title: Regulation of mucosal immunity in the female reproductive tract: the role of sex hormones in immune protection against sexually transmitted pathogens.
abstract: The immune system in the female reproductive tract (FRT) does not mount an attack against human immunodeficiency virus (HIV) or other sexually transmitted infections (STI) with a single endogenously produced microbicide or with a single arm of the immune system. Instead, the body deploys dozens of innate antimicrobials to the secretions of the FRT. Working together, these antimicrobials along with mucosal antibodies attack viral, bacterial, and fungal targets. Within the FRT, the unique challenges of protection against sexually transmitted pathogens coupled with the need to sustain the development of an allogeneic fetus, has evolved in such a way that sex hormones precisely regulate immune function to accomplish both tasks. The studies presented in this review demonstrate that estradiol (E2 ) and progesterone secreted during the menstrual cycle act both directly and indirectly on epithelial cells, fibroblasts and immune cells in the reproductive tract to modify immune function in a way that is unique to specific sites throughout the FRT. As presented in this review, studies from our laboratory and others demonstrate that the innate and adaptive immune systems are under hormonal control, that protection varies with the stage of the menstrual cycle and as such, is dampened during the secretory stage of the cycle to optimize conditions for fertilization and pregnancy. In doing so, a window of STI vulnerability is created during which potential pathogens including HIV enter the reproductive tract to infect host targets.
authors.affiliation: Department of Physiology and Neurobiology, Geisel School of Medicine at Dartmouth, One Medical Center Drive, Lebanon, NH, USA.
authors.forename: Charles R
authors.initials: CR
authors.lastname: Wira
authors.forename: John V
authors.initials: JV
authors.lastname: Fahey
authors.forename: Marta
authors.initials: M
authors.lastname: Rodriguez-Garcia
authors.forename: Zheng
authors.initials: Z
authors.lastname: Shen
authors.forename: Mickey V
authors.initials: MV
authors.lastname: Patel
mesh_terms: D004847:Epithelial Cells / Q000276:immunology / Q000821:virology; D004958:Estradiol / Q000276:immunology*; D005260:Female; D005836:Genitalia, Female / Q000276:immunology* / Q000821:virology; D015658:HIV Infections / Q000276:immunology* / Q000517:prevention & control / Q000821:virology; D006801:Humans; D007108:Immune Tolerance; D018928:Immunity, Mucosal; D008214:Lymphocytes / Q000276:immunology / Q000821:virology; D008264:Macrophages / Q000276:immunology / Q000821:virology; D008597:Menstrual Cycle / Q000276:immunology; D009092:Mucous Membrane / Q000276:immunology* / Q000473:pathology / Q000821:virology; D011247:Pregnancy; D011374:Progesterone / Q000276:immunology*
chemical_list: D011374:Progesterone; D004958:Estradiol
keywords: Epithelial cells; female reproductive tract; fibroblasts; immune cells; mucosal immunity; sex hormones
references.citation: FEMS Immunol Med Microbiol. 2003 Aug 18;38(1):59-64
references.pmid: 12900056
references.citation: J Immunol. 2006 Jun 1;176(11):6647-55
references.pmid: 16709823
references.citation: Immunol Rev. 2005 Aug;206:306-35
references.pmid: 16048557
references.citation: Am J Reprod Immunol. 2007 Aug;58(2):111-9
references.pmid: 17631004
references.citation: J Natl Cancer Inst. 2003 Aug 6;95(15):1128-37
references.pmid: 12902442
references.citation: PLoS One. 2010 Dec 14;5(12):e14306
references.pmid: 21179465
references.citation: Immunology. 2003 May;109(1):137-46
