Journal of Theoretical Biology. 2015 Jun 21;375:95-100. doi: 10.1016/j.jtbi.2014.12.015.

Thyroid autoimmunity as a window to autoimmunity: An explanation for sex differences in the prevalence of thyroid autoimmunity

 

Merrill, SJ a,b, Mu Y a

a Center for Devices and Radiological Health, U.S. Food and Drug Administration, Silver Spring, MD 20993, USA

b Department of Mathematics, Statistics and Computer Science, Marquette University, Milwaukee, WI 53201-1881, USA

 

Abstract

Autoimmune thyroid diseases (AITDs), predominately Graves’ disease and Hashimoto’s thyroiditis, comprise the most common autoimmune diseases in humans. Both have the production of anti-thyroid antibody as an important aspect and both are much more prevalent in females, being at least 10 times more common than in males. Using these two clues, a hypothesis for the initiation of thyroid autoimmunity is proposed that helps to make the case that the thyroid is one of the most sensitive sites for autoimmunity and helps account for the prevalence and the observed sex differences in AITDs and associated diseases, such as type1 diabetes and Latent Autoimmune Diabetes in Adults (LADA).

The primary mechanisms proposed involve the underlying state of inflammation as a result of the adipokines, especially leptin, TNF-α, and IL-6,and the receptors able to recognize pathogen-associated molecular patterns(PAMP’s)and damage-associated molecular patterns (DAMP’s) through Toll-like receptors (TLR) and other receptors present on thyrocytes. The adipokines are produced by adipose tissue, but have hormone-like and immune modulating properties. As the levels of leptin are significantly higher in females, an explanation for the sex difference in thyroid autoimmunity emerges. The ability of the thyrocytes to participate in innate immunity through the TLR provides an adjuvant-like signal and allows for the action of other agents, such as environmental factors, viruses, bacteria, and even stress to provide the initiation step to break tolerance to thyroid self-antigens.

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.

 

Supplement:

Autoimmunity requires a self-antigen, to which one is normally tolerant; and a mechanism to overcome tolerance to that antigen. In the case of thyroid autoimmunity, primarily Graves’ disease and Hashimoto’s autoimmune thyroiditis, the self-antigens are components of the thyroid. In Graves’ disease, the thyroid stimulating hormone (TSH) receptor and for Hashimoto’s, thyroglobulin and other thyroid components are self-antigens targeted by aspects of the immune response. The most difficult aspect of understanding any particular autoimmune disease, however, involves describing the mechanisms employed to overcome the tolerant state and initiate a self-sustaining immune response.

In the case of thyroid autoimmunity, one is faced with also understanding the nature of the sex differences in incidence, with at least 10 times as many women as men getting the disease (1). Explanations for this difference have naturally investigated either estrogen-related differences, pregnancy, or the X chromosome (2). Except in genetically rare cases, however, these differences have not been conclusively demonstrated as a cause. More recently, sex differences in miRNA expression has been proposed as a possible cause of the sex differences (3).

In this study, we propose a simpler and more direct explanation, and one that correlates with other autoimmune conditions, obesity, and diabetes (both Type I and II). The first facet of the proposed mechanism involves adipokines, which have been implicated in several autoimmune diseases (reviewed in (4)). The inflammatory nature of these molecules provides the first step in the initiation of autoimmunity. With the exception of genetically susceptible individuals, experimental autoimmune conditions require an adjuvant for the initiation – a second factor needs to provide an adjuvant signal. In the case of the thyroid, recent discovery of the ability of thyrocytes to identify and respond to pathogen-associated molecular patterns (PAMP) through Toll-like and other receptors (reviewed in (5)) can provide the (non-specific) adjuvant signal. The third factor is a specific trigger – often a molecular mimic to one of the thyroid self-antigens. The impressively long list of bacteria, viruses, and proteins as potential triggers, have made identification of “the” trigger cause impossible. In addition, the trigger need only start the response, and then need not be present after the self-sustaining autoimmune aspects of the response appear.

The adipokines (especially leptin, IL-1, IL-6, and TNF-a) also play a role through the disruption of the hypothalamic-pituitary axis controlling thyroid function and in reducing the regulatory T cells (Treg) numbers in the thyroid (6). This disruption renders the thyrocytes more likely to provide the adjuvant signal and lowers the ability of immune response to impede initiation of an autoimmune response.

Understanding the sex-differences in the incidence of thyroid autoimmunity can be understood through the role of the adipokines, and the realization of the sex-differences in the levels in leptin (7), independent of body mass index.

The hypothesized steps are summarized in Figure 1.

 

fig1

Figure 1. Steps leading to thyroid autoimmunity. In first step, the rate of production of adipokines by adipose tissue (effect in bold arrows), has an important sex difference.

 

The findings and conclusions in this paper have not been formally disseminated by the Food and Drug Administration and should not be construed to represent any agency determination or policy.

 

References

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  2. Lleo A, Battezzati P, Selmi C, Gershwin M, Podda M 2006 Is autoimmunity a matter of sex? Autoimmun. Rev. 7:626-630.
  3. Dai R, Ahmed S 2014 Sexual dimorphism of miRNA expression: a new perspective in understanding the sex bias of autoimmune diseases. Ther. Clin. Risk Manag. 10: 151–163.
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  5. Kawashima A, Yamazaki K, Hara T, Akama T, Yoshihara A, Sue M, Tanigawa K, Wu H, Ishido Y, Takeshita F et al. 2013 Demonstration of innate immune responses in the thyroid gland: potential to sense danger and a possible trigger for autoimmune reactions. Thyroid 23: 477-487.
  6. Matarese G, Procaccini C, De Rosa V, Horvath T, La Cava A 2010 Investigations of thyroid hormones and antibodies in obesity: leptin levels are associated with thyroid autoantibodies independent of bioanthropometric, hormonal, and weight-related determinants. J. Clin. Endocrinol. Metab. 95: 3965-3972.
  7. Hickey M, Israel R, Gardiner S, Considine R, McCammon M, Tyndall G, Houmard J, Marks R, Caro J 1996 Gender differences in serum leptin levels in humans. Biochem Mol. Med. 59:1-6.

 

 

Contact:

Stephen J. Merrill

Professor

Department of Mathematics, Statistics and Computer Science

Cudahy Hall

Marquette University

Milwaukee, WI 53201-1881

stephen.merrill@marquette.edu

http://www.mscs.mu.edu/~stevem/

 

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