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

Abstract

Autoimmune diseases including multiple sclerosis predominantly affect females. Although high levels of sex hormones, particularly estrogen (E2), can reduce proinflammatory immune responses, it remains unclear if a lack of endogenous sex hormones might affect treatment with exogenous sex hormones. Pretreatment with E2 almost completely prevents intact female and male mice from developing clinical and histological signs of experimental autoimmune encephalomyelitis (EAE) by promoting various regulatory immune cell phenotypes. To evaluate the effects of exogenous estrogen in the absence of endogenous sex hormones, the current study compared EAE severity and the emergence of different immunoregulatory cell populations after E2 pretreatment of ovariectomized (OVX) female versus male mice. We found that E2 equally protected both OVX females and males from EAE over a 21 day observation period concomitant with reduced total cell numbers in spleen and spinal cord (males only), but enhanced percentages of CD19+CD5+CD1dhi, CD19+CD138+CD44hi and CD19+Tim-1+ Breg cells, CD8+CD122+ Treg cells and CD11b+206+ARG-1+ anti-inflammatory M2-like monocytes/macrophages in both groups. In contrast, E2 decreased the percentage of CD4+CD25+FoxP3+ Treg cells in OVX females but increased these Treg cells in males and intact female mice. These data suggest that with the exception of CD4+CD25+FoxP3+ Treg cells, E2 protection against EAE promotes highly overlapping immunoregulatory subsets in OVX females and males.

Regulatory B cells in experimental stroke

“…Other studies demonstrated that B cells played a role in EAE disease initiation but that Breg cells, particularly B10 cells, could down‐regulate activation of encephalitogenic T cells and reduce ongoing disease severity . Our own studies demonstrated that the strongly protective effect of oestrogen pretreatment on EAE induction was mediated in large part by IL‐10‐producing Breg cells. We found that oestrogen‐treated B‐cell‐deficient μ MT −/− mice were not protected from EAE, whereas transfer of WT IL‐10‐producing B cells before oestrogen administration could protect the recipient WT mice from subsequent EAE induction .…”

Tuftsin Combines With Remyelinating Therapy and Improves Outcomes in Models of CNS Demyelinating Disease

“…Flow cytometry was used as an additional method to evaluate the inflammatory state of microglial/macrophage phenotypes at the peak of the disease. An additional set of pro- and anti-inflammatory markers was utilized; CD11b was used to identify the microglia/macrophage population, CD86 as a marker of pro-inflammatory microglia/macrophages ( 40 ), and CD206 as a marker of anti-inflammatory microglia/macrophages ( 40 , 41 ) (Figure 6A ). Whereas, number of microglia/macrophages in untreated mice and mice treated with either drug alone was variable, mice treated with the dual therapy had significantly less CD11b + cells present in the spinal cord compared to control mice, indicating less overall inflammation in the spinal cord (Figure 6B ).…”

Sex Hormones in Acquired Immunity and Autoimmune Disease

“…E2 is protective in the EAE model of autoimmune disease in both male and ovariectomized female mice and this effect is partially mediated by modulation of Tregs ( 194 ). Estrogen upregulated PD1 expression in CD4+FoxP3+ Tregs, and PD1 levels rather than the frequency of Tregs, correlated with the degree of E2-mediated EAE protection.…”