Clinical and experimental evidence suggests that autoimmunity is more prevalent in women than men. For example, women develop rheumatoid arthritis and lupus at rates of ~ 4:1, and 9:1 compared to men, respectively. There are two likely explanations for this.
First, immune reactivity is more enhanced in females compared to males. This is generally attributed to sex hormone levels. The female sex hormones estrogen and prolactin are both immunomodulators and are implicated in autoimmunity. Also, in a mouse model of lupus oopharectomy (surgical removal of ovaries) postpones disease onset and ameliorates lupus activity. This and other data indicate that sex hormones can have an activating effect on the immune system, which could activate the immune system to the point of autoimmunity.
Not all data indicates that sex hormones play an important role in autoimmunity. Female patients with rheumatoid arthritis often experience remission during pregnancy when estrogen levels are at their peak. In fact, another reason that gender may influence the induction of autoimmunity is a process called X chromosome inactivation.
To maintain appropriate levels of gene expression, females inactivate one of their two X chromosomes. Normally this happens in about 50% of the female’s paternal and maternal cells resulting in a mosaic expression of paternal and maternal genes on X chromosomes. However, cases of skewed silencing (greater than 75% inactivation of one allele) occur. These women have a large population of cells with one X chromosome inactivated and small population of cells with the other X chromosome inactivated. Some cells from the small population may not be represented in the bone marrow and thymus, explaining a possible mechanism of autoimmunity. Of note, bias in X chromosome inactivation has been observed in Juvenile Rhuematoid Arthritis.
In sum, having a more active immune system or two copies of X chromosome alleles cuts both ways: increased resistance to infection but greater propensity to develop autoimmunity.
I thought this post was really interesting. I think sex differences are reflected in almost every physiological system. I had not thought about how skewed silencing in females could result in an autoimmune reactions, but of course now it seems so obvious. It would be interesting to see what autoimmunities males are more prone to.
ReplyDeleteThis is quite the case of a double-edged sword. This is an interesting consequence of X inactivation in females that I never would have considered. Are there any studies on the incidence of autoimmunity in XXY males, who I would suppose would be more likely to develop autoimmunity due to X inactivation as well?
ReplyDeleteHeather,
ReplyDeleteFrom the little that I have dug up on the subject it seems that if an individual has more than one X chromosome (including XXX and XXY individuals) X inactivation causes inactivation of all but one X chromosome. Since skewed X inactivation is abnormal it might become a numbers game, i.e. the proportion of individuals that develop skewed XCI (~4.5% but this is a moving target since XCI skewing increases with age!) in a XXY population (1 in 500 males) ends up being ~0.0045% (1/500*0.5(chance of being male)*4.5%).
I don't know if those numbers make too much sense but I think that you are right, XXY might be a risk factor for male autoimmunity but the population of potentially affected individuals is small, which may make it difficult to study. However, it would be interesting to see if there is any link between XXY and autoimmunity.
Does a more active immune system in females also mean that women have a higher rate of rejection of organ transplants? Did you find any data on this? Just curious. Great topic!
ReplyDeleteAmy,
ReplyDeleteI didn't find any info on different rates of organ rejection, however, I would predict that it wouldn't play a role because of the immunosuppression that organ recipients receive. There may be more to it than that but that is my two cents.