October 14, 2021
When it comes to the likelihood of developing an autoimmune disease such as lupus, there is a clear difference between sexes, with 9 women diagnosed for every one man. Two recent studies, both funded by the Lupus Research Alliance (LRA), offer insight into what may be driving this difference. Part of the reason may be due to a phenomenon called X-inactivation escape, which can cause genes that determine gender to be turned on at different levels in women versus men.
Lupus symptoms linked with accumulation of age-associated B cells
In the first study, published in the journal Nature Communications, LRA grantee Dr. Alessandra B. Pernis and colleagues at the Autoimmunity and Inflammation Program, Hospital for Special Surgery and Weill Cornell Medical College looked at a subset of immune cells, called age-associated B cells. This unique type of B cell plays a role in determining how the immune system responds to viruses as well as autoimmune disorders. Moreover, the number of age-associated B cell increase as the person gets older and are thought to contribute to “immunosenescence,” a process known as a gradual decline in the strength of the immune system with age. The development and activity of age-associated B cells depend on two molecules present on these cells, Toll-like Receptor 7 (TLR7) and TLR9. Although it’s been known that these cells are involved in autoimmune disorders, it has remained unclear how they contribute to autoimmunity.
To answer this question, researchers studied mice with a lupus-like condition that causes an accumulation of age-associated B cells. They found that more of these cells accumulated in female mice versus male mice, and that they turned into B cells that fueled inflammation. This accumulation of age-associated B cells was found to be the result of the TLR7 gene, which is located on the female X chromosome, and is present at higher levels in female mice.
X-inactivation is a biological process that equalizes gene expression on the X chromosome
TLR7 is a gene known to undergo a variable escape X-inactivation. X-inactivation is a biological process that is meant to compensate for the different number of sex chromosomes in women versus men. Since women have two X chromosomes, while men only have one, a lack of X chromosome in men could create an imbalance in the overall amount of gene expression in men versus women. Since gene expression ultimately leads to the formation of proteins with a specific function, differing levels can have an impact on a cell’s function. X-inactivation, means that only one copy of a gene, known as an allele, is expressed in women, while the second copy is inactivated. X-inactivation therefore ensures that females, like males, have one functional copy of the X chromosome in each body cell.
However, about 10% of the genes on the X chromosome “escape” X-inactivation which means that the expression of these genes is present in women at higher levels than in men. Interestingly, up to 30% of genes located on the X chromosome are capable of “variable escape”, which means that only some women compared to men have higher levels of gene expression or that women versus men have gene expression elevated in some but not all tissues or organs. Currently, there is still much to learn about the potential role of variable escape X-inactivation in diseases such as lupus, where there is a clear difference in the likelihood of women developing the disease, as opposed to men.
Study shows diseases influenced by gender have a high number of genes showing X-inactivation escape
In the second study, published in the journal Genome Research, Dr. Laura Carrel and team at Penn State College of Medicine used her LRA grant to develop a method to look at genes that escape X-inactivation. To study these genes, they used data collected by RNA sequencing, a method that detects the presence and amounts of message (ribonucleic acid or RNA), which is a metric for measuring gene expression levels, in samples from specific body tissues. They then tested this method using data from the UK Biobank, which is a biobank following volunteers to assess the role of genetic and environmental factors in the progression of disease.
What they found was a higher number of escape and variable escape X-inactivation genes in diseases that are influenced by gender. This result, in addition to the first study’s conclusions about the effect of the differential expression of TLR7 in female mice, suggests that differences in X-inactivation escape may be an explanation for why a disease such as lupus develops in women more than men.
“Women’s higher propensity to develop lupus than men has been a long-standing question,” noted LRA Chief Scientific Officer Dr. Teodora Staeva. “These new studies offer important mechanistic insights that could guide therapeutic interventions.”