New model of MS: Response against infected B-Cells

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New model of MS: Response against infected B-Cells

Postby frodo » Mon Mar 27, 2017 3:15 am

A recent failure with Tysabri has shed some light into MS pathogenesis. It seems that is not EBV itself, but some B-cells infected by EBV, the cause of MS.
This confirms previous works in this area that found the same problem in the "ectopic b-cells follicles".
The authors of the article propose a model about how lesions develop in this context.

Image

Source:
Massive intracerebral Epstein-Barr virus reactivation in lethal multiple sclerosis relapse after natalizumab withdrawal
http://www.sciencedirect.com/science/ar ... 2817300553
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And an old post of anonymoose

Postby frodo » Mon Mar 27, 2017 4:18 am

Anonymoose also posted long ago about something similar. His original post is at rituxan-rituximab-f39/topic23062.html

I reproduce his original extract here:

B cells and oligoclonal antibodies are present in the cerebrospinal fluid (CSF) of multiple sclerosis (MS) patients but their target antigens remain unknown. The focus of this study was to produce autoantibodies of MS patients based on B cell immortalization and to further characterize the obtained antibodies based on antigen reactivity and diversity.

Peripheral blood mononuclear cells (PBMC), isolated peripheral immunoglobulin G+ (IgG+) B cells or CSF cells were infected with Epstein-Barr virus (EBV) in the presence of irradiated allogeneic PBMC and B cell stimulating factors to obtain continually dividing B cell lines. B cell immortalization was verified by screening the culture supernatant for antibody production using dot blotting. Clonality of the immortalized B cell lines was verified using a B cell spectratyping procedure. To screen for autoreactivity, binding of the produced antibodies to a human oligodendroglioma (HOG) cell line, PBMC and an epithelial alveolar carcinoma cell line (A549) was analyzed by flow cytometric analysis.

We obtained 288 immortalized B cell lines from 15 MS patients, 29 B cell lines from 8 patients with a non- or other inflammatory neurological disease (NIND/OIND) and 37 B cell lines from 3 patients with clinically isolated syndrome (CIS). Most B cell lines were obtained from the PBMC although 7 B cell lines were isolated from the CSF of 1 MS patient and 2 from 1 NIND patient. B cell spectratyping analysis indicated that more than 82% of the immortalized B cell lines were monoclonal, eliminating the need for cloning. HOG-specific intracellular binding was shown for antibodies from 3 immortalized B cell lines while intracellular binding to both HOG and A549 cells but not to PBMC was demonstrated for 37 other B cell lines, all generated from PBMC of MS patients. In addition, binding to all examined cell types was found in 34 immortalized B cell lines. Further, intracellular binding to HOG cells was confirmed for several of the immortalized B cell lines by immunocytochemistry.

B cell immortalization has proved to be a useful method for the production of antibodies. Autoreactivity of the generated monoclonal antibodies has been demonstrated and is now further examined by detecting antibody binding to healthy and diseased brain tissue from human and rhesus monkey. Moreover, characterization of the obtained B cell lines based on diversity is currently in progress by sequencing the immunoglobulin heavy chain genes.

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Replying again to myself

Postby frodo » Tue Apr 11, 2017 9:40 am

Replying again to myself, I have found some previous evidence about the possibility of EBV-infected B-cells. The first one I have found is from 2007 "Dysregulated Epstein-Barr virus infection in the multiple sclerosis brain" (http://jem.rupress.org/content/204/12/2899?papetoc=). They say:

"Here, we show that intracerebral accumulation of EBV-infected B cells and plasma cells is a regular feature of MS and identify ectopic B cell follicles as main sites of viral persistence. We also provide evidence for a relationship between acute inflammation and EBV reactivation in the MS brain"

The ectopic B-cell follicles are accumulations of B-cells in the meninges. They seem to be related to the damage to the gray matter and the progressive phase.

Here I copypaste some other results, summarising the situation of the research in this field.

Maybe the most clear indicator of the B-cell problems is the efectivity of Rituxan. In fact B-cell depletion should occur in a natural way in MS, being the T-cells responsible for killing the sick B-cells (CD8+ T-cells). In MS patients this does not happen ("Defective T-cell control of Epstein–Barr virus infection in multiple sclerosis", http://www.nature.com/cti/journal/v6/n1 ... 1687a.html)

Moreover, in a small study in one secondary progressive MS patient, the injection of cytotoxic T cells designed to kill the host EBV-infected B cells produced a remission of the disease (http://www.cell.com/trends/molecular-me ... 71-4914(16)30149-6.pdf)

The mouse EAE models do not work as expected. Instead, it has been found that a kind of monkeys, the marmosets, have a similar behaviour having EAE and B-cells infection. Instead of using EBV they have an equivalent virus (CalHV3, http://journals.sagepub.com/doi/abs/10. ... 7317690184). In this cases, the CD8+ Tcells targeted myelin instead of the infected B-cells. Several reports point out that there is a problematic protein named EBNA1 (http://onlinelibrary.wiley.com/doi/10.1 ... 21886/full, http://www.neurology.org/content/62/12/2277.short, http://link.springer.com/article/10.100 ... 010-9201-3)

It seems that the EBV-infected marmoset is the most accurate model that we have for MS. Instead of human EBV they use a similar family of viruses named lymphocryptovirus (LCVs) of which the previous CalHV3 is one of them. In these experiments the mutual influence between Tcells and Bcells is similar to the corresponding situation in human MS (http://www.nature.com/cti/journal/v6/n2 ... 0171a.html, http://www.jimmunol.org/content/197/4/1074.short)

Finally there is a good review about the subject at http://www.cell.com/trends/molecular-me ... 71-4914(16)30149-6
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Re: New model of MS: Response against infected B-Cells

Postby Scott1 » Tue Apr 11, 2017 2:43 pm

Hi,

Go here http://www.nature.com/cti/journal/v3/n1 ... 1425a.html and download the PDF.

Regards,
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Re: New model of MS: Response against infected B-Cells

Postby frodo » Thu Apr 13, 2017 10:24 am

Scott1 wrote:Hi,

Go here http://www.nature.com/cti/journal/v3/n1 ... 1425a.html and download the PDF.

Regards,


Thanks!!! It seems that the evidence of EBV is overwhelming.

It also seems that I have to correct the attributions in my first post. According to the article that Scott1 posted, the first article that postulated the theory of infected B-cells was in 2003: "Pender MP. Infection of autoreactive B lymphocytes with EBV, causing chronic autoimmune diseases. Trends Immunol 2003"
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Re: New model of MS: Response against infected B-Cells

Postby frodo » Wed Jun 21, 2017 6:37 am

More evidence about the EBV-infected b-cells theory:


Half of progressive MS patients treated with Epstein-Barr virus sensitised T-cells see symptom reduction (11/05/17)

http://www.ms-uk.org/half-progressive-m ... -reduction

and

Epstein-Barr and herpes viruses linked to childhood MS (15/05/17)

http://www.ms-uk.org/epstein-barr-and-h ... -ms-150517
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