B cells in Multiple Sclerosis - on idiotopes and antigen presentation
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AbstractThe role of B cells in pathophysiology of multiple sclerosis has been of great interest to wide array of researchers after the introduction of B cell depleting therapies demonstrated significant effects on central nervous system inflammation. In particular memory B cells have been suggested as an important subset. In multiple sclerosis patients both T and B cells aggregate in perivascular cuffs and the meninges of the central nervous system and are associated with areas of demyelination causing disability of the patients. Clonal expansion of T and B cells intrathecally suggests specific responses are driving the inflammation, but collaboration between the cell types have been suggested to be dysregulated. Identifying the disease driving agent or process is therefore a major goal. Identifying ways to target the pathogenic cells is another. In this thesis, I discuss the potential of idiotopes as drivers of this dysregulated T-B collaboration. Idiotopes are epitopes derived from immunoglobulin variable regions, and thus the B cell receptors themselves. It has previously been demonstrated that T cells specific to idiotopes can initiate and drive pathological immune responses. In multiple sclerosis idiotope-specific T cells were demonstrated in two patients, suggesting such a mechanism could be relevant to investigate further. Due to the vast diversity of immunoglobulin repertoires, particularly among mutated variable regions, this has been a challenge to pursue in more patients. The work presented herein addresses this, by using bioinformatic prediction tools to identify potentially antigenic idiotopes in multiple sclerosis patients. By using neural network prediction tools built by collaborators, we were able to identify key areas of multiple sclerosis patient immunoglobulin heavy chain variable regions with predicted high affinity for human leukocyte antigen class II molecules. These were associated with areas of high likelihood for endosomal processing. The predictions were further investigated and validated using in vitro assays in order to identify key factors in immunoglobulin degradation and in order to identify autologous, idiotope-specific T cells. Our findings suggest that multiple sclerosis patients have a repertoire of idiotope-specific T cells, responding to immunoglobulin heavy chain variable region peptides. All in all, the results suggest idiotopes participate in the dysregulated T-B collaboration occurring in multiple sclerosis. This thesis further addresses how idiotope-driven T-B collaboration fits with current and previous knowledge of multiple sclerosis immunopathology and how this aligns with our current understanding of therapeutic mechanisms of action. Finally, I discuss the implications of our findings in both healthy immune regulation and potentially in dysregulation occurring in other auto-immune diseases.
List of papers
|Paper I - Høglund R.A., Lossius A., Johansen J.N., Homan J., Benth J.Š., Robins H., Bogen B., Bremel R.D. and Holmøy T. In Silico Prediction Analysis of Idiotope-Driven T–B Cell Collaboration in Multiple Sclerosis. Frontiers in Immunology, 2017, 8:1255. The article is included in the thesis. Also available at: https://doi.org/10.3389/fimmu.2017.01255|
|Paper II - Høglund R.A.*, Torsetnes S.B.*, Lossius A., Bogen B., Homan E.J., Bremel R.D. and Holmøy T. Human cysteine cathepsins degrade immunoglobulin G in vitro in a predictable manner. International Journal of Molecular Sciences, 2019, 20(19), 4843. *Shared first-authorship. The article is included in the thesis. Also available at: https://doi.org/10.3390/ijms20194843|
|Paper III - Høglund R.A., Bremel R.D., Homan E.J., Torsetnes S.B, Lossius A. and Holmøy T. CD4+ T cells in the blood of MS patients respond to predicted epitopes from B cell receptors found in spinal fluid. Frontiers in Immunology, 2020, 11:598. The pre-print version of the article is included in the thesis. The published artivle available at: https://doi.org/10.3389/fimmu.2020.00598|
|Paper IV - Høglund R.A., Polak J., Vartdal F., Holmøy T. and Lossius A. B-cell composition in the blood and cerebrospinal fluid of multiple sclerosis patients treated with dimethyl fumarate. Multiple sclerosis and related disorders. 2018, 26, pp. 90-55. https://doi.org/10.1016/j.msard.2018.08.032|