Why do women have a higher risk of developing autoimmune disorders?
The Leptin Theory in Autoimmune Thyroiditis and Multiple Autoimmune Syndrome
Why do women have a higher risk of autoimmune disease? I have wondered about this question ever since I started reading the scientific research on autoimmune disorders. The thread running through nearly all of the studies I have read is that women are x-times more likely to develop y autoimmune disease than men. A 2014 article, Thyroid autoimmunity as a window to autoimmunity: An explanation for sex differences in the prevalence of thyroid autoimmunity, proposes a compelling theory that I call The Leptin Theory.
This foray into theoretical frameworks to explain the sex differences in autoimmune thyroid disease may seem distant from Multiple autoimmune syndrome, but the authors Merrill and Mu actually use what is known about Multiple autoimmune syndrome to support their theory, which is how this theory became part of my literature review for Multiple autoimmune syndrome. The research that I have reviewed so far on Multiple autoimmune syndrome supports the authors argument that
Seeing the thyroid as one of the most sensitive sites for autoimmunity, means that for many autoimmune disorders, if autoimmunity is present, it is likely to also be present in the thyroid – and that that condition in the thyroid was probably earlier. The evidence is seen in multiple autoimmune syndrome.”
Across numerous autoimmune diseases studied in the context of polyautoimmunity—Systemic sclerosis, Systemic Lupus Erythematosus, Rheumatoid arthritis, Multiple sclerosis, Sjogren’s syndrome—Autoimmune thyroid disease co-occurs most frequently (References 1,4,6,7). Thus, understanding the root cause of autoimmunity in the thyroid is arguably the foundation for understanding autoimmunity elsewhere in the body.
The authors note that there is a large sex difference in the prevalence of the two most common Autoimmune thyroid diseases, with a 10-fold difference in prevalence rates of Graves’ disease among women, compared to men, and a 226-fold difference in prevalence rates of Hashimoto’s thyroiditis among women, compared to men. Their theoretical framework rests on three basic pillars: known sex differences in Leptin levels, Leptin’s proposed impact on the thyroid, and autoimmunity and the unique qualities of thyroid cells.
Sex Differences in Leptin Levels
The sex differences in circulating Leptin levels could be the distinguishing factor between prevalence rates of autoimmune diseases in women, compared to men. Leptin is a hormone secreted from fat tissue that influences multiple endocrine functions, bone metabolism and energy balance in the body (References 2,3). Leptin levels diverge between males and females beginning with a rise in Leptin levels in young girls leading up to puberty, and a decrease in Leptin levels in boys as testosterone levels increase. In females,
This increase begins a life-long dance between leptin and low-grade inflammation.
Leptin is a hormone, but it’s also a cytokine. Cytokines are a class of protein that exert either a pro-inflammatory or anti-inflammatory effect on other cells (Reference 2). Cytokines, broadly, have the power to induce a fever, activate or increase macrophages (big eating cells that consume pathogens), increase phagocytosis (the destruction of cells through being consumed by other cells), cause the differentiation of white blood cells from their general-purpose parent cells, activate other defensive cytokines, activate immune cytokines, activate healing responses, and activate anti-inflammatory processes (Reference 2). Leptin is a pro-inflammatory cytokine. It stimulates the production of other inflammatory cytokines. It promotes chemotaxis of cells, which is the attraction and concentration of existing circulating inflammatory cells and cytokines to a site of inflammation. I can’t help but think of Leptin as the crazy party-goer leaning out the window and yelling “Hey y’all, party’s over here!” to passing immune cells/cytokines/antibodies, who then pack themselves into the tiny apartment with the raging party. Leptin also protects white blood cells against destruction, so they continue their work of attacking and destroying cells past their usual life span.
