IL-10 producing B cells partially restore E2-mediated protection against EAE in PD-L1 deficient mice

Abstract

Women with Multiple sclerosis (MS) often experience clinical improvement during pregnancy, indicating that sex hormones might have therapeutic effects in MS. Our previous studies have demonstrated that B cells and PD-L1 are crucial for E2 (17β-estradiol) - mediated protection against experimental autoimmune encephalomyelitis (EAE). We here demonstrate that transfer of IL-10+ B cells into E2-treated PD-L1−/− mice after EAE induction could partially restore E2-mediated protection and decrease the frequency of pro-inflammatory cells in the CNS compared to E2/saline treated PD-L1−/− mice. Hence, co-administration of IL-10+ B cells and E2 might have a powerful therapeutic potential for treatment of EAE.

Estrogen induces multiple regulatory B cell subtypes and promotes M2 microglia and neuroprotection during experimental autoimmune encephalomyelitis

“…Moreover, it was shown that the frequency of IL-10 producing B cells (B10) increases during normal pregnancy (Fettke et al, 2014, Jensen et al, 2013). In agreement with these studies, we previously reported that estrogen-induced protection against EAE is B cell dependent and that this protection also depends on the expression of programmed death-ligand 1 (PD-L1) on B10 cells (Bodhankar et al, 2013a, Zhang et al, 2015a). …”

The regulatory role of B cells in autoimmunity, infections and cancer: Perspectives beyond IL10 production

“…This report provided insights about how important it would be to consider the timing of the autoimmune disease and the roles of the different B cell populations when establishing therapeutic treatments involving depletion or an autologous adoptive transference. Furthermore, PD-L1 + IL-10 + B cells were shown to be the key players in estrogen (E2)-mediated protection against EAE [57][58][59]. E2 has been proved to protect mice from EAE, while this protection was abrogated in B cell-deficient (muMT) mice [60].…”

Estrogen protects both sexes against EAE by promoting common regulatory cell subtypes independent of endogenous estrogen

“…Both OVX female (Fig 3a) and male mice (Fig 3b) had a significant increase in the frequency of B10 (p<0.0001), Tim-1 B cells (p<0.001 and p<0.05 respectively) and plasmablasts (p<0.05 and p<0.0001, respectively) in E2 treated mice compared to sham treated mice. In addition to secreting IL-10, B10 cells also up regulate the expression of PD-L1 which is important in E2 protection against EAE (Bodhankar et al 2013; Zhang et al 2015). Both intact females (Benedek et al 2016) and OVX females treated with E2 had a significantly increased frequency of CD19 + PD-L1 hi cells in the spleen compared to sham treated mice (Fig 3a, p<0.0001).…”

“…Treatment with E2 does not change the frequency of splenic B cells but it does shift the frequency of multiple regulatory B cell (Breg) subsets, including B10, Tim-1 + , and plasmablasts, (Benedek et al 2016) all of which produce IL-10 and can modulate T cell function (Ding et al 2011; Iwata et al 2011; Matsumoto et al 2014; Matsushita et al 2010). B10 cells also up regulate the expression of programmed death ligand 1 (PD-L1) which is critical for E2 dependent protection from EAE (Bodhankar et al 2013; Zhang et al 2015). In addition to increasing regulatory lymphocytes, E2 treatment also increases anti-inflammatory macrophages (Benedek et al 2017).…”