(Selected Tables and Figures referenced, but not present in this blog
can be found in their corresponding Science Version blogs)
It’s time to revisit female bias in immunology, “for better and for worse,” in this case, more “for worse.” The prevalence of autoimmune diseases in females is an area of intense research and speculation as to its causes. This blog will briefly address some of the most popular theories from the evolutionary, individual development, disease occurrence, and immunologic explanations.
Autoimmune 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 the possible causes, some of which we have discussed already in numerous blogs and some not yet presented:
Male testosterone protection (speculation);
Pregnancy factors (evidence-based science);
Genetic 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 evolutionary development wherein women seem 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 risks for dysregulation and loss of homeostasis or abnormal balance pf physiologic forces (speculation);
The “hygiene hypothesis” that compromises the microbiome and increases the risk of autoimmune disease (greater in females due to inherent differences between males and females or “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 immune chemistry 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 (not involved in protein synthesis process) abundant on the female X chromosome and essential in how genes produce the organism’s (person’s) physical characteristics (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 contributors 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.
Beyond XCI, other interesting associations in the disease producing or protective causes 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 or 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) present in the microbiome upregulate interleukins and TNF-a and further contribute to the causes of autoimmune diseases. Finally, the modification of gene expression from SCFA metabolism and its byproducts and interactions between gut microbiota and the innate immune system disrupt homeostasis and also contribute to the disease process in autoimmunity. Confusing? Don't worry, you're not alone.
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