Why are females generally more susceptible to developing autoimmune diseases? A new study in The Journal of Experimental Medicine indicates that the answer might lie in the expression levels of the nuclear receptor peroxisome-proliferator-activated receptor- (PPAR) in T cells.

PPAR is a nuclear hormone receptor that acts as a ligand-activated transcription factor. It regulates whole-body lipid and glucose homeostasis and, in immune cells, inhibits inflammatory pathways by repressing the activity of the transcription factors nuclear factor-B (NF-B) and JUN, which promote T helper 1 (T_H1)-cell differentiation. As a more prominent role for PPAR has been reported for the regulation of lipid metabolism in male rodents compared with female rodents, Dunn et al. asked whether this gender dichotomy might extend to include the anti-inflammatory activities of PPAR.

They examined the clinical course of experimental autoimmune encephalomyelitis (EAE; a T_H1-cell-mediated mouse model of multiple sclerosis) in male and female wild-type versus PPAR-deficient mice. Ppara^-/- male mice developed more severe EAE than deficient female mice, compared with their wild-type counterparts. Further analysis indicated that T cells from the male Ppara^-/- mice were hyperresponsive to T-cell-receptor stimulation and triggered an earlier onset of EAE than T cells from female Ppara^-/- mice. Therefore, it seems that intrinsic differences in T cells between the male and female mice contributed to the more severe acute EAE that developed in the male Ppara^-/- mice.

PPAR expression was higher in CD4⁺ T cells from male wild-type mice than those from female wild-type mice at both the mRNA and protein levels. The expression of PPAR was also shown to be sensitive to the androgenic hormone testosterone: expression of PPAR was reduced in male mice by castration and increased in female mice following treatment with a testosterone metabolite. As expected, PPAR expression repressed the binding of NF-B and JUN to DNA in T cells; T cells from Ppara^-/- male mice produced higher levels of the T_H1 cytokines interferon- (IFN) and tumour-necrosis factor (TNF), and lower levels of T_H2 cytokines.

So, males could be less prone to developing T_H1-cell-mediated autoimmune responses owing to their higher androgen levels, which drives the expression of PPAR in T cells; this could help to explain the increased susceptibility of females to developing autoimmune diseases.

ORIGINAL RESEARCH PAPER

1. Dunn, S. E. et al. Peroxisome proliferator-activated receptor (PPAR) expression in T cells mediates gender differences in development of T cell-mediated autoimmunity. J. Exp. Med. 29 January 2007 (doi:doi: 10.1084/jem.20061839) | Article |