiological, virological, and immunological evidence supports a major role for EBV in autoimmune disorders, including, multiple sclerosis (MS), systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), juvenile idiopathic arthritis, inflammatory bowel disease, celiac disease, and type 1 diabetes.

The injected EBV infected tumours into mice and got a few where the tumours went into the brain, they then took them and did it again and again until they had a line that ended up in the brain in all mice. So then they looked at the genes and found some that were more different from the original tumor. So is this how EBV causes MS, it makes some B cells more able to migrate into the central nervous system.

Ostepontin apparently binds to alpha 4/beta 1 integrin and this binds to vascular cell adhesion molecule 1 (VCAM1) in the inflamed brain, block osteopontin and perhaps it stops trafficking, but I’m not sure ths axis is that important in mice and the brains of the mice are not inflammed so no VCAM-1. Antibodies against osteopontin inhibits EAE

Epigenetic Plasticity Enables CNS-Trafficking of EBV-infected B Lymphocytes.Soldan SS, Su C, Lamontagne RJ, Grams N, Lu F, Zhang Y, Gesualdi JD, Frase DM, Tolvinski LE, Martin K, Messick TE, Fingerut JT, Koltsova E, Kossenkov A, Lieberman PM.PLoS Pathog. 2021 Jun 9;17(6):e1009618. doi: 10.1371/journal.ppat.1009618. Online ahead of print.

Subpopulations of B-lymphocytes traffic to different sites and organs to provide diverse and tissue-specific functions. Here, we provide evidence that epigenetic differences confer a neuroinvasive phenotype. An EBV+ B cell lymphoma cell line (M14) with low frequency trafficking to the CNS was neuroadapted to generate a highly neuroinvasive B-cell population (MUN14). MUN14 B cells efficiently infiltrated the CNS within one week and produced neurological pathologies. We compared the gene expression profiles of viral and cellular genes using RNA-Seq and identified one viral (EBNA1) and several cellular gene candidates, including secreted phosphoprotein 1/osteopontin (SPP1/OPN), neuron navigator 3 (NAV3), CXCR4, and germinal center-associated signaling and motility protein (GCSAM) that were selectively upregulated in MUN14. ATAC-Seq and ChIP-qPCR revealed that these gene expression changes correlated with epigenetic changes at gene regulatory elements. The neuroinvasive phenotype could be attenuated with a neutralizing antibody to OPN, confirming the functional role of this protein in trafficking EBV+ B cells to the CNS. These studies indicate that B-cell trafficking to the CNS can be acquired by epigenetic adaptations and provide a new model to study B-cell neuroinvasion associated CNS lymphoma and autoimmune disease of the CNS, including multiple sclerosis (MS).

So what to the infected EBV cells do when they get in the brain, are they a target for EBV reactive T cells? is it something else? Maybe if EBV makes a memory B cell and by chance it expresses a receptor that is specific for a CNS protein and EBV make cells more likely to migrate into the CNS…by chance in increases the change of a B cell getting activated in the brain and what next?. Maybe this goes some way to explaining what may occur in MS. I am sure there is more to this Jigsaw.

General Disclaimer: Please note that the opinions expressed here are those of the author and do not necessarily reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust.

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  • They mention that EBV has been associated by other auto immune diseases. This is what I found on pubmed..gov.


    Epstein-Barr virus (EBV) infection is associated with rheumatoid arthritis (RA) in adults, though the nature of the relationship remains unknown. Herein, we examine the contribution of viral infection to the severity of arthritis in mice. We provide the first evidence that latent gammaherpesvirus infection enhances clinical arthritis, modeling EBV’s role in RA. Mice latently infected with a murine analog of EBV, gammaherpesvirus 68 (gHV68), develop more severe collagen-induced arthritis and a Th1-skewed immune profile reminiscent of human disease. We demonstrate that disease enhancement requires viral latency and is not due to active virus stimulation of the immune response. Age-associated B cells (ABCs) are associated with several human autoimmune diseases, including arthritis, though their contribution to disease is not well understood. Using ABC knockout mice, we provide the first evidence that ABCs are mechanistically required for viral enhancement of disease, thereby establishing that ABCs are impacted by latent gammaherpesvirus infection and provoke arthritis.

  • Very conflicting reuslts

    For every paper in favor off Ebv relation with Ms pathogenesis there is another against

    Molecular signature of Epstein-Barr virus
    infection in MS brain lesions

    Together, our observations suggest an uncharacterized link between the EBV virus life cycle and
    MS pathogenesis


    Epstein-Barr virus-specific CD8 T cells selectively 1 infiltrate the multiple sclerosis brain and
    interact locally with virus infected cells: clue for a virus-driven immunopathological mechanism


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