It seems that at one point or another during the school year, everyone is sick. The sore throat, residual cough, and sniffling nose all sit behind you in lecture or keep the trash can stacked with used tissues. Yet, it's essential to know that each of these symptoms is an active sign of an extraordinary defense system built into each of our bodies—the immune system. 

Rather than being confined to a set of organs, the immune system is a broad-spanning network composed of cell interactions and protein activities within specific tissues. Its protective mechanisms are three-fold: there are the physical barriers, inclusive of mucous membranes that trap harmful molecules, the innate system, with cells programmed to detect and destroy foreign substances, and the adaptive system, which houses cells with an additional specialized feature—the ability to learn and memorize an intruder's surface proteins. In the event of a secondary exposure to this disease-causing agent, these adaptive immune cells will act more efficiently to destroy the introduced intruder, working swiftly to protect the body. 

However, these latter two systems—the innate and adaptive responses—are also responsible for autoimmune diseases, in which cells that are usually considered "self" are recognized as “foreign," triggering an immune response. In effect, immune cells may destroy one's tissues or organs.

Interestingly, biological females, who have two X chromosomes, are more likely to develop autoimmune disease than biological males, who have an X and a Y chromosome. However, the underlying mechanisms driving this phenomenon are unclear, and many studies point to a number of different variables. Sex hormones, X chromosomes, microchimerisms (the presence of cells from a mother in her genetically distinct progeny), environmental factors, higher autoantibodies (proteins produced by the immune system that attack oneself), and microbiome activities have all been listed as suspects in this sex-dependent anomaly. 

Yet in a recent development toward understanding what drives this sex bias, a study conducted by researchers at Stanford Medicine found that a specific RNA molecule called Xist could be responsible for this disparity between biological sexes. 

The key to finding this molecule came from the fact that biological females have two X chromosomes, as compared to the single X chromosome in males. Along with housing genes related to sex determination, the X chromosome holds instructions for many different traits, including those for sex development, brain function, and other bodily processes.

X chromosomes are bigger and store more information than Y chromosomes. Thus, in order to "even out" the amount of hereditary information between males and females, biological females undergo an inactivation process whereby one X chromosome is effectively silenced at random. This process is achieved by the Xist molecule, whose gene is present on X chromosomes in both biological males and females, yet whose production only occurs in biological females. 

Xist is a molecule made of RNA, an essential molecule in directing protein synthesis. Typically, RNA acts as a transcript that is read and translated into protein. However, a specific type of RNA—called long noncoding RNA—does not encode instructions for specific proteins at all; rather, this type remains a long stretch of dormant subunits. 

Even while dormant, long noncoding RNA has implications in a variety of different biological processes, including changing the likelihood of the cellular machinery reading instructions from genes. According to the Stanford study, Xist can also bind proteins to itself, and these proteins can bind to each other, in effect creating a string of related molecules.

Of the nearly 100 proteins that have been identified that do this, many are known to be associated with autoimmune diseases. The researchers then hypothesized that if males were to produce Xist, a similar complex of proteins would form, and autoinflammatory symptoms would follow. 

To follow this hypothesis, researchers implanted a bioengineered version of Xist into the genomes of two mouse strains, one of which was susceptible to autoimmune disease and the other resistant to them. After periods of observation, the researchers found that Xist's presence had no visible effect on the mice. However, when a stressor known to induce symptoms of an autoimmune condition was injected into both the males who made Xist and the ones who did not, the mice with Xist developed the autoimmune symptoms at a rate similar to that of female mice. Thus, while Xist may be the source of proteins associated with autoimmune disease, an additional environmental trigger or stress is required to jumpstart symptoms. 

Even so, this research points to an exciting advance in the field of immunology, which continues to be vast and complex to many researchers. The next step would be to begin searching for solutions to this sex-related oddity.