A new approach explaining female susceptibility to auto-immune disease

Science

Although women have an extra X chromosome compared to men, an inactivation mechanism allows genes to be equally expressed between the sexes. However, certain genes are said to escape this inactivation. These include TLR7, known to promote the development of systemic lupus erythematosus (SLE) and other auto-immune diseases. The etiological approach is becoming clearer...

Systemic lupus erythematosus (SLE), a disease in which affected individuals produce auto antibodies against their own nucleic acids, particularly occurs in females, together with males who abnormally have two X chromosomes (Klinefelter syndrome). Faced with this disease, and particularly disorders involving the immune system, men and women are not, in fact, equal. The mechanisms responsible for sex-related differences in the immune response involve sex hormones, the microbiota or even genes related to sex chromosomes.

Jean-Charles Guéry and his team* studied the role of a key actor in antiviral immunity, Toll-like receptor 7 (TLR7), also known to promote the development of SLE when overexpressed by B lymphocytes in mice. Their hypothesis: given the existence of an inactivation mechanism limiting the expression of genes carried by the second X chromosome in women, and bearing in mind that the gene encoding TLR7 is precisely carried by the X chromosome, could the predisposition of women for developing SLE be based on this gene escaping inactivation? "This mechanism could lead to overexpression of TLR7 in certain cells, such as B lymphocytes, and result in an increased risk of developing auto antibodies", explains the researcher. This hypothesis is far from being a mere fantasy since the literature describes escape for 10 to 30% of genes, according to their nature or according to the cells concerned.

Escape observed in 30% of cells analyzed

2 X chromosomes
2 X chromosomes © Inserm/Heard, Edith/Institut Curie

By developing an analytical model on single cells, to determine whether TLR7 is expressed from either of the two X chromosomes, the researchers noted that the receptor is simultaneously produced by both chromosomes in approximately 30% of cells, in all of the immune cell subpopulations analyzed (B lymphocytes, monocytes and plasmacytoid dendritic cells), not only in females, but also in males suffering from Klinefelter syndrome.

Jean-Charles Guéry explains: "We then wanted to establish a causal relationship between this phenomenon and the functional response of B lymphocytes to TLR7 ligands. We thus showed that memory B lymphocytes in females proliferate better than those in males, and are enriched with cells expressing two copies of TLR7.  Naive B lymphocytes expressing these two alleles also have a larger capacity to differentiate into IgG-producing B lymphocytes. These two combined effects could contribute to an increased risk of producing auto antibodies and, consequently, developing auto-immune disease".

This study strongly suggests that this mechanism could be the reason why males suffering from Klinefelter syndrome are predisposed to SLE. It sheds greater light on the etiology of the disease and, consequently, allows new therapeutic perspectives to be envisaged.

"We will now continue our research so as to evaluate whether we can predict disease severity by assaying TLR7 expression by B lymphocytes", adds Jean-Charles Guéry. "In addition to shedding light on SLE and, more broadly, auto-immune diseases, these results could provide valuable information for other auto-immune disorders involving TLR7, or HIV infection, to which men and women respond differently". Since numerous immunity genes are carried by sex chromosomes, escape from inactivation involving other X-genes undoubtedly warrants further investigations.

Note:

*Inserm Unit 1043/CNRS/Université de Toulouse 3,Sex-related differences in immunity: mechanisms and physiopathology team, Centre de Physiopathologie de Toulouse-Purpan, CHU Purpan

Source

M Souyris et al. TLR7 escapes from X chromosome inactivation in immune cells. Science Immunology 2018  https://doi.org/10.1126/sciimmunol.aap8855