references.pmid: 12709027
references.citation: J Steroid Biochem. 1984 Jan;20(1):509-13
references.pmid: 6708533
references.citation: PLoS One. 2012;7(6):e38100
references.pmid: 22675510
references.citation: Am J Reprod Immunol. 2010 Jun;63(6):544-65
references.pmid: 20367623
references.citation: Nat Rev Mol Cell Biol. 2001 Apr;2(4):285-93
references.pmid: 11283726
references.citation: Am J Reprod Immunol. 2013 May;69(5):463-74
references.pmid: 23398087
references.citation: Histol Histopathol. 2001 Apr;16(2):541-51
references.pmid: 11332710
references.citation: J Immunol. 2006 May 15;176(10):6219-24
references.pmid: 16670332
references.citation: Cell. 2000 Mar 3;100(5):575-85
references.pmid: 10721994
references.citation: FASEB J. 2005 Aug;19(10):1368-70
references.pmid: 15928195
references.citation: Gastroenterology. 1999 Oct;117(4):953-61
references.pmid: 10500079
references.citation: J Immunol. 2005 Oct 1;175(7):4265-73
references.pmid: 16177066
references.citation: Gynecol Obstet Invest. 2003;55(2):110-3
references.pmid: 12771458
references.citation: Science. 1995 Dec 15;270(5243):1811-5
references.pmid: 8525373
references.citation: Mucosal Immunol. 2011 May;4(3):335-42
references.pmid: 21048705
references.citation: Cell Immunol. 2004 Jul;230(1):23-32
references.pmid: 15541716
references.citation: FEMS Immunol Med Microbiol. 2003 Aug 18;38(1):13-22
references.pmid: 12900050
references.citation: Mol Hum Reprod. 2000 Feb;6(2):191-6
references.pmid: 10655462
references.citation: Oral Dis. 1997 May;3 Suppl 1:S64-9
references.pmid: 9456660
references.citation: Hum Immunol. 2005 May;66(5):469-82
references.pmid: 15935884
references.citation: J Infect Dis. 2002 Jun 1;185(11):1606-13
references.pmid: 12023766
references.citation: Trends Immunol. 2007 Nov;28(11):503-10
references.pmid: 17950666
references.citation: Arch Gynecol Obstet. 2006 Jan;273(4):195-202
references.pmid: 16208476
references.citation: J Virol. 2002 Feb;76(4):1866-75
references.pmid: 11799181
references.citation: Biol Reprod. 2005 Apr;72(4):814-21
references.pmid: 15576826
references.citation: Immunology. 2004 Dec;113(4):524-33
references.pmid: 15554931
references.citation: Am J Reprod Immunol. 2005 Oct;54(4):193-202
references.pmid: 16135010
references.citation: J Invest Dermatol. 2003 Jun;120(6):1058-66
references.pmid: 12787135
references.citation: Biol Reprod. 1997 Oct;57(4):936-42
references.pmid: 9314600
references.citation: J Invest Dermatol. 2003 Mar;120(3):420-7
references.pmid: 12603855
references.citation: J Proteome Res. 2009 Oct;8(10):4622-32
references.pmid: 19670903
references.citation: Biol Reprod. 1994 Mar;50(3):461-6
references.pmid: 8167216
references.citation: Integr Comp Biol. 2006 Dec;46(6):1082-7
references.pmid: 21672809
references.citation: Am J Reprod Immunol. 2006 Oct;56(4):218-29
references.pmid: 16938110
references.citation: J Immunol. 1997 Mar 15;158(6):3017-27
references.pmid: 9058841
references.citation: Immunology. 2005 May;115(1):99-107
references.pmid: 15819702
references.citation: J Cell Biochem. 2003 Feb 1;88(2):408-17
references.pmid: 12520544
references.citation: Hum Reprod. 2009 Jun;24(6):1427-35
references.pmid: 19228761
references.citation: J Clin Endocrinol Metab. 2004 Dec;89(12):6155-67
references.pmid: 15579772
references.citation: AIDS. 2007 Feb 19;21(4):467-76
references.pmid: 17301565
references.citation: Hum Immunol. 1989 Mar;24(3):195-205
references.pmid: 2925453
references.citation: J Clin Invest. 1998 Apr 15;101(8):1633-42
references.pmid: 9541493
references.citation: Hum Reprod. 2005 Jun;20(6):1439-46
references.pmid: 15734755
references.citation: J Immunol. 2005 Nov 15;175(10):6509-16
