Autoimmunity & its Increased Prevalence in Women

What is autoimmunity?

The immune system functions to protect the body from foreign invaders; it utilizes a variety of cell types to mount a response against foreign antigens, targeting them for destruction. When autoimmune diseases develop, the immune system has become dysregulated and has begun attacking the body’s own tissues and cells (self-antigens), leading to increasingly severe symptoms and markers of inflammation. Digestive issues are common in most autoimmune diseases, likely due to the inflammatory nature of autoimmunity, as well as the fact that over 70% of our immune system originates in the gut.

Autoimmunity vs auto-inflammation

Although auto-inflammatory diseases have been differentiated from autoimmune diseases, some overlap has been indicated.¹ Auto-inflammatory diseases usually involve the innate immune system, whereas autoimmunity is a dysregulation of the acquired immune system, but both can present with similar inflammatory symptoms and genetic associations.¹

What causes autoimmune diseases?

Many theories exist on what causes autoimmunity to develop. Although there seems to be a genetic component involving multiple genes, environmental triggers might play a larger role in the development of autoimmune diseases.

• Intestinal permeability (leaky gut)

  • Intestinal permeability is common in patients with an autoimmune disease. Increased zonulin activity (whose release can be triggered by gliadin, a glycoprotein in wheat) is thought to contribute to intestinal permeability (leaky gut) and a decreased epithelial barrier.² Leaky gut has been shown to lead to an increased expression of inflammatory cytokines. Dysbiosis might also be a cause of leaky gut, possibly by increasing inflammation or by other mechanisms.² Conversely, beneficial microbes can protect the epithelial barrier and be used as a treatment for autoimmunity.² Considering all the environmental factors that modify the microbial balance of the gut and induce dysbiosis, it is hard to elucidate all the possible mechanisms that contribute to the development of autoimmunity.

• Over-sanitization & the hygiene hypothesis

  • The idea underlying the hygiene hypothesis is that our over-sanitized society has left our immune systems under-trained and over-bored, causing them to be overactive to harmless substances, leading to allergies and autoimmunity. A lack of exposure to microbes during early childhood might also account for the decreased diversity and lack of commensal microbes in our guts. There has been a massive rise in allergies and atopic dermatitis/eczema in industrialized countries in recent years, corresponding with a massive rise in antibacterial soaps, cleaning products, and an obsession with excessive cleanliness.

• Environmental toxins

  • Exposure to environmental agents, such as trichloroethylene, smoking, silica, pristane, pesticides, and mercury, can trigger autoimmunity in genetically susceptible individuals.³ This might be due to the dysbiotic effects these toxins have on the gut microbiome that then leads to inflammation and leaky gut, rather than directly due to the toxin exposure.³ However, most of these environmental chemicals do induce inflammation in the body.³

• Prolonged T-cell Activation & Dysregulation of Appropriate Apoptosis

  • Another hypothesis in autoimmune disease development is a prolonged T-cell activation and reduced rate of apoptosis due to genetic defects (increased BCL-2 expression or caspase deficiencies).⁴ The initial T-cell activation could be triggered by another infection, perhaps explaining virally-induced onsets of autoimmunity.

There are also X-linked chromosomal factors, as well as a hormonal component, that increases the prevalence of autoimmunity in women, as described below. Other blog posts might also explore an epigenetic role in autoimmunity. Overall, each theory shares inflammation as a driver of symptoms and disease.

Why are autoimmune diseases more prevalent in women?

Women are significantly more likely to develop autoimmunity than men, and it is thought that this is due to sex-dependent, hormonally-driven immune system differences.⁵ Women display a Th1 dominance, providing them with a more aggressive immune response and a decreased susceptibility to infections. This Th1 dominance comes at the cost of increasing the risk for autoimmunity. Men, on the other hand, have a balance of Th1 to Th2 that favors Th2 dominance.⁵ Women also have a higher CD4:CD8 ratio than men of the same age, who show a higher CD8:CD4 ratio.⁵ From an evolutionary perspective, it makes sense that women would have a more aggressive immune response, as they traditionally needed to stay healthy in order to reproduce. Interestingly enough, when women become pregnant, there is a Th2 shift, as a result of the high levels of estrogen; this serves to promote fetal tolerance and prevent the mother from rejecting the fetus.⁵

How do we diagnose autoimmune diseases?

Autoimmune diseases are often diagnosed long after the initial onset of symptoms and inflammation due to rigid testing criteria that allow it to proliferate and worsen before being considered an autoimmune disease. Naturopathic medicine aims to take an early, preventative approach to autoimmunity, especially when it comes to aging women or women with hormonal imbalances. This involves baseline testing of inflammatory markers and environmental toxin exposure. Important tests to look at are blood plasma concentrations of C-reactive protein (which is made in the liver and whose concentration is increased in the blood in response to inflammation), TNFalpha, IL-6, IL-1, and IL-17. Erythrocyte sedimentation rate should also be considered as a potential test, as fibrinogen released with CRP from the liver binds to erythrocytes, speeding up ESR and indicating inflammation. Additionally, ELISA (enzyme-linked immunoassay) tests can detect antibodies against the self.

Intuition is largely unacknowledged in medicine; however, one can often sense when something is wrong in his or her body. Do not allow lingering notions of “female hysteria” to allow you to ignore signs and symptoms that something isn’t quite right, even if initial tests appear normal.

As with most diseases, prioritizing prevention is key in autoimmunity. Autoimmunity is a term used categorize a wide range of diseases with varying symptoms of inflammation, all of which result from an overactive immune response. Allergies and atopic dermatitis fall under the umbrella of immune system over-activity. Of the more than 80 types of autoimmune diseases, none currently have a pharmaceutical cure. Patients are usually prescribed drugs that offer symptom suppression. Rather than suppress symptoms, dampen the immune response through immunosuppressants, and ignore underlying causes, naturopathic physicians aim to reduce the inflammatory load and address the root cause in order to alleviate autoimmunity.

References

1. El-Shebiny EM, Zahran ES, Shoeib SA, Habib ES. Bridging autoinflammatory and autoimmune diseases. Egypt J Intern Med [Internet]. 2021;33(1). Available from: http://dx.doi.org/10.1186/s43162-021-00040-5  

2. Kinashi Y, Hase K. Partners in leaky gut syndrome: Intestinal dysbiosis and autoimmunity. Front Immunol [Internet]. 2021;12:673708. Available from: http://dx.doi.org/10.3389/fimmu.2021.673708  

3. Khan MF, Wang H. Environmental exposures and autoimmune diseases: Contribution of gut microbiome. Front Immunol [Internet]. 2019;10:3094. Available from: http://dx.doi.org/10.3389/fimmu.2019.03094  

4. Clemens MJ, van Venrooij WJ, van de Putte LB. Apoptosis and autoimmunity. Cell Death Differ [Internet]. 2000 [cited 2023 Feb 13];7(1):131–3. Available from: https://www.nature.com/articles/4400633  

5. Dodd KC, Menon M. Sex bias in lymphocytes: Implications for autoimmune diseases. Front Immunol [Internet]. 2022;13:945762. Available from: http://dx.doi.org/10.3389/fimmu.2022.945762