Memory B cells are there to help CD4 T cells

Memory B Cells present antigen to CD4 T cells in multiple sclerosis, so T cells are on top of the pile and B cells are there to help the baddie T cells. Therefore, the status quo is maintained and everything is super.

However, has the latest autoantigen in MS been found?




Multiple sclerosis is an autoimmune disease that is caused by the interplay of genetic-, particularly the HLA-DR15 haplotype, and environmental risk factors. How these etiologic factors contribute to generating an autoreactive CD4+ T cell repertoire is not clear. Here, we demonstrate that self-reactivity, defined as “autoproliferation” of peripheral Th1 cells, is elevated in patients carrying the HLA-DR15 haplotype. Autoproliferation is mediated by memory B cells in an HLA-DR dependent manner. Depletion of B cells in vitro and therapeutically in vivo by anti-CD20 effectively reduces T cell autoproliferation. T cell receptor deep sequencing showed that in vitro autoproliferating T cells are enriched for brain-homing T cells.

In MS there are cells that are spontaneously proliferating in the blood. These can be found in the brain of people with MS. The cells that are proliferating are mainly memory T cells and they respond via a mechanism involving MHC class II and they produce interferon gamma (TH1) cells.

The B cells (Switched memory and to some extent non-switched) upregulate HLA-DR and drive the auto proliferation by T cells.

This is proliferation is not blocked by targeting CD40 on the B cells perhaps not surprising if EBV creates CD40 mimicks. However it could be blocked by bruton tyrosine kinase inhibitors. So maybe a mechanism of action of BTK inhibitors. 


They looked at cells found in CNS lesions and this consisted of T cells where it seems that the CD8 cells present are abundant in the periphery also suggesting that they were trafficking in perhaps by a bystander mechanisms. However, there were CD4 clones that may have expanded in the CNS. This study elegantly examined the recognition target of the cells and they recognised nucelotide exchange factors (RASGRPs), notabtly RAS guanyl-releasing protein 2. Other people recognised this target too. Is this the cause of autoimmunity in MS?

A nice piece of work that I have yet to adequately digest but I have my doubts.

Based on Message the target is expressed by nerves but it is is also found in other tissues, including lymphocytes. Is this why there is autoproliferation? 

Anyway a trial is now planned to block the immune response to this antigen. 

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