references.pmid: 16272305
references.citation: Annu Rev Cell Dev Biol. 2006;22:207-35
references.pmid: 16771626
references.citation: Am J Obstet Gynecol. 1985 Apr 15;151(8):1115-25
references.pmid: 3920915
references.citation: J Exp Med. 2003 Mar 3;197(5):669-74
references.pmid: 12615907
references.citation: Proc Natl Acad Sci U S A. 1997 Jun 10;94(12):6535-40
references.pmid: 9177253
references.citation: Curr Womens Health Rev. 2008 May;4(2):102-117
references.pmid: 19644567
references.citation: PLoS Pathog. 2010 Apr 08;6(4):e1000852
references.pmid: 20386714
references.citation: J Reprod Immunol. 2005 Oct;67(1-2):1-12
references.pmid: 16213914
references.citation: J Reprod Immunol. 1998 Dec;41(1-2):331-9
references.pmid: 10213321
references.citation: Mol Cell Biochem. 2002 May-Jun;234-235(1-2):225-8
references.pmid: 12162438
references.citation: Immunology. 2010 Feb;129(2):207-19
references.pmid: 19824918
references.citation: Am J Reprod Immunol. 2004 Oct;52(4):252-62
references.pmid: 15494046
references.citation: Cell. 2000 Mar 3;100(5):587-97
references.pmid: 10721995
references.citation: Reprod Biol Endocrinol. 2005 Dec 29;3:74
references.pmid: 16384532
references.citation: Infect Immun. 2002 Feb;70(2):577-83
references.pmid: 11796585
references.citation: Mucosal Immunol. 2008 Jul;1(4):317-25
references.pmid: 19079193
references.citation: Am J Obstet Gynecol. 1999 Oct;181(4):915-20
references.pmid: 10521753
references.citation: Infect Immun. 2004 Jun;72(6):3684-7
references.pmid: 15155685
references.citation: Adv Immunol. 1989;47:187-376
references.pmid: 2683611
references.citation: Cell. 1990 Jul 27;62(2):207-10
references.pmid: 2196994
references.citation: J Immunol. 2005 Jan 15;174(2):992-1002
references.pmid: 15634923
references.citation: Mol Hum Reprod. 1999 Jul;5(7):656-61
references.pmid: 10381821
references.citation: Fertil Steril. 2010 Oct;94(5):1764-8
references.pmid: 20004388
references.citation: Nat Immunol. 2002 Oct;3(10):975-83
references.pmid: 12352970
references.citation: J Exp Med. 2005 Dec 19;202(12):1659-68
references.pmid: 16352738
references.citation: AIDS. 2003 Nov 7;17(16):F39-48
references.pmid: 14571200
references.citation: Trends Cell Biol. 1998 Oct;8(10):404-10
references.pmid: 9789329
references.citation: Hum Reprod. 2006 Jun;21(6):1618-22
references.pmid: 16478763
references.citation: AIDS Res Hum Retroviruses. 1998 Apr;14 Suppl 1:S51-5
references.pmid: 9581884
references.citation: Endocrinology. 2007 Jan;148(1):218-31
references.pmid: 17038551
references.citation: Clin Immunol. 2007 Jul;124(1):69-76
references.pmid: 17524808
references.citation: Mol Hum Reprod. 2003 Apr;9(4):189-98
references.pmid: 12651900
references.citation: Am J Reprod Immunol. 2011 Mar;65(3):196-211
references.pmid: 21294805
references.citation: Am J Physiol Lung Cell Mol Physiol. 2007 Jul;293(1):L69-76
references.pmid: 17384084
references.citation: Prog Clin Biol Res. 1981;70:381-94
references.pmid: 7031698
references.citation: Am J Pathol. 1999 Jan;154(1):239-47
references.pmid: 9916938
references.citation: Cancer Res. 2005 Nov 1;65(21):9914-22
references.pmid: 16267016
references.citation: J Invest Dermatol. 2003 Mar;120(3):411-9
references.pmid: 12603854
references.citation: Int Immunopharmacol. 2006 Jun;6(6):1020-8
references.pmid: 16644489
references.citation: J Leukoc Biol. 2004 Sep;76(3):667-75
references.pmid: 15178706
references.citation: Curr Gene Ther. 2004 Jun;4(2):199-206
references.pmid: 15180586
references.citation: Curr HIV Res. 2012 Apr;10(3):218-27
references.pmid: 22384841
references.citation: Am J Reprod Immunol. 1997 Nov;38(5):350-9
references.pmid: 9352027
