The prevalence of autoimmune diseases in females is an area of intense research and speculation as to its etiologies. This blog will briefly address some of the most popular theories from the evolutionary, phylogenetic, ontogenetic, pathogenetic, and immunologic explanations.
Autoimmune immune diseases occur in females at a rate of two to one over males (6.4% of women vs. 2.7% of men). In fact, it is estimated that 78% of people affected by autoimmune diseases are women. There is an abundance of theories as to why there is such a strong female predilection for autoimmune diseases. Some are based on speculation, but most on evidence-based science. A listing (and labeling) of some (not all) of those possible causes include:
Male testosterone protection (speculation);
Pregnancy factors (evidence-based science);
Gene expression (evidence-based science);
Embryologically, women confer first immunity to their babies suggesting a stronger immune system than the father (evidence-based science);
“Pregnancy brain” where fetal cells from the embryo transfer to the mother during pregnancy and remain in her brain for life producing a “potential” autoantigenic effect (evidence-based science and speculation);
Women, as traditional caregivers, suggest a kind of phylogeny (evolutionary development of women seems to produce more absolute lifelong antibody levels than men) thus producing a stronger immune system but increased risk for innate immune dysregulation (speculation);
Females tend to have more body fat than males, thus more immune cells (evidence-based science);
Women live longer, thus producing more antibodies that contribute to a longer life, but also create a greater potential risk for dysregulation and abnormal homeostasis (speculation);
The “hygiene hypothesis” that compromises the microbiome and increases the risk of autoimmune disease (greater in females due to sexual dimorphism) (evidence-based and speculation);
Probably more theories abound, including any you might identify in other blog discussions.
I mentioned way back in Blog #12 that we would be revisiting X Chromosome Inactivation (XCI) with some frequency in subsequent discussions. Well, here is the first revisit and it’s a big one. Beyond the 10 possible explanations for autoimmune disease being most prevalent in females, XCI may just be the most credible and validated science-based theory. It all has to do with XCI’s and its intimate relationship with microRNA.
It is well understood that sex hormones are an enormous factor in the regulation and dysregulation of immunity. Predominant influences of female estrogen and progesterone both increase and decrease proinflammatory mediators and are believed to be responsible for autoantibody development, autoimmune stimulation, and corresponding autoimmune diseases. More so, perhaps, estrogens regulate microRNAs (miRNA), the noncoding RNA gene abundant on the female X chromosome and essential in gene expression (as mentioned in Blog #10). Also, about 15% of genes escape the XCI process, called “escapees”, all of which recent research has confirmed as primary attributions to the female bias for autoimmune diseases, especially SLE. Paradoxically, the relationship of the X chromosome, in combination with XCI and XCI “escape” provides the basis of “protection” (vs. risk) for females against certain cancers and an increased risk for males. The escapees play a significant role in oncogenesis (cancer production) and will be further discussed in the later blogs on cancer. But after all is said and done regarding definitive causes of autoimmune diseases (and cancers), understanding their etiologies remain relatively nascent and will require an enormous amount of continuing research.
Other interesting associations in the pathogenesis of autoimmune disease include the effects of the microbiome (remember that from Blog #13?). Its unrelenting effort to control CI becomes a mitigating force against autoimmune diseases, even cancers as it modulates the immune system. Dysbiosis (imbalance in the gut microbiome) is another important environmental factor that has been linked to the onset of different autoimmune diseases. The “gut microbiota-innate immunity axis” and symbiotic bacteria (short-chain fatty acids or SFCA) upregulate IL-6, IL-12, IFN, and TNF and further contribute to the pathogenesis of autoimmune diseases. Finally, epigenetic modulation from SCFA metabolic by-products and interactions between gut microbiota and the innate immune system disrupt homeostasis and also contribute to the pathogenic process of autoimmune diseases
Discussion Questions:
The potential causes of the prevalence of autoimmune diseases in females are almost countless. Can you identify what you think the 3 most likely causes are and explain the reasons for your choices?
XCI has multiple characteristics that support its likely association with female autoimmune prevalence. Can you name the features of XCI that contribute to female autoimmune bias?
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