T Lymphocytes Do Not Directly Mediate the Protective Effect of Estrogen on Experimental Autoimmune Encephalomyelitis

Abstract

Gender influences mediated by 17␤-estradiol (E2) have been associated with susceptibility to and severity of autoimmune diseases such as diabetes, arthritis, and multiple sclerosis. In this regard, we have shown that estrogen receptor-␣ (Esr1) is crucial for the protective effect of 17␤-estradiol (E2) in murine experimental autoimmune encephalitis (EAE), an animal model of multiple sclerosis. The expression of estrogen receptors among various immune cells (eg, T and B lymphocytes, antigen-presenting cells) suggests that the therapeutic effect of E2 is likely mediated directly through specific receptor binding. However, the target immune cell populations responsive to E2 treatment have not been identified. In the current study, we induced EAE in T-cell-deficient, severe combined immunodeficient mice or in immunocompetent mice with encephalitogenic T cells from wildtype Esr1؉/؉ or Esr1 knockout (Esr1؊/؊) donors and compared the protective E2 responses. The results showed that E2-responsive, Esr1؉/؉ diseaseinducing encephalitogenic T cells were neither necessary nor sufficient for E2-mediated protection from EAE. Instead, the therapeutic response appeared to be mediated through direct effects on nonlymphocytic, E2-responsive cells and down-regulation of the inflammatory response in the central nervous system. These results provide the first demonstration that the protective effect of E2 on EAE is not mediated directly through E2-responsive T cells and raise the alternative possibility that nonlymphocytic cells such as macrophages, dendritic cells, or other nonlymphocytic cells are primarily responsive to E2 treatment in

Gender Differences in 1,25 Dihydroxyvitamin D3 Immunomodulatory Effects in Multiple Sclerosis Patients and Healthy Subjects

“…This suggests that E2's effects on vitamin D metabolism are mediated primarily through ERa and is consistent with observations indicating that immunomodulatory effects of E2 are dependent on ERa signaling (53,73). Expression of both ERs was reported on lymphocytes, and it was recently shown that E2-mediated suppression of certain genes, such as IFN-g and RANTES in the EAE model, is dependent on the presence of ERa (74). These results are consistent with observations showing treatment of EAE with an ERa-selective ligand reduces CNS inflammation, resulting in delayed onset, as well as decreased incidence and severity of disease.…”

Medium-dose estrogen ameliorates experimental autoimmune encephalomyelitis in ovariectomized mice

“…Recently, we demonstrated that treatment of EAE with pregnancy levels of estrogen invariably reduced subsequent neurologic disease, in part, through a suppression of T H 1 and T H 17 cell functions and a shift toward T H 2 and T reg cells (Haghmorad et al 2014a). Polanczyk et al (2004) demonstrated that protective effects of estrogen treatment were not mediated through direct action on the encephalitogenic T-cells, and that both immune and CNS cells were required in propagating immunomodulatory effects of E2. The exact molecular mechanisms in mediating regulatory effects of E2 in EAE have not yet been identified; T reg cells are prime immunoregulatory candidates since their numbers were increased by E2 in EAE-protected mice (Polanczyk et al 2007;Wang et al 2010).…”

Estrogen-mediated protection of experimental autoimmune encephalomyelitis: Lessons from the dissection of estrogen receptor-signaling in vivo

“…[17,25] This notion was itself subsequently challenged by experiments suggesting that the protective action of E2 was not mediated directly by E2-responsive T-cells, but rather through indirect effects on other lymphoid cells or nonlymphoid tissues. [27,28] In an adoptive EAE model, it was shown that ERα expression in encephalitogenic T-cells was dispensable for E2-mediated EAE protection. [27] Likewise, we reported that low dose E2-therapy at the time of disease induction blunted acute EAE development in the absence of ERα expression in hematopoietic cells.…”

“…[27,28] In an adoptive EAE model, it was shown that ERα expression in encephalitogenic T-cells was dispensable for E2-mediated EAE protection. [27] Likewise, we reported that low dose E2-therapy at the time of disease induction blunted acute EAE development in the absence of ERα expression in hematopoietic cells. [28] In this latter model, however, protection was mainly effective during the acute phase of EAE and was not associated with immunomodulatory effects on autoantigen-specific CD4 T-cell responses in lymphoid organs in vivo.…”

“…[27,28] This was shown, however, in two models designed to avoid or restrict any potential effects of E2 at the time of the induction of autoantigen-specific CD4 + T-cell responses in vivo. [27,28] Consequently, we applied a well-established model of estrogen-mediated EAE protection to investigate whether the anti-inflammatory effect of E2 was due to a direct action of E2 on a particular immune cell population.…”