For many many years we have been fed a diet of MS is an autoimmune disease of T cell reactivity to myelin basic protein. This has been lapped up by researchers and with any dissenting voices their papers are destined to the impact factor nothing bin. However, there is only one problem with this idea and that is good evidence. Myelin basic protein is easy to make and is water soluble and easy to get T cell responses to it so its importance grew and grew.
Importantly trials to tolerize against this protein have been done and done again and they have consistently failed and one trial seemed to make disease worse but caused a peripheral nerve disease. MS is supposed to be a CNS disease
When scientists looked in a none/less-biased way, T cell responses to myelin basic protein did not appear and again we get the same answer here.
Introduction: The autoantigen repertoire in multiple sclerosis (MS) remains largely uncharacterised, but is of central importance for understanding disease induction and progression mechanisms and for development of antigen-specific immunotolerance therapies.
Objectives: To perform a large unbiased screening of T cell reactivity against CNS-expressed proteins and to verify and characterise MS-specific immune responses in independent cohorts.
Aim: To identify novel T cell autoantigens in MS.
Methods: Using a novel in vitro method of direct antigen delivery via 1µm beads coated with a library of proteins from the Human Protein Atlas, we screened for T cell autoreactivity against 63 CNS-expressed proteins in a FluoroSpot assay using a cohort of natalizumab treated persons with MS (MS-nat, n=16) (These would have the disease causing cells trapped in the blood) and matched healthy controls (HC, n=9). Hits were verified in two separate cohorts: one with MS-nat (n=61), HCs (n=28) and one with MS-untreated (n=31), HCs (n=20), and persons with other neurological disease (n=19). Autoreactive cells were analysed using flow cytometry and encephalitogenicity of the autoantigens was examined via immunisation of SJL/J and DBA/1 mice.
Results: Four screened CNS proteins, Fatty acid binding protein 7 (FABP7), Prokineticin-2 (PROK2), Reticulon-3 (RTN3), and Synaptosomal associated protein 91kDa (SNAP91) elicited higher IFNγ, IL-22 and/or IL-17A responses in MS-nat compared to HCs. Higher IFNγ responses were verified for all antigens in MS-untreated (p=0.0118, p=0.001, p=0.0002, and p=0.0162 for FABP7, PROK2, RTN3, and SNAP91 respectively), and for PROK2 and RTN3 in MS-nat (p=0.001 and p=0.005). Increased IL-17A and IL-22 responses were also observed in MS-nat. Reactivity to more than one autoantigen was shown to be MS-selective. Autoreactive T cells were predominantly but not solely CD4+, expressed GM-CSF and, while dependent on HLA-DR, were present both in DRB1*15:01 positive and negative subjects. Immunisation in two mouse strains induced heterogeneous immune responses and immunohistochemistry revealed significant CNS leukocyte infiltration in response to all autoantigens.
Conclusion: The present study represents one of the largest systematic efforts in the search for MS autoantigens and identifies four novel T cell targets in MS: FABP7, PROK2, RTN3 and SNAP91. It demonstrates the heterogeneity and individual autoreactive profiles amongst patients and highlights targets for future diagnostic tools and immunomodulatory therapies in MS.
So the major point here is where is myelin basic protein and the answer is nowhere to be found. Where are these molecules found?
One asks why would MS be a oligodendrocyte related disease if these are important. In this study they immunize mice and get EAE but as long as the antigen is expressed somewhere in the CNS, whether it is on astrocytes, nerves or oligodendrocytes you can get EAE, if it expressed outside of the CNS you can get disease there too.
However can you get T cell responses to myelin…Sure if oligodendrocytes get damaged they will release their contents, some finds it way into dendritic cells/macrophages/B cells and gets presented to T cells…so the autoreactivity could be secondary rather than the primary problem
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