Paper - Dysregulation of the Vitamin D Nuclear Receptor may contribute to the higher prevalence of some autoimmune diseases in women

Type: Paper
Authors: Amy D. Proal, Paul J. Albert, Trevor Marshall PhD
Publication: Annals of the New York Academy of Sciences
Citation: long:19758159
See also: Pre-print

Researchers have noted that the incidence of autoimmune diseases such as Hashimoto’s thyroiditis is markedly higher in women than in men, but to date the reason for this disparity has been unclear. The Vitamin D Nuclear ReceptorA nuclear receptor located throughout the body that plays a key role in the innate immune response. (VDRThe Vitamin D Receptor. A nuclear receptor located throughout the body that plays a key role in the innate immune response.) is expressed in the human cycling endometrium. Because the VDR controls expression of the Cathelicidin Family of antimicrobial peptides found primarily in immune cells and transcribed by the Vitamin D Receptor. and beta Defensin antimicrobial peptidesBody’s naturally produced broad-spectrum antibacterials which target pathogens. (AmPs), dysregulation of the receptor greatly compromises the innate immune responseThe body's first line of defense against intracellular and other pathogens. According to the Marshall Pathogenesis the innate immune system becomes disabled as patients develop chronic disease.. Increasing evidence indicates the presence of a chronic, intraphagocytic metagenomic microbiotaThe community of bacterial pathogens including those in an intracellular and biofilm state which cause chronic disease. in patients with autoimmune disease that may survive by dysregulating the VDR. VDR dysregulation in turn prevents the breakdown of the active vitamin D metabolite 1,25-hydroxyvitamin D (1,25-DPrimary biologically active vitamin D hormone. Activates the vitamin D nuclear receptor. Produced by hydroxylation of 25-D. Also known as 1,25-dihydroxycholecalciferol, 1,25-hydroxyvitamin D and calcitirol.) by CYP24. In silicoExperiment technique performed on computer or via computer emulation. data suggest that when 1,25-D rises above its normal range it binds the alpha/beta thyroid receptors, the glucocorticoid receptor (GCR) and the androgen receptor (AR), displacing their native ligands and causing an array of hormonal imbalances. If T3 is displaced from alpha thyroid, thyroiditis may result. Since the VDR, GCR, and AR also express multiple families of AmPs, expression of these natural antibiotics further wanes in response to dysregulation by 1,25-D. The end result is a system-wide drop in AmP expression that may allow pathogens to spread with greater ease. Because women have an extra site of VDR expression in the endometrium, the drop in AmP expression associated with nuclear receptorIntracellular receptor proteins that bind to hydrophobic signal molecules (such as steroid and thyroid hormones) or intracellular metabolites and are thus activated to bind to specific DNA sequences which affects transcription. dysregulation may disproportionately affect them. This would cause women to accumulate higher bacterial loads than their male counterparts, particularly during early pregnancy when 1,25-D levels rise by 40%.