Antigenic key to MS?…….Again

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Recently at ECTRIMS we heard of a plan for antigen-specific tolerance against 12 peptides against MBP. MOG, PLP, RASPGPR2 and GDP-L-fucose synthase to treat MS, starting in Spring 2022 (R Martin ECTRIMS2021).

Where did the latter two targets come from?

The answer in what we call a “fishing trip” to find targets these two were pulled out

Eurpoean patent EP3586866A1

As you know I have questioned whether myelin basic protein is really a good target for autoimmunity. This is due to its peripheral nervous system expression. If it was all important you may expect alot more peripheral nerve involvement in MS. In this respect PLP and MOG are better candidates as they are CNS-restricted. However we have a MOG-related condition and this is not classic MS.

What about the new targets? Before I start we have been here umpteen times before and all those candidates have been “put to the sword

I haven’t seen any dissenters yet. But one certainly question RASGRP2. There is no doubt that RASGRP2 is expressed by B cells and can induce autoproliferation of T cells, but as a candidate antigen for MS, it leaves a lot to be desired. Most notabably its expression in the CNS is dubious in my humble opinion

Left Jelic et al. Cell 2018:175:85. Note there is little staining in the white matter (WM) the Grey Matter has a brown Hue suggested to be postivie staining but look at top left there is a cut-off blood vessel with a big brown centre. This due could be due to non-specific staining possibly from endogenous peroxidase, which is in red blood cells (but it wasnt’t seen in the controls). So is this staining artefact as getting background in grey matter areas in staining is not uncommon, even if the negative control looks as clean as a whistle. MS is not just a grey matter disease there is nothing in the white matter (left) and based on expression data (middle/right. http://www.biogps.com, http://www.genomicscape.com; protein atlas.org) RASGRP2 is expressed on lymphocytes but is not really expressed in the brain, so you ask…..Why MS?

GDP-L-fucose synthase is also known as TSTA3 was found to make some MS T cells proliferate. This also is not really expressed much in the brain

http://www.brainseq.org. Not alot of RASGRP2 or TSTA3 in oligodendrocytes compared to PLP and MOG expression

They were pulled out of the brain but does it mean that they are important. The vast majority of T cells will be pulled into the brain because they have the right homing receptors. They could accumulate in the brain. If they dont find their target in the brain they leave or die. I was prompted to do this reading, which I have shared, about these targets by the paper below

Cruciani C, Puthenparampil M, Tomas-Ojer P, Jelcic I, Docampo MJ, Planas R, Manogaran P, Opfer R, Wicki C, Reindl M, Jelcic I, Lutterotti A, Martin R, Sospedra M. T-cell specificity influences disease heterogeneity in multiple sclerosis. Neurol Neuroimmunol Neuroinflamm. 2021;8(6):e1075.

Background and Objectives Encouraged by the enormous progress that the identification of specific autoantigens added to the understanding of neurologic autoimmune diseases, we undertook here an in-depth study of T-cell specificities in the autoimmune disease multiple sclerosis (MS), for which the spectrum of responsible autoantigens is not fully defined yet. The identification of target antigens in MS is crucial for therapeutic strategies aimed to induce antigen-specific tolerance. In addition, knowledge of relevant T-cell targets can improve our understanding of disease heterogeneity, a hallmark of MS that complicates clinical management.

Methods The proliferative response and interferon gamma (IFN-γ) release of CSF-infiltrating CD4+ T cells from patients with MS against several autoantigens was used to identify patients with different intrathecal T-cell specificities. Fresh CSF-infiltrating and paired circulating lymphocytes in these patients were characterized in depth by ex vivo immunophenotyping and transcriptome analysis of relevant T-cell subsets. Further examination of these patients included CSF markers of inflammation and neurodegeneration and a detailed characterization with respect to demographic, clinical, and MRI features.

Results By testing CSF-infiltrating CD4+ T cells from 105 patients with MS against seven long-known myelin and five recently described GDP-L-fucose synthase peptides, we identified GDP-L-fucose synthase and myelin oligodendrocyte glycoprotein (35-55) responder patients. Immunophenotyping of CSF and paired blood samples in these patients revealed a significant expansion of an effector memory (CCR7 CD45RA) CD27 Th1 CD4+ cell subset in GDP-L-fucose synthase responders. Subsequent transcriptome analysis of this subset demonstrated expression of Th1 and cytotoxicity-associated genes. Patients with different intrathecal T-cell specificities also differ regarding inflammation- and neurodegeneration-associated biomarkers, imaging findings, expression of HLA class II alleles, and seasonal distribution of the time of the lumbar puncture.

Discussion: Our observations reveal an association between autoantigen reactivity and features of disease heterogeneity that strongly supports an important role of T-cell specificity in MS pathogenesis. These data have the potential to improve patient classification in clinical practice and to guide the development of antigen-specific tolerization strategies.

So good luck with the trial and hopefully the tolerance will show a reduction in T cell proliferation, but will it cure MS?

We can come back in a few years to get the answer

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