The Lamen

Illustration of a woman finding her way out of an X-shaped maze.

Feb 8, 2024 | Immunology

The disproportionate burden of autoimmune diseases in women

Nearly 80 percent of autoimmune sufferers are female — the X chromosome might hold the secret

Image: Generated with Bing AI

The immune system heals wounds, detects and destroys aged cells, fights off a broad range of microbial cells, and clears out toxic and allergenic substances. Of the 1.8 trillion cells it employs, several are involved in continuous surveillance, on the lookout for anything that might attack your cells.

In a normal immune response, B cells in the body create Y-shaped antibodies, whose two short arms form antigen-binding sites — binding to pathogens or their toxins and thereby blocking them from infecting or destroying your body’s cells. In some instances, however, the immune system turns on the very thing it was supposed to protect.

The idea seemed farfetched to Nobel Prize-winner Paul Ehrlich, who dismissed the theory of autoimmunity, stating that the immune system wouldn’t go attacking healthy cells since that “would be dysteleological to the highest degree.” At the turn of the 20th century, Ehrlich coined the term “horror autotoxicus” to explain how all organisms selectively avoid autotoxicity.

Even if so horrifying to be dismissed as impossible, adherents of Ehrlich’s theories have failed to explain the underlying immune drive to damage healthy tissue.

Autoimmune diseases are a group of over 80 conditions whose manifestations vary from life-threatening organ failure to subtle misgivings that are easily dismissed. A scarcity of characteristics has made identifying autoimmune diseases a challenge — scientists are unable to consistently link biological hallmarks to the pathology of the disease.

The defining feature of most autoimmune diseases is autoantibodies, or the antibodies formed against self-proteins. It’s the nature of these autoantibodies that often defines the type and severity of an autoimmune condition.

But even a mistaken immune response alone fails to explain the sudden appearance of autoantibodies in the bloodstream. Even more fascinating is how women are much more susceptible to autoimmune diseases than men nearly — 8 out of every 10 autoimmune cases appear in women. The discrepancy is even greater in some cases. In the case of lupus and Sjögren’s disease, 90 to 95 percent of sufferers are female.

According to a new explanation for this discrepancy, gene misregulation might be what provokes this antagonistic immune response.

A gene that fails to “turn off” might be to blame

Owing to the foundational discovery laid by biologist Nettie Stevens, we know most male mammals have an X and a Y chromosome, while most females have two Xs. The Y chromosome — encoded with inherent genetic components — encodes several genes that differentiate males from females, which made scientists believe that it’s counterpart had little importance.

But the X chromosome has since been recognized as an essential cog of the female cellular machinery.

This dismissive attitude might partly be explained by the fact that one of the X chromosomes in females was inactivated during embryogenesis, leaving both males and females at an even genetic playing field — each with a single active X chromosome in hand.

The X chromosome contains upwards of 1,200 genes. If both X chromosome and all their genes were to remain active, they would in theory produce twice as many copies of proteins.

Biological dogma therefore dictates X-chromosome inactivation, a form of dosage compensation where one of the two X chromosomes is randomly turned off during embryonic development.

This inactivation is initiated by the Xist RNA, which spreads along the entire X chromosome to establish transcriptional silencing. The extra X chromosome eventually becomes what is called the Barr body — a dark misshapen mass that coils up in itself to hide nearly all its thousand-plus genes.

A photograph of a calico cat.

Calico cats, which are always female, display a mixture of fur colors depending on which of its two X chromosomes has been inactivated. Depending on which copy of the X chromosome is silenced, a patch of orange or black appears on the cat. Photo: Camila Benítez via Pexels

As suggested by the new study published in Cell, these proteins essential to X-chromosome inactivation might themselves drive an autoimmune reaction.

Almost a decade ago, dermatologist and molecular geneticist Howard Chang had an epiphany: since Xist is normally expressed only in XX cells, it seemed logical that the Xist-associated proteins might trigger an autoimmune response.

Identifying close to a hundred proteins that either bound to Xist or to the proteins bound to it, Chang realized how many of these “Xist collaborator proteins” were linked to autoimmune disorders.

His research team then selected a strain of mice in which the females are at a high risk of lupus, while the males never develop the autoimmune disease. The male mice were then genetically engineered so that they too produced Xist.

The researchers found that the males in which the Xist gene was activated developed lupus-like autoimmunity at a rate approaching that of females. They also concluded that Xist itself didn’t induce autoimmunity — it also required an irritant that produced some tissue-damaging stress.

But an Xist-induced autoimmune reaction is one of the weaker arguments. The fact that many X-linked genes are directly linked to autoimmune disease signals how these conditions may largely be determined by the X chromosome. The protein TLR-7, for example, has been associated with lupus, polymyositis, and Sjögren’s syndrome.

Research has also spotlighted how X inactivation may not occur how scientists previously thought: An estimated 20 percent or more of X-linked genes are thought to escape the silencing. Encoding for double the proteins could be what triggers an autoimmune response in women, the hypothesis presumes. But genetics don’t determine every outcome.

Women also harbor a stronger immune system: they have higher levels of circulating antibodies, have more T cells and B cells in their blood, and develop a more robust cytokine response to infections. But the stronger immune response might be a double-edged sword.

The hyper-vigilant female immune system satisfies an evolutionary need

An observation that supports this hypothesis is that autoimmune disorders often appear during key transitional events, like puberty, pregnancy, or menopause. These events are coincided by a sweeping endocrine transition, and a consequent risk of autoimmune diseases like multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematosus.

Pregnancy, in particular, represents a unique immunological state. The maternal immune system modulates its condition to reinforce surveillance and repair while accommodating the fetus’ own active immune system.

The developing fetus represents foreign tissue in which half the DNA comes from the father. The pregnancy compensation hypothesis suggests that the mother’s immune system modulates itself owing to the stress exerted by the genetically distinct placenta and fetus. This immunosuppressive effect may have protected women from certain immune-related conditions and might account for the disparities in autoimmune functioning.

A story published in Scientific American notes how decreasing pregnancy rates, especially in developed countries, support the pregnancy compensation hypothesis. Women — especially in developed countries — spend a much smaller time of their lives pregnant than they did years ago, which means that their immune systems may not be suppressed as often.

But the precise mechanism for the development of autoimmunity remains unclear. A growing consensus now suggests that it requires a mix of genetic predisposition and environmental stressors. Emerging evidence suggests that the intestinal microbiome and endocrine-disrupting chemicals may also in part drive the increased autoimmunity risk.

Autoimmune diseases are typically treated with non-disease-specific immunomodulatory drugs. Scientists highlight how understanding their underlying mechanism is key to developing targeted therapies. One potential method involves selectively binding to rogue B cells, while another insists on rebuilding “tolerance” — the immune system’s ability to ignore self-antigens while attacking foreign ones.