Growing pains, painful acne, menstruation, pubic hair, and voice cracks – these are some of the physical changes many of us can remember as we unavoidably stepped into teenhood. Puberty marks a crucial period in sexual maturation characterized by alterations in the composition and levels of our sex hormones which drive sex-specific changes in physical appearance. Androgens, primarily found in men, and estrogens, predominant in women, constitute two major classes of sex hormones. Testosterone is the primary androgen, whereas estradiol is the predominant form of estrogen. During puberty, testosterone levels surge dramatically, escalating 250-fold in boys aged 6 to 20. Similarly, estradiol levels undergo a significant increase, multiplying by 15-fold in girls aged 7 to 23. Although testosterone and estrogen are often considered male and female-specific hormones due to their sex-specific effects, they are found in both sexes.
Beneath the physical changes we tend to associate with puberty, sex hormones have also been shown to regulate components of the immune system. For instance, estrogen has been shown to trigger immune cells to release pro- and anti-inflammatory molecules known as cytokines. Evidence suggests that estrogen stimulates the production of the pro-inflammatory cytokine interferon gamma (IFNγ) – a key player in the immune response to viruses – and adolescent girls produce higher levels of IFNγ than boys after 12 years of age. It has also been reported that women produce higher levels of antibodies in response to vaccination during enhanced states of estrogen production, such as pregnancy. Estrogen directs the macrophage – a type of immune cell – to help in the development of breast mammary ducts in females, whereas macrophages in males safeguard fertility by suppressing inadvertent or harmful immune responses in the testes during puberty. Clearly, sex hormones regulate multiple facets of the immune system in healthy individuals – but could this suggest their involvement in immune-related disease?
Autoimmunity refers to a type of pathological immune response in which the body attacks and damages its own tissues. For reasons which remain unclear, numerous autoimmune diseases show a sex bias towards women. Given the wide-ranging effects of sex hormones on the immune system, the presence of an autoimmune sex-bias suggests the involvement of sex hormones in the development of autoimmunity. Indeed, the incidence of autoimmune disease in women specifically increases during and after puberty.
Self-antigens are molecules the body normally recognizes as its own, but are mistakenly targeted in autoimmunity. The immune system employs many different checkpoints to prevent the development and persistence of auto-reactive immune cells, or immune cells that target self-antigens. Collectively, these checkpoints confer tolerance to self-antigens. A breakdown in tolerance refers to an autoimmune response where the body, due to auto-reactive immune cells escaping tolerance checkpoints, is no longer tolerant to self-antigen. For example, auto-reactive B cells can produce auto-antibodies that wreak havoc within the body by attacking self-antigens, leading to tissue damage and chronic inflammation.
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that presents as widespread inflammation in the joints, lungs, kidneys, skin, brain, and blood vessels. Patients with SLE tend to experience waves of symptoms, or flare-ups. Approximately 90% of patients diagnosed with SLE are women. Could such a strong sex-bias have something to do with estradiol levels alone? It’s likely not that simple, since some studies suggest that women with SLE have higher plasma levels of estradiol compared to healthy women, while others find no significant differences. Auto-antibody levels have been shown to increase in prevalence during puberty in adolescent girls, suggesting that puberty plays a role in autoimmune development. Still, the extent to which puberty-associated sex hormones contribute to auto-antibody production remains poorly understood. A study from Brazil tracked cytokine levels in teen SLE patients, in which 92% of patients were adolescent girls with an average age of 15. When compared to healthy participants, the study found increased levels of IL-10 in SLE patients, a cytokine known to stimulate the production of auto-antibodies. Interestingly, treating immune cells taken from SLE patients with estradiol provokes higher levels of IL-10 and auto-antibody production. This suggests a complex relationship between sex hormones, cytokine production, and auto-antibodies in SLE development during puberty.
Rheumatoid arthritis (RA) is another sex-biased autoimmune disorder that specifically causes inflammation in the joints. Predisposition to RA is associated with specific variants in genes essential for recognizing pathogens, likely because these variants encode proteins that mistakenly target self-antigens rather than foreign ones. One of the more well-characterized self-antigens known to cause RA are proteins that contain citrulline, a modified form of the amino acid arginine. The conversion of arginine to citrulline is catalyzed by a distinct group of enzymes, which happen to be controlled by estradiol. This exemplifies how two distinct genetic factors can cooperate to cause disease whereby a predisposition to recognizing self-antigens and a sex-biased increase in the level of self-antigens conspire to cause autoimmunity. However, many questions remain to be answered: Do males have lower levels of enzymes that convert arginine to citrulline? Do other sex hormones control the levels of these enzymes? Are the levels of these enzymes increased during puberty in either sex?
Yet another interesting aspect of sex-biased autoimmunity lies in chromosomal inactivation. Unlike males, females have two X chromosomes. To properly balance the expression of genes on X chromosomes, female cells “silence” one of two X chromosomes at random – but this may not always be the case. Evidence suggests that some cells escape X-chromosome inactivation, leading to increased expression of genes. In particular, it has been shown that X-chromosome inactivation in female B cells leads to increased expression of the X-chromosome gene encoding Toll-like receptor 7 (TLR7) – an intracellular “sensor” which normally recognize parts of viruses but can also recognize self-antigens. Female B cells that have increased TLR7 expression appear to have a survival advantage, lending to the idea that auto-reactive B cells can outcompete healthy B cells. Upon TLR7 activation, these auto-reactive B cells can go on to produce auto-antibodies. Strikingly, expression of TLR7 increases in females after puberty, but this increase was not shown to be related to estradiol. Could this effect be independent of sex hormones or perhaps hormones altogether?
It has become increasingly clear that sex hormones play a role in the development of female-biased autoimmunity, particularly during puberty. The extent to which estrogens can be attributed to autoimmune development during puberty remains unclear, since evidence suggests they are not the only contributors to autoimmunity in predisposed individuals. Sex-biased autoimmunity instead appears to be a complex waltz between sex hormones and various compartments of the immune system. Even this may be an oversimplified explanation, as other puberty-associated hormonal and non-hormonal factors seem to be at play. As we continue to unravel the role of sex hormones on the immune system, puberty emerges not only as a rite of passage but also as a means to better understand sex-biased autoimmunity.
Leon Baronijan
