Deviant number of X chromosomes and autoimmunity
Abnormalities in chromosome numbers are usually serious. The exception is abnormalities in the number of sex chromosomes. Men who have an extra X chromosome (Klinefelter syndrome, 47, XXY), and women who have an extra X chromosome (triple X syndrome, 47, XXX), may have minor symptoms or signs, and be unaware that they have an extra X chromosome. A missing chromosome is not normally consistent with viability, but here, too, the sex chromosomes are an exception. Women who lack part of or a whole X chromosome (Turner syndrome) are short, have gonadal dysgenesis and a number of other characteristic features. Common to these three X chromosomal anomalies is a high prevalence of autoimmune disease.
Systemic lupus erythematosus is a rare and serious autoimmune disease that most frequently affects women (Table 1). Men with Klinefelter syndrome have the same high prevalence of systemic lupus erythematosus as women (15), and also have a high prevalence of autoimmune thyroid disease, primary Sjögren's syndrome, Addison's syndrome, diabetes, multiple sclerosis and rheumatoid arthritis compared with men without a known chromosomal anomaly (3). Women with systemic lupus erythematosus and primary Sjögren's syndrome have a higher prevalence of triple X syndrome than women without these syndromes (16) (Table 1).
Women with Turner syndrome had twice as much risk of autoimmune disease as women in a control group (17). They have a high prevalence of Hashimoto's thyroiditis, but otherwise the autoimmune diseases that predominate in Turner syndrome are different from those that predominate in Klinefelter syndrome. Turner syndrome is particularly associated with autoimmune diseases where there is no pronounced gender difference, such as diabetes, and systemic lupus erythematosus is very rare (17).
While Turner syndrome is rare, loss of an X chromosome in peripheral blood cells (monosomy X) occurs frequently in women, particularly elderly women. A higher prevalence of monosomy X, most pronounced in T and B lymphocytes, has been found in autoimmune thyroid disease, systemic sclerosis and primary biliary cirrhosis (18) (Table 1).
A higher prevalence of autoimmune disease, in cases of both too many and too few X chromosomes, indicates that it is the dose of certain X-linked genes that is critical. A double expression of genes on the X chromosome may also arise in women with a normal number of X chromosomes, since 10–15% of the genes on the X chromosome are not inactivated. An example of this has been found in a mouse model of systemic lupus erythematosus. The female mice had overexpression of the immune-related X-linked gene toll-like receptor 8 (Tlr8) due to incomplete inactivation (19). Double expression of genes may also arise due to reactivation of genes on the inactive X chromosome. There is evidence that the inactive X chromosome in lymphocytes is disposed to partial reactivation, which may result in overexpression of immune-related genes (20). Not only overexpression, but also the absence of expression of genes on the X chromosome results in a higher risk of autoimmunity, as seen in Turner syndrome and acquired monosomy X in peripheral blood cells.
Micro-RNA (miRNA) can regulate gene expression. X-linked miRNA-mediated suppression of immunosuppressive genes is a new field of research that may contribute to a better understanding of why so many women are affected by autoimmune diseases (21).
Most studies of gender differences and autoimmunity have been conducted on women, particularly women with an autoimmune disease in which the gender difference is most pronounced. It has been maintained that attention should also be directed at why men so seldom are affected, with focus on possible protective factors in men (22).