This is a hardcore read for those interested. There is quite alot of hardcore science to digest here and in the end result the idea is that B cells are acting as antigen presenting cells for T cells. I guess therefore that we need to see the effect of T cell immunotherapy in the modern era where people are not scared of T cell depletion
Antigen Presentation by B Cells in Multiple Sclerosis.Zamvil SS, Hauser SL.N Engl J Med. 2021 ;384(4):378-381
B-cell depletion with anti-CD20 monoclonal antibodies is highly effective in treating all forms of multiple sclerosis solidified this new understanding that B cells play a central role in pathogenesis.
It is now recognized that antigen-educated memory B cells and antibody-secreting plasmablasts, circulate between the bloodstream and the central nervous system (CNS) and are probably activated in both compartments.
These B cells are proinflammatory and produce “oligoclonal bands”, the characteristic indication of the presence of immunoglobulin molecules in the cerebrospinal fluid (CSF) that has long been used in the diagnosis of multiple sclerosis, but most appear to be nonpathogenic.
The focus then shifted to the presentation of antigens by B cells to T cells. Indeed, in some laboratory models, antigen presentation by B cells is an obligate requirement for the generation of pathogenic T cells and clinical manifestations of CNS disease.
Apparently it was a surprise that memory B cells from HLA-DR15+ patients with multiple sclerosis could activate CD4+ T cells in the absence of exogenous proteins and identified a peptide of RAS guanyl-releasing protein 2 (RASGRP2), an intracellular protein, that was responsible for this T-cell autoproliferation. RASGRP2 is also expressed in cortical gray matter neurons, leading to the possibility that presentation of RASGRP2 by HLA-DR15 molecules expressed on B cells stimulates CD4+ T cells that then target RASGRP2 in the brain. [Only problem is that gene expression data do not support the idea that RASGRP2 is a major CNS protein and the staining is artefactual the strongest expression is inside the blood vessel. many years ago it was shown that B cells present the dominant antigen expressed in the MS brain, this HspB5 or alpha B crystallin…but this forgotten].
The repertoire of antigens presented by B cells is not limited to proteins recognized by their surface antibody idiotype, as previously thought, but rather includes a rich array of endogenous peptides. In addition, the repertoire of peptides presented exclusively by B cells, and not by other antigen-presenting cells, is also large. It is quite remarkable that a substantial proportion of these peptides presented by class II HLA molecules on B cells appear to be fragments of the class II molecules themselves. Further, some of these class II–derived self-peptides are a source of potential molecular mimicry with viral, bacterial, or cell-surface autoantigens, possibly triggering, sustaining, or regulating T-cell–mediated autoimmunity. Finally, it is worth highlighting the fact that the genomic architecture of the multiple sclerosis–associated HLA-DRB1*15 haplotype is unique because of the presence of the “additional” DRB allele (DRB5*01:01), which is absent on most other common HLA class II haplotypes in humans. Perhaps this feature helps to explain its genetic association with multiple sclerosis risk, in that it may serve as a source of peptides that are cross-reactive with encephalitogenic antigens.