T lymphocytes do not directly mediate the protective effect of estrogen on experimental autoimmune encephalomyelitis

Magdalena J. Polanczyk, Richard E. Jones, Sandhya Subramanian, Michael Afentoulis, Cathleen Rich, Melissa Zakroczymski, Paul Cooke, Arthur A. Vandenbark, Halina Offner

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54 Scopus citations


Gender influences mediated by 17β-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-α (Esr1) is crucial for the protective effect of 17β-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+/+ disease-inducing 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 EAE.

Original languageEnglish (US)
Pages (from-to)2069-2077
Number of pages9
JournalAmerican Journal of Pathology
Issue number6
StatePublished - Dec 2004

ASJC Scopus subject areas

  • Pathology and Forensic Medicine


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