Type: Conference presentation
Presenter: Amy Proal
Conference: 6th International Congress on Autoimmunity
Location: Porto, Portugal
Date: September 11, 2008
See also: Notes from the 2008 International Congress on Autoimmunity by Amy Proal
I'm going to examine why autoimmune diseases such as Hashimoto's Thyroditis are much more likely to occur in women than in men, especially during the childbearing years. For example, in the study described by Prof. Marshall in which both sexes are allowed to participate equally, out of 104 subjects surveyed, 24 have Hashimoto's, and only 3 of them are men.
What might be going on? Well, one obvious difference between the sexes is that they express hormones at different levels.
As Professor Marshall and other researchers have shown, the VDR controls important components of innate immunity, particularly the transcription of the cathelecidin and beta Defensin antimicrobial peptides.1)
Vigano's recent work has confirmed a 1978 study showing that the active vitamin D metabolite 1,25-D is expressed in the human cycling endometrium.2) He also showed, using Western blot analysis (see slide) and immunohistochemistry (see slide) that both cycling and early pregnant endometrial cells express the VDR, which is activated by 1,25-D. Finally, he noted 40% increase in 1,25-D production in the early pregnant decidua.
The endometrium may have evolved to express the VDR and produce 1,25-D in an effort to offset the drop in cell mediated immunity that occurs during the weeks before menstruation, or possibly to stimulate the infant innate immune system during gestation - a time when the adaptive immune system is not yet competent.
But increasing evidence indicates that at some point in the history of man, a microbiota composed largely of intraphagocytic and biofilm bacteria evolved a way to take advantage of the innate immune response by creating ligands that dysregulate VDR activity. For example Prof. Marshall has identified that the sulfonolipid capnine, which is produced by gliding biofilm bacteria, is a strong VDR antagonist. I should add that we refer to this microbiota as the Th1 pathogens as their presence is associated with elevated interferon gamma. Since the Th1 pathogens are able to dysregulate the VDR, they have perverted what the body intended to be a protective environment during pregnancy and menstruation into one that allows them to flourish. When the ligands they create disable the VDR, expression of betaDefensin and cathelecidin is curtailed rather than activated.
And unfortunately, VDR dysregulation may instigate a series of other events that would allow the Th1 pathogens to further proliferate. You can see from this figure that when active, the VDR transcribes CYP24, an enzyme that breaks 1,25-D down into the inactive vitamin D metabolites. But what happens if the VDR is dysregulated by the Th1 pathogens? Under such conditions CYP24 is no longer transcribed and 1,25-D levels are able to rise without a feedback system to keep them in check.
Marshall's in silico modeling indicates that 1,25-D also has a strong affinity for the body's other nuclear receptors, suggesting that at high levels it can interfere with their activity. Since I'm discussing Thyroiditis lets take a look at the effects of elevated 1,25-D on thyroid alpha.
Here is the emulation of the alpha thyroid nuclear receptor (ThRa). Marshall has shown that 1,25-D has a very high affinity for ThRa - a kD value of 8.41. Normally levels of T3 (which has a kD 7.20 for ThRa) keep 1,25-D out of the binding pocket, but as 1,25-D rises due to VDR dysregulation it starts to proportionately displace T3 and block transcription by thyroid alpha. The same thing should happen with thyroid beta since Marshall has shown that 1,25-D has a Kd of 8.44 for the receptor.
So, when 1,25-D displaces T3, the genes with alpha thyroid promoters can no longer be transcribed. T3 gets displaced, therefore the thyroid can't function properly resulting in the phenomenon known as thyroid hormone resistance. This explains why increasing levels of thyroid hormone may be necessary to keep 1,25-D out of ThRa as the disease progresses, a measure that is palliative but not curative. And since all the type 1 nuclear receptors work as a group, when transcription by ThRa is dysregulated, system wide gene transcription is also affected.
And as I mentioned before, this same pattern is be repeated when it comes to several of the body's other nuclear receptors. For example, Marshall has shown that 1,25-D has a kD of 8.05 for the Androgen receptor, and a kD of 8.12 for the Glucocorticoid receptor. So elevated 1,25-D can displace cortisol and testosterone from their target receptors as well, leading to an array of other hormonal imbalances.
An additional effect is also of importance. By disabling the nuclear receptors, 1,25-D also has detrimental effects on system-wide AMP production. Just as the VDR expresses cathelecidin and betaDefensin, other nuclear receptors also express AMPs. Take a look at this table which presents data taken from a recent analysis of AMP expression by Brahmachary. You can see that the Glucocorticoid receptor, the Androgen receptor, and the Vitamin D Receptor, seem to be in control of 20, 17 and 16 families respectively, out of 22 analyzed.
So disabling the VDR with flow on effects to glucocorticoid, thyroid, androgen, and other nuclear receptors delivers a knockout blow to the body's antimicrobial peptide production. Disabling the VDR and subsequently the AMPs is a very logical thing for pathogens to have done, so much so that if such a survival mechanism were possible, it seems very likely it would have evolved.
It comes as little surprise then that hormonal dysregulation is so intricately connected to autoimmune disease. For example, you can see here that most of the patients with Hashimoto's analyzed by our study have also been diagnosed with other inflammatory or autoimmune diseases. In fact, only 8% of subjects with Hashimoto's have Hashimoto's alone.
We now have a pathway in the molecular biology showing how these apparently diverse physiological conditions can interact. Essentially, VDR dysregulation and the system-wide drop in AMP expression that it instigates allow the Th1 pathogens that Marshall describes in autoimmune disease to proliferate with greater ease. Since patients are immunocompromised, they also pick up new pathogens including viral co-infections. And what's more, since women have an extra site of VDR gene transcripton - the endometrium - they express more VDRs than men. So the over-expersison of VDR in women means that, as they age, they are disproportionately affected by the drop in AMP expression associated with VDR dysfunction. So they accumulate heavier bacterial loads exhibit greater morbidity than their male counterparts.
This model may also explain why women with autoimmune disease often find their symptoms escalate after pregnancy. Since 1,25-D production rises by 40% in the pregnant decidua, its ability to dysregulate the nuclear receptors and the AMPs they express is particularly prevalent during this time. So at least during the early periods of gestation, bacterial load can likely increase with exceptional ease.
I should also add that Marshall has shown that 25-D, which is derived from supplemental vitamin D is able to displace exogenous ligands from the nuclear receptors just as easily as 1,25-D - marking yet another way in which it is able to suppress the innate immune response.
So it may indeed be possible that VDR dysregulation plays a significant role in the higher incidence of autoimmune disease observed among women, and that vitamin D supplementation could further account for the skew in incidence. More research is needed.
Finally, I would like to add one more thing. When it comes to correlating disease incidence with low levels of vitamin D, it's also incredibly important to consider the alternate hypothesis, which is that the low levels of vitamin D may not be causing the disease but may simply be a result of the disease process. So, a low level of vitamin D correlated with an illness may simply be an indicator that the disease process has taken an effect in that patient.
Thank you, and I appreciate your time.