Reply: X chromosome short arm involvement in autoimmune diseases: comment on the report by Sharma, et al

Studying Klinefelter’s syndrome (male 47,XXY) and triple X (female 4,7XXX), we propose that the number of X chromosomes mediates the female bias of systemic lupus erythematosus (SLE) and Sjögren’s syndrome (SS). Our recent paper described SLE and SS patients with extremely rare X chromosome aneuploides in which distal Xp was triplicated, implicating genes lying on the short arm of X¹. Brooks points out that X-linked chronic granulomatosus disease (X-CGD) can also have gene duplication from Xp21.2 to Xp terminus, and some female carriers of X-CDG have a cutaneous lupus-like illness. In addition, male X-CGD patients have also been described with discoid lupus², but we do not find a reported association of systemic lupus erythematosus with X-CGD disease or carrier state, except for a single case report³. Several other primary immune deficiencies are associated with SLE⁴.

Brooks, et al. also propose that distal Xp genes may be involved in autoimmunity⁵. A central point is that many genes on distal Xp escape X inactivation. This is clearly the case but varies based upon tissue and development⁶. However, escape of X inactivation by some genes in the X-linked regions of the X chromosome, especially Xp, is a part of normal human physiology⁶. Thus, there may be no reason to evoke a disruption of X inactivation as a cause of autoimmune disease. There are several competing hypotheses for how an X chromosome dose effect might operate. For example, skewed X inactivation, acquired X monosomy, fetal chimerism and female X mosaicism, and X chromosome reactivation. We have reviewed the evidence for and against these hypotheses^{1, 7}. Brooks and colleagues propose the X-chromosome-nucleolus nexus, which predicts abnormal X inactivation⁵.

We found excess 47,XXX and 47,XXY in SLE or SS, but not in primary biliary cirrhosis or rheumatoid arthritis^7–9. Thus, we conclude that there is more than one path to sex-bias in autoimmunity. Data from Turner’s syndrome supports this notion in that these patients have excess type 1 diabetes, autoimmune thyroid disease (AITD) and celiac disease¹⁰, while neither RA nor SLE is over-represented^{10, 11}. AITD is in highest excess among Turner’s syndrome patients with an Xq isochrome^{12, 13}. These patients have one copy of Xp but three copies of Xq, in contrast to what we report in SLE and SS, and Brooks hypothesizes for autoimmune disease. Again, suggesting multiple pathways.

As noted by Brooks, there are a number of candidate genes at distal Xp, but only two have shown genetic association with SLE. These are TLR7 and CXorf21¹⁴, both of which escape X inactivation in various immune cells⁶. The associations and this physiology certainly makes these enticing possibilities for mediating an X chromosome dose effect in SLE and SS.