references.citation: J Reprod Immunol. 2003 Jun;59(1):1-16
references.pmid: 12892899
references.citation: Immunology. 2001 Apr;102(4):434-40
references.pmid: 11328377
references.citation: Immunology. 1987 Jun;61(2):207-13
references.pmid: 3298023
references.citation: Biol Reprod. 2002 Apr;66(4):1016-23
references.pmid: 11906921
references.citation: J Infect Dis. 1997 Sep;176(3):740-7
references.pmid: 9291323
references.citation: Am J Reprod Immunol. 2008 Mar;59(3):212-24
references.pmid: 18201283
references.citation: Curr Opin Cell Biol. 2005 Oct;17(5):453-8
references.pmid: 16098725
references.citation: J Immunol. 2004 Dec 1;173(11):6760-6
references.pmid: 15557169
references.citation: Baillieres Clin Obstet Gynaecol. 1993 Dec;7(4):701-13
references.pmid: 8131311
references.citation: Menopause. 2007 Nov-Dec;14(6):1012-9
references.pmid: 17572644
references.citation: Lab Invest. 2000 May;80(5):617-53
references.pmid: 10830774
references.citation: AIDS. 2000 Sep 29;14(14):2101-7
references.pmid: 11061650
references.citation: Nat Rev Immunol. 2002 Feb;2(2):77-84
references.pmid: 11910898
references.citation: Am J Reprod Immunol. 2009 Jul;62(1):60-71
references.pmid: 19527233
references.citation: PLoS One. 2010 Jun 29;5(6):e11366
references.pmid: 20614007
references.citation: PLoS One. 2013 Apr 17;8(4):e62069
references.pmid: 23614015
references.citation: Lab Invest. 1992 Nov;67(5):628-34
references.pmid: 1434540
references.citation: Biol Reprod. 2003 Sep;69(3):1091-8
references.pmid: 12773432
references.citation: Nat Rev Immunol. 2006 Nov;6(11):859-68
references.pmid: 17063186
references.citation: J Clin Pathol. 1985 Jun;38(6):644-52
references.pmid: 3891790
references.citation: Biol Reprod. 2006 Sep;75(3):387-94
references.pmid: 16707768
references.citation: Fertil Steril. 2009 Sep;92(3):1107-1109
references.pmid: 19423096
references.citation: Nature. 1996 Aug 29;382(6594):829-33
references.pmid: 8752280
references.citation: J Cell Physiol. 1999 Oct;181(1):55-66
references.pmid: 10457353
references.citation: Microbes Infect. 2003 Jan;5(1):59-67
references.pmid: 12593974
references.citation: Clin Diagn Lab Immunol. 2000 May;7(3):515-8
references.pmid: 10799472
references.citation: AIDS. 2008 Oct 1;22(15):1909-17
references.pmid: 18784454
references.citation: PLoS One. 2012;7(12):e52738
references.pmid: 23300756
references.citation: Infect Immun. 2005 Aug;73(8):4823-33
references.pmid: 16040996
references.citation: Immunology. 2004 Jan;111(1):13-5
references.pmid: 14678193
references.citation: J Virol. 2012 Mar;86(5):2715-28
references.pmid: 22190722
references.citation: Nat Rev Immunol. 2003 Sep;3(9):697-709
references.pmid: 12949494
references.citation: Wound Repair Regen. 2006 Jan-Feb;14(1):2-10
references.pmid: 16476066
references.citation: Nat Rev Immunol. 2003 Sep;3(9):710-20
references.pmid: 12949495
references.citation: J Soc Gynecol Investig. 1998 May-Jun;5(3):114-21
references.pmid: 9614639
references.citation: EMBO J. 2006 Aug 9;25(15):3534-45
references.pmid: 16858414
references.citation: Eur J Immunol. 2001 Jul;31(7):1981-8
references.pmid: 11449350
references.citation: Am J Reprod Immunol. 2005 Feb;53(2):65-76
references.pmid: 15790340
references.citation: Am J Reprod Immunol. 2006 Nov-Dec;56(5-6):321-8
references.pmid: 17076676
references.citation: Microsc Res Tech. 1997 Sep 1;38(5):488-99
references.pmid: 9376652
references.citation: J Acquir Immune Defic Syndr. 2008 Apr 15;47(5):529-34
references.pmid: 18209681
references.citation: Am J Pathol. 1998 May;152(5):1247-58
references.pmid: 9588893
references.citation: Immunology. 2004 Jul;112(3):428-36
references.pmid: 15196211