The Immune System in

Reproductive Tract Throughout

Menstrual Cycle
Budi Wiweko

Reproductive Immunoendocrinology
Division
Department of Obstetrics and Gynecology
Faculty of Medicine University of
Indonesia
Dr. Cipto Mangunkusumo General
Hospital

Outline of this talk

1. Introduction
2. Immune system in female
reproductive tract
3. Menstrual cycle and female
immune system
4. Take home messages

Introduction
Immune
system in
female
reproductive
tract
Menstrual
cycle and
female
immune
system
Take home
messages

Basic concept of mucosal immunity

Kiyono et al. Adv Drug Deliver Rev, 1995

Introduction
Immune
system in
female
reproductive
tract
Menstrual
cycle and
female
immune
system
Take home
messages

The mucous membranes are one of the

largest organs of the body
They cover a surface area of more than
400m2 (equivalent to one and a half tennis
courts)
Comprise the linings of the gastrointestinal,
urogenital and respiratory tracts
Brandtzaeg. J Reprod Immunol, 1997

Introduction
Immune
system in
female
reproductive
tract
Menstrual
cycle and
female
immune
system

The mucous membranes produce a special type of

antibody called secretory IgA or sIgA
This antibody is secreted as a dimer, joined at the nonantigen binding end by a protein known as the J chain

Take home
messages
Brandtzaeg. J Reprod Immunol, 1997

Introduction
Immune
system in
female
reproductive
tract
Menstrual
cycle and
female
immune
system
Take home
messages

The mucosal surfaces of the body are particularly

vulnerable to infection
They are thin and permeable barriers to the
interior
of the body because of their physiological
activities
gas exchange (the lungs)
food absorption (the gut)
sensory activities (eyes, nose, mouth, and throat)
reproduction (uterus and vagina)

Introduction
Immune
system in
female
reproductive
tract
Menstrual
cycle and
female
immune
system
Take home
messages

Bacteri
a
Viruses

Sperm

Fetus

l
a
e
d
big

Immune system of female reproductive tract is

the first line of defense against sexually
transmitted
diseases (STDs)
Aflatoonian. J Reprod Immunol, 2008

Introduction
Immune
system in
female
reproductive
tract
Menstrual
cycle and
female
immune
system
Take home
messages

The female reproductive tract is a unique

immunological site that is required to protect the
mucosa from a variety of pathogens without
compromising the development of an allogenically
distinct fetus
There are more than 30 different types of
parasites, bacteria and viruses that infect the female
reproductive tract

Hickey et al. J Reprod Immunol, 2011

Introduction
Immune
system in
female
reproductive
tract
Menstrual
cycle and
female
immune
system
Take home
messages

Components of the humoral and cellular immune

system are present throughout the female genital
tract which is both an inductive and an effector site
for immune response

Zhongmin. Clin Immunol, 2001

Introduction
Immune
system in
female
reproductive
tract

The mucosal immune system in genital tract

consist of
resident population of monocytes and T cells in the
submucosa of the vagina and cervix
They are influenced by immunoglobulins (Igs),
cytokines and reproductive hormones

Menstrual
cycle and
female
immune
system
Take home
messages

Franklin. J Reprod Immunol, 1999

Introduction
Immune
system in
female
reproductive
tract
Menstrual
cycle and
female
immune
system

The upper female reproductive tract, consisting of the

Fallopian tubes, uterine endometrium and endocervix is
lined by a single layer of columnar epithelial cells linked by
tight junctions

Take home
messages

Overlying the cells is a protective mucus layer. Secretion is

generally preferential towards the apical/luminal
compartment with a gradient across the epithelial layer
from lumen to tissue. Underlying the epithelial cells are
Hickey immune
et al. J Reprod
Immunol, 2011
innate and adaptive
cells

Introduction
Immune
system in
female
reproductive
tract
Menstrual
cycle and
female
immune
system

