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Estradiol regulation of innate immune protection in the human female reproductive tract / by Mickey Vinay Patel.

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Author	Patel, Mickey Vinay.
Title	Estradiol regulation of innate immune protection in the human female reproductive tract / by Mickey Vinay Patel.
Date	2013
Abstract	Estradiol is a key regulator of immune protection in the female reproductive tract (FRT). Its concentration varies during the menstrual cycle, leading to changes in innate immune protection. In this thesis, I demonstrate the multiple levels at which estradiol modulates innate immunity in uterine and vaginal epithelial cells and stromal fibroblasts, and how these may alter the likelihood of HIV transmission. Human vaginal epithelial cells (VEC) and vaginal secretions were recovered using a menstrual cup. VEC were shown to constitutively secrete the anti-HIV proteins human beta-defensin 2 (HBD2) and elafin. Estradiol, but not progesterone, inhibited secretion of both proteins. Conditioned media from VEC treated with estradiol contained no anti-HIV activity, but cells treated with a combination of estradiol and progesterone reduced infectivity of an R5 HIV strain, but not an X4 strain. In vaginal secretions there was no change in the concentration of anti-HIV proteins and antiviral activity across the menstrual cycle suggesting that secreted immune protection remains relatively constant in the lower FRT. The role of Type I and Type III interferons (IFN) in protecting the upper FRT is relatively unknown. Uterine epithelial cells (UEC) are exquisitely sensitive to the viral mimic poly (I:C) and upregulated IFN[beta], IL-29 and a panel of interferon-stiimulated genes (ISG), independently of estradiol. A similar response to poly (I:C) was seen with uterine stromal fibroblasts (USC), but estradiol abrogated the increase in ISG expression. While both UEC and USC induced ISG in response to Type I IFN (IFN[beta]), only UEC responded strongly to Type III IFN (IL-29), suggesting that IL-29 primarily acts upon the epithelium in the upper FRT. IL-29 increases secreted anti-HIV activity by UEC and USC, suggesting that it plays an important role in FRT antiviral defense. The results presented in this thesis demonstrate that the effect of estradiol on immune protection in the FRT is pleiotropic, cell-specific and unique to disti
Description	xvi, 286 leaves : ill. (some col.) 28 cm.
Format	application/pdf
Advisor	Charles R. Wira, Paul M. Guyre, Jack E. Bodwell, Surendra Sharma
College	Dartmouth Medical School. Department of Physiology.
Issuing Body	Dartmouth Dissertations are made available through the Dartmouth Digital Library.
Degree	Thesis (Ph.D.)--Dartmouth College.
Copyright	All rights reserved. No part of this book may be reproduced in any form by any electronic or mechanical means without permission in writing from the author.
DOI	http://dx.doi.org/10.1349/ddlp.998

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