The immune imbalance between follicular regulatory and helper T cells in myelin oligodendrocyte glycoprotein IgG-associated disease

Myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD) is a newly defined inflammatory demyelinating disease of the central nervous system. Currently, no immuno-modulatory treatment has been approved for MOGAD. We explored the function of follicular regularoty T (Tfr) and follicular helper T (Tfh) cells in patients with MOGAD. The number of circulating Tfr and Tfh cells and their expression of functional markers were accessed by flow cytometry. Circulating Tfr, memory Tfh, and B cells were further sorted and co-cultured in vitro to examine the influence of Tfr on Tfh-mediated B cell differentiation. In patients with MOGAD, the percentages of circulating Tfh elevated while the frequencies of circulating activated Tfr cells decreased significantly. The Tfh/Tfr ratios positively correlated with the percentage of plasmblasts. In vitro, Tfh cells from patients with MOGAD exhibited a stronger capacity to promote the differentiation of plasmablasts through producing interleukin (IL)-21 than non-Tfh cells from patients, whereas Tfr cells suppressed this Tfh-mediated plasmablast expansion, to a similar extent of IL-1 receptor antagonist (IL-1Ra). We revealed an immune imbalance of Tfr and Tfh cells in MOGAD. Tfr and IL-1Ra could be potential therapeutic targets in MOGAD. Evidence before this study Myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD) is a newly defined inflammatory demyelinating disease of the optic nerve, brain and spinal cord (central nervous system). It is thought to be caused by a pathogenic auto-antibody targeting MOG protein. There is no approved immuno-modulatory treatment for the disease now. We previously observed intense T cell infiltration which was even more dominant than B cells in the acute lesion of MOGAD, inspiring the investigation of T-B cell crosstalk. In a flow cytometric study, we observed an increased level of circulating follicular helper T (Tfh) cells in patients with MOGAD. Tfh cells have been proved to help B cell mature and produce antibodies. On the other hand, follicular regulatory T (Tfr) cells are newly characterized subset of regulatory T cells, found to suppress Tfh cells via a previously uncharacterized interleukin-1 axis. Added value of this study We explored the role of Tfr and Tfh cells, and their influence on B cells in the pathogenesis of MOGAD. We found that in patients with MOGAD, the percentages of circulating Tfh elevated while the frequencies of circulating activated Tfr cells decreased significantly. The Tfh/Tfr ratios positively correlated with the percentage of plasmblasts. In vitro, Tfh cells from patients with MOGAD exhibited a stronger capacity to promote the differentiation of plasmablasts through producing interleukin −21 than non-Tfh cells from patients, whereas Tfr cells suppressed this Tfh-mediated plasmablast expansion, to a similar extent of interleukin-1 receptor antagonist (IL-1Ra). Implications of all the available evidence These findings suggest an immune imbalance between Tfr and Tfh, and the subsequent B cell over activation involve in MOGAD pathogenesis. The immunosuppressive Tfr-IL-1Ra axis could be a potential therapeutic target for MOGAD.