EAE becomes a B cell Disease

‘t Hart BA, Dunham J, Faber BW, Laman JD, van Horssen J, Bauer J, Kap YS.A B Cell-Driven Autoimmune Pathway Leading to Pathological Hallmarks of Progressive Multiple Sclerosis in the Marmoset Experimental Autoimmune Encephalomyelitis Model.
Front Immunol. 2017 Jul 11;8:804. doi: 10.3389/fimmu.2017.00804.

The absence of pathological hallmarks of progressive multiple sclerosis (MS) in commonly used rodent models of experimental autoimmune encephalomyelitis (EAE) hinders the development of adequate treatments for progressive disease. Work reviewed here shows that such hallmarks are present in the EAE model in marmoset monkeys (Callithrix jacchus). The minimal requirement for induction of progressive MS pathology is immunization with a synthetic peptide representing residues 34-56 from human myelin oligodendrocyte glycoprotein (MOG) formulated with a mineral oil [incomplete Freund’s adjuvant (IFA)]. Pathological aspects include demyelination of cortical gray matter with microglia activation, oxidative stress, and redistribution of iron. When the peptide is formulated in complete Freund’s adjuvant, which contains mycobacteria that relay strong activation signals to myeloid cells, oxidative damage pathways are strongly boosted leading to more intensive pathology. The proven absence of immune potentiating danger signals in the MOG34-56/IFA formulation implies that a narrow population of antigen-experienced T cells present in the monkey’s immune repertoire is activated. This novel pathway involves the interplay of lymphocryptovirus-infected B cells with MHC class Ib/Caja-E restricted CD8+ CD56+ cytotoxic T lymphocytes.

This study they make it a disease of virally infected B cell, but it doesn’t stop there EAE is made into a B cell disease.

Differential effects of FTY720 on the B cell compartment in a mouse model of multiple sclerosis.Bail K, Notz Q, Rovituso DM, Schampel A, Wunsch M, Koeniger T, Schropp V, Bharti R, Scholz CJ, Foerstner KU, Kleinschnitz C, Kuerten S.J Neuroinflammation. 2017 Jul 24;14(1):148. doi: 10.1186/s12974-017-0924-4.

BACKGROUND: MP4-induced experimental autoimmune encephalomyelitis (EAE) is a mouse model of multiple sclerosis (MS), which enables targeted research on B cells, currently much discussed protagonists in MS pathogenesis. Here, we used this model to study the impact of the S1P1 receptor modulator FTY720 (fingolimod) on the autoreactive B cell and antibody response both in the periphery and the central nervous system (CNS).
METHODS:MP4-immunized mice were treated orally with FTY720 for 30 days at the peak of disease or 50 days after EAE onset. The subsequent disease course was monitored and the MP4-specific B cell/antibody response was measured by ELISPOT and ELISA. RNA sequencing was performed to determine any effects on B cell-relevant gene expression. S1P1 receptor expression by peripheral T and B cells, B cell subset distribution in the spleen and B cell infiltration into the CNS were studied by flow cytometry. The formation of B cell aggregates and of tertiary lymphoid organs was evaluated by histology and immunohistochemistry. Potential direct effects of FTY720 on B cell aggregation were studied in vitro.
RESULTS: FTY720 significantly attenuated clinical EAE when treatment was initiated at the peak of EAE. While there was a significant reduction in the number of T cells in the blood after FTY720 treatment, B cells were only slightly diminished. Yet, there was evidence for the modulation of B cell receptor-mediated signaling upon FTY720 treatment. In addition, we detected a significant increase in the percentage of B220+ B cells in the spleen both in acute and chronic EAE. Whereas acute treatment completely abrogated B cell aggregate formation in the CNS, the numbers of infiltrating B cells and plasma cells were comparable between vehicle- and FTY720-treated mice. In addition, there was no effect on already developed aggregates in chronic EAE. In vitro B cell aggregation assays suggested the absence of a direct effect of FTY720 on B cell aggregation. However, FTY720 impacted the evolution of B cell aggregates into lymphoid organs.
CONCLUSIONS:The data suggest differential effects of FTY720 on the B cell compartment in MP4-induced EAE.

Fingolimod is said to be an treatment that traps white blood cells in lymph glands in this study but the B cells in the blood weren’t affected but B cell numbers go up in spleen and so is it blocking their exit into the blood.  Does fingolimod make your lymph glands get bigger? It should if the theory about how it works is correct.  It may has a some anti-B cells effect but this model is so toned-down such that a B cell effect may be seen, but the simple message I think is that EAE is a T cell-mediated issue and so it probably lacks predictive value to detect agents that affect relapsing MS

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  • Your conclusions on the marmoset paper are interesting. Is marmoset EAE a B cell disease alone? These authors contend that the B cell (viral?) and T cell are at interplay. Clearly if this is the case, B cell depletion would work in this model as with MS. Likely T cell depletion as well? This would seem more relevant than the Biozzi where CD20 depletion doesn't seem to work by recent article.

    Skimming monkey article however I found interesting points. Many things of MS like GM injury and oxidative damage/iron also are reflected in the monkey model. Seems like this would be quite a model of high predictive value would it not?

  • An underlying low-grade chronic intravascular haemolysis is a potential source of the iron whose deposition along blood vessels in multiple sclerosis plaques contributes to the neurodegeneration and consequent brain atrophy seen in progressive disease. Chelators of free serum iron will be ineffective in preventing this neurodegeneration, because the iron (Fe2+) is chelated by haemoglobin.

  • Luis, there is a second, revised version of the article. As it seems, there are more causes of neurodegeneration, other than demyelination. Add the fact that there is no autoimmunity against myelin, and magically MS becomes a whole different disease than previously thought.

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