Article - Testosterone might protect males from autoimmune disorder?

Male-specific IL-33 expression regulates sex-dimorphic EAE susceptibility
Abigail E. Russi, Mark E. Ebel, Yuchen Yang and Melissa A. Brown

PNAS 2018; published ahead of print January 29, 2018, https://doi.org/10.1073/pnas.1710401115

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1. Edited by David Artis, Weill Cornell Medical College, New York, NY, and accepted by Editorial Board Member Philippa Marrack December 22, 2017 (received for review June 8, 2017)
   

Significance
Women are much more likely to develop autoimmune diseases, such as systemic lupus erythematous, rheumatoid arthritis, and multiple sclerosis. Sex hormones, including estrogen and testosterone, clearly influence disease susceptibility, but the precise cellular and molecular targets of these hormones have remained unexplained. While most studies have focused on what causes the damaging inflammation in females, there is also much to be learned by studying the factors that confer protection to males. Using a mouse model of multiple sclerosis, a CNS demyelinating disease, we identified a testosterone-driven pathway mediated by mast cell-dependent IL-33 expression that limits the development of a destructive immune response in males. The identification of such pathways has important therapeutic implications.

Abstract
The cellular and molecular basis of sex-dimorphic autoimmune diseases, such as the CNS demyelinating disease multiple sclerosis (MS), remains unclear. Our studies in the SJL mouse model of MS, experimental autoimmune encephalomyelitis (EAE), reveal that sex-determined differences in Il33 expression by innate immune cells in response to myelin peptide immunization regulate EAE susceptibility. IL-33 is selectively induced in PLP139–151-immunized males and activates type 2 innate lymphoid cells (ILC2s), cells that promote and sustain a nonpathogenic Th2 myelin-specific response. Without this attenuating IL-33 response, females generate an encephalitogenic Th17-dominant response, which can be reversed by IL-33 treatment. Mast cells are one source of IL-33 and we provide evidence that testosterone directly induces Il33 gene expression and also exerts effects on the potential for Il33 gene expression during mast cell development. Thus, in contrast to their pathogenic role in allergy, we propose a sex-specific role for both mast cells and ILC2s as attenuators of the pathogenic Th response in CNS inflammatory disease.

http://www.pnas.org/content/early/2018/01/25/1710401115