Leptin’s Impact on the Thyroid
The authors hypothesize that higher levels of circulating Leptin in women provides a signal in the thyroid that triggers inflammation due to the unique qualities of thyroid cells (more on that in a minute). Separately, they hypothesize that Leptin affects the thyroid in other ways, including through the hypothalamus-pituitary-thyroid axis. I don’t have access to all of the studies they cite, but the one I was able to access is a study on several specific adipokines—cytokines that originate from fat cells—but not on Leptin specifically. The particular impact of Leptin on the thyroid, or through the hypothalamus-pituitary-thyroid axis, may be an open question. The authors do clarify that for the purposes of their theoretical framework, they are referring to all adipokines as Leptin, which I take to mean that they are using scientific evidence on the function of other adipokines, and evidence on the specific function of Leptin may be lacking at the time of their writing. This is the nature of theories, I suppose.
Autoimmunity and the Unique Qualities of Thyroid Cells
Thyroid cells have their own innate immune function. Thyroid cells are able to recognize the molecular patterns of pathogens (viruses, bacteria, toxins, etc), as well as molecular signals sent by tissue damaged by injury. When thyroid cells recognize these molecular patterns, it triggers several inflammatory mechanisms. The thyroid is the only autoimmune target organ with a hormone that stimulates its growth, thereby increasing thyroid self molecules (antigens) susceptible to attack from antibodies. Thyroid cells that are under stress can also act as antigen presenting cells to antibodies. And this could be one of many points where thyroid self-antigens are accidentally presented to antibodies and over time reduce immune tolerance of thyroid self-antigens.
Why it Matters
The Leptin Theory is just a theory. If the connections the authors outline can be proven scientifically, then it offers a potent target for treatment, as the author of a different 2017 review article further outlines.
it has been suggested to limit leptin bioavailability…through antibody-based antagonism…in autoimmunity it could reduce immune hyperactivity and slow the progression of chronic inflammation leading to target tissue damage. (Reference 3)
The downside to antibody-based antagonism is immune suppression. Another possible treatment that side-steps immune suppression as an adverse effect are treatments better targeted specifically toward Leptin.
thus targeted approaches considering selective targeting of the leptin pathway might be considered to reduce this possibility. For example, useful leptin-based targets could be SOCS3 (an important factor of leptin resistance and negative feedback), PTP1B (which dephosphorylates Jak2 on OB-R), and SHP2 (which is critical for leptin signaling through downregulation of the ObRb-STAT3 pathway and the promotion of ERK signaling) (Reference 3)
Okay, I won’t pretend that I know exactly what the author La Cava (Reference 3) is referring to in this list of potential points of treatment for increased circulating Leptin levels as it relates to autoimmunity—and I don’t have time to research it right now (hopefully someday!). What matters to me is that there are potential targets for treatments based on Leptin’s potential role in autoimmunity. For a hormone and cytokine that was only discovered in the mid-1990’s, I’m impressed by the speed of discovery.
References
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Huether, S. E., & Mccance, K. L. (2008). Understanding pathophysiology. Mosby.
La Cava A. Leptin in inflammation and autoimmunity. Cytokine. 2017 Oct;98:51-58. doi: 10.1016/j.cyto.2016.10.011. PMID: 27916613; PMCID: PMC5453851.
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Merrill SJ, Mu Y. Thyroid autoimmunity as a window to autoimmunity: An explanation for sex differences in the prevalence of thyroid autoimmunity. J Theor Biol. 2015 Jun 21;375:95-100. doi: 10.1016/j.jtbi.2014.12.015. Epub 2015 Jan 6. PMID: 25576242.
Ordoñez-Cañizares MC, Mena-Vázquez N, Redondo-Rodriguez R, Manrique-Arija S, Jimenez-Núñez FG, Ureña-Garnica I, Fernández-Nebro A. Frequency of Polyautoimmunity in Patients With Rheumatoid Arthritis and Systemic Lupus Erythematosus. J Clin Rheumatol. 2022 Jan 1;28(1):e38-e43. doi: 10.1097/RHU.0000000000001574. PMID: 32956154.
Rojas-Villarraga A, Amaya-Amaya J, Rodriguez-Rodriguez A, Mantilla RD, Anaya JM. Introducing polyautoimmunity: secondary autoimmune diseases no longer exist. Autoimmune Dis. 2012;2012:254319. doi: 10.1155/2012/254319. Epub 2012 Feb 20. PMID: 22454759; PMCID: PMC3290803.