The Role of Hormones and Sex Chromosomes in Autoimmune Disease

Chromosomally female individuals (referred to as female here) are more likely to develop autoimmune diseases than those chromosomally male (referred to as male here). We also see differences in response to infections. The underlying reason for these differences is an ongoing area of active research. A recent review article published in Nature Review Immunology titled “The conneXion between sex and immune responses”  discusses our current understanding. 

One known factor is the differences in hormones between these two groups. Hormones like testosterone, progesterone and estrogen can impact the function of immune cells and lead to proinflammatory or antiinflammatory impacts depending on their concentration and combination.  

Another factor is the chromosomal makeup themselves: females have two X chromosomes, while males have one X and one Y chromosome.  The X chromosome contains many immune cell genes. Typically, one copy of X is turned off through a process known as X-inactivation. This should help keep the levels of immune cell genes similar between males and females. However, this process does not always occur correctly, and the second X chromosome can sometimes escape inactivation. This can increase the amount of certain immune cells genes produced in the cells of females, and can contribute to the development of autoimmune diseases and immune function. 

Current research suggests it is likely a combination of hormones and X-linked differences that predisposes females to autoimmune disease. More research in this realm will help develop treatments targeting these factors.

Citation:

Forsyth, K.S., Jiwrajka, N., Lovell, C.D. et al. The conneXion between sex and immune responses. Nat Rev Immunol 24, 487–502 (2024). https://doi.org/10.1038/s41577-024-00996-9