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The Immune System inReproductive Tract Throughout

Menstrual Cycle

Budi Wiweko

Reproductive ImmunoendocrinologyDivisionDepartment of Obstetrics and Gynecology

Faculty of Medicine niversity ofIndonesia

Dr! "ipto Mangunkusumo General

#ospital


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Outline of this talk

%! Introduction

&! Immune system in female

reproductive tract

'! Menstrual cycle and femaleimmune system

(! )ake *ome messages


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Introduction

Immunesystem infemalereproductive

tract

Menstrualcycle andfemale

immunesystem

)ake *omemessages

Basic concept of mucosal immunity

+iyono et al! ,dv Drug Deliver Rev- %../


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)*e mucous membranes are one of t*elargest organs of t*e body

)*ey cover a surface area of more t*an

(00m&1e2uivalent to one and a *alf tenniscourts3

"omprise t*e linings of t*e gastrointestinal-

urogenital and respiratory tracts

Introduction


tract


immunesystem

)ake *omemessages

Brandt4aeg! $ Reprod Immunol- %..5


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)*e mucous membranes produce a special type of

antibody called secretory Ig, or sIg,

)*is antibody is secreted as a dimer- 6oined at t*e non7

antigen binding end by a protein known as t*e $ c*ain

Introduction


tract


immunesystem

)ake *omemessages

Brandt4aeg! $ Reprod Immunol- %..5


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)*e mucosal surfaces of t*e body are particularly

vulnerable to infection

)*ey are t*in and permeable barriers to t*einterior

of t*e body because of t*eir p*ysiological

activities gas e8c*ange 1t*e lungs3

food absorption 1t*e gut3

sensory activities 1eyes- nose- mout*- and t*roat3

reproduction 1uterus and vagina3

Introduction


tract


immunesystem

)ake *omemessages


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Immune system of female reproductive tract ist*e 9rst line of defense against se8uallytransmitted

diseases 1:)Ds3

Introduction


tract


immunesystem

)ake *omemessages

Bacteria

;iruses

:perm Fetus

,


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Introduction


tract


immunesystem

)ake *omemessages

)*e female reproductive tract is a uni2ue

immunological site t*at is re2uired to protect t*e

mucosa from a variety of pat*ogens wit*out

compromising t*e development of an allogenically

distinct fetus

#ickey et al! $ Reprod Immunol- &0%%

There are more than 30 diferent types oparasites, bacteria and viruses that inect the emalereproductive tract


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Introduction


tract


immunesystem

)ake *omemessages

"omponents of t*e *umoral and cellular immune

system are present t*roug*out t*e female genital

tract w*ic* is bot* an inductive and an e>ector site

for immune response

?*ongmin! "lin Immunol- &00%


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)*e mucosal immune system in genital tractconsist of

resident population of monocytes and ) cells in t*esubmucosa of t*e vagina and cervi8

)*ey are in


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Introduction


tract


immunesystem

)ake *omemessages

)*e upper female reproductive tract- consisting of t*eFallopian tubes- uterine endometrium and endocervi8 islined by a single layer of columnar epit*elial cells linked bytig*t 6unctions

Overlying t*e cells is a protective mucus layer! :ecretion isgenerally preferential towards t*e apical@luminalcompartment wit* a gradient across t*e epit*elial layer

from lumen to tissue! nderlying t*e epit*elial cells areinnate and adaptive immune cells#ickey et al! $ Reprod Immunol- &0%%


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Introduction


tract


immunesystem

)ake *omemessages

)*e lower female reproductive tract- consisting of t*eectocervi8 and vaginais covered by a layer of strati9ed

s2uamous epit*elial cells

:imilar to t*e upper female reproductive tract- epit*elialcells are protected by a mucus layer! )*e lower femalereproductive tract *as a resident commensal bacterialpopulation t*at produces lactic acid t*us lowering vaginal

p#! Below t*e epit*elial layer are innate and adaptiveimmune cells



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Introduction


tract


immunesystem

)ake *omemessages

)*e mucosa of vaginaand ectocervi8consist of keratini4ed- strati9ed s2uamousepit*elium and underlying vascularsubmucosa

Andocervi8consist of a simple columnarepit*elium covering a vascular submucosa

+iyono et al! ,dv Drug Deliver Rev- %../


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Introduction


tract


immunesystem

)ake *omemessages

)*e innate immune responseof upper female reproductivetract epit*elial cells to an

invading pat*ogen! Apit*elialcells e8press a panel of)oll7likereceptors 1)Rs3 and RIG7likereceptors 1RRs3 t*at allowt*em to recogni4e and respondto bacteria or viruses

)*e )ype I interferon 1IFC3response 1green arrows- middlesection of panel "3 is a potentdefense system in femalereproductive tract cells!

,dditionally- in response topat*ogens and se8 *ormones-antimicrobials andcytokines@c*emokines aresecreted to confer broadspectrum protection#ickey et al! $ Reprod Immunol- &0%%


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Introduction


tract


immunesystem

)ake *omemessages

Innate immune system competence is ofcritical importance in preventing microbial

penetration

In t*is conte8t- it is important to consider t*edi>erences in t*e microenvironments of t*e

sterileE upper and non7sterile

#orne et al! Reproduction- &00=

:I:ecretory leucocyte protease in*ibit


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TH !"#CTIO# $#% %ISTRIB"TIO# O! C&&S I# TH "''R!M$& R'RO%"CTI( TR$CT )!$&&O'I$# T"BS* "TRI#

$#% #%OCR(IC$& M"COS$+ $#% TH &O,R !M$&R'RO%"CTI( TR$CT )CTOCR(IC$& $#% ($-I#$&M"COS$+



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Introduction


tract


immunesystem

)ake *omemessages

Reproductive *ormones *ave been s*own to playkey

roles in t*e regulation of mucosal immunity of t*e

female genital tract

Astrogenincreasing selective transport of Ig,

into t*e cervical mucus

Franklin! $ Reprod Immunol- %...


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Introduction


tract


immunesystem

)ake *omemessages

,dult women are moresusceptible to :)Isduring menses andt*e follicular p*ase-

and less likely to beinfected during t*eluteal p*ase

)*e concentration of genital tractimmunoglobulins in adult women are varyt*roug* t*e menstrual cycleand relatedto ovarian *ormone concentrations

:*rier et al! $ ,dolescent #ealt* Brief- &00'


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Introduction


tract


immunesystem

)ake *omemessages

Mucosal Immunity of The

$dolescent!emale -enital Tract

ydia , :*rier- Frederick Bowman

$ournal of ,dolescent #ealt*- &00'

)*is study soug*t to c*aracteri4e mucosalimmunity of t*e adolescent genital tractsduring t*e cycle and determine ifadolescent *ave more suppressedimmunoglobulin level in t*e follicular p*aset*an adults

,dolescent *ad a greater drop in IgG in t*efollicular p*ase and may be more sensitive

to estradiol t*an adults


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Introduction


tract


immunesystem

)ake *omemessages

:e8ually transmitted infections 1:)Is3

disproportionately a>ect female adolescents


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Introduction


tract


immunesystem

)ake *omemessages

B cell numbers and activity mig*t increase in t*e peri7

ovulatory period!

Monocyte numbers increase during t*e luteal p*ase-

w*ile t*eir I7% and )CFH production develop in opposing

fas*ion

Results on C+ cell number and activity *ave been

con


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Introduction


tract


immunesystem

)ake *omemessages

In t*e case of autoimmune conditions- :A and M:appear to worsen premenstrually- w*ile R, worsensduring menstruation

rigione! ,utoimmune reviews- &0%&


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Introduction


tract


immunesystem

)ake *omemessages

Characteri.ation of

immunoglobulins and cytokinesin human cervical mucus/

in0uence of e1ogenous andendogenous hormone

RD Franklin- W# +utte*

$ournal of Reproductive Immunology- %...

)*is study soug*t to determine t*e e>ect ofe8ogenous *ormoneson reproductive tractimmunity in women on O" and tocompare t*e results wit* respects tonaturally cycling women


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Introduction


tract


immunesystem

)ake *omemessages

)*e peak concentration of Ig, and IgG occurred

appro8imately one day before t*e estradiol peak6ust

before ovulation

Franklin! $ Reprod Immunol- %...


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Introduction


tract


immunesystem

)ake *omemessages


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Introduction


tract


immunesystem

)ake *omemessages


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Introduction


tract


immunesystem

)ake *omemessages

Distribution of ) cells at di>erent sites of t*e lowerreproductive tract during various stages of menstrualcycle

Ma et al! "lin Immunol- &00%

Cormal


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Introduction


tract


immunesystem

)ake *omemessages

%! Immune response in t*e female reproductivetract must deal wit* potential bacterial andviral pat*ogens- allogeneic spermato4oa andimmunologically distinct fetus

&! Immunoglobulins in t*e cervical mucusreac*ed peak levels before ovulation

'! "*anges in t*e concentration ofimmunoglobulin in cervicovaginal secretions

are not due to c*anges of t*e immune cellspopulation in t*e genital tract at di>erenttime of cycles


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TH$#2 3O"


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