The lower female reproductive tract, consisting of the

ectocervix and vagina is covered by a layer of stratified
squamous epithelial cells

Take home
messages

Similar to the upper female reproductive tract, epithelial

cells are protected by a mucus layer. The lower female
reproductive tract has a resident commensal bacterial
population that produces lactic acid thus lowering vaginal
pH. Below theHickey
epithelial
innate
and adaptive
et al. Jlayer
Reprodare
Immunol,
2011
immune cells

Introduction
Immune
system in
female
reproductive
tract
Menstrual
cycle and
female
immune
system

The mucosa of vagina and ectocervix

consist of keratinized, stratified squamous
epithelium and underlying vascular
submucosa

Take home
messages

Endocervix consist of a simple columnar

epithelium covering a vascular submucosa
Kiyono et al. Adv Drug Deliver Rev, 1995

The innate immune response

of upper female reproductive
tract epithelial cells to an
invading pathogen. Epithelial
cells express a panel of Toll-like
receptors (TLRs) and RIG-like
receptors (RLRs) that allow
them to recognize and respond
to bacteria or viruses

Introduction
Immune
system in
female
reproductive
tract

The Type I interferon (IFN)

response (green arrows, middle
section of panel C) is a potent
defense system in female
reproductive tract cells.

Menstrual
cycle and
female
immune
system
Take home
messages
Hickey et al.

Additionally, in response to
pathogens and sex hormones,
antimicrobials and
cytokines/chemokines are
secreted to confer broad
J Reprod
Immunol,
2011
spectrum
protection

Introduction
Immune
system in
female
reproductive
tract
Menstrual
cycle and
female
immune
system

Innate immune system competence is of

critical importance in preventing microbial
penetration
In this context, it is important to consider the
differences in the microenvironments of the
sterile upper and non-sterile

SLPI:
Secretory leucocyte protease inhibito

Take home
messages
Horne et al. Reproduction, 2008

THE FUNCTION AND DISTRIBUTION OF CELLS IN THE UPPER

FEMALE REPRODUCTIVE TRACT (FALLOPIAN TUBES, UTERINE
AND ENDOCERVICAL MUCOSA) AND THE LOWER FEMALE
REPRODUCTIVE TRACT (ECTOCERVICAL AND VAGINAL
MUCOSA)

Hickey et al. J Reprod Immunol, 2011

Introduction
Immune
system in
female
reproductive
tract
Menstrual
cycle and
female
immune
system

Reproductive hormones have been shown to play

key
roles in the regulation of mucosal immunity of the
female genital tract
Estrogen increasing selective transport of IgA
into the cervical mucus

Take home
messages
Franklin. J Reprod Immunol, 1999

Introduction
Immune
system in
female
reproductive
tract
Menstrual
cycle and
female
immune
system
Take home
messages

Adult women are more

susceptible to STIs
during menses and
the follicular phase,
and less likely to be
infected during the
luteal phase

The concentration of genital tract

immunoglobulins in adult women are vary
through the menstrual cycle and related
to ovarian hormone concentrations
Shrier et al. J Adolescent Health Brief, 2003

Journal of Adolescent Health, 2003

Introduction
Immune
system in
female
reproductive
tract
Menstrual
cycle and
female
immune
system
Take home
messages

Mucosal Immunity of The

Adolescent
Female Genital Tract
Lydia A Shrier, Frederick Bowman

This study sought to characterize mucosal

immunity of the adolescent genital tracts
during the cycle and determine if
adolescent have more suppressed
immunoglobulin level in the follicular phase
than adults
Adolescent had a greater drop in IgG in the
follicular phase and may be more sensitive
to estradiol than adults

Introduction
Immune
system in
female
reproductive
tract
Menstrual
cycle and
female
immune
system
Take home
messages

Sexually transmitted infections (STIs)

disproportionately affect female adolescents

Introduction
Immune
system in
female
reproductive
tract
Menstrual
cycle and
female
immune
system
Take home
messages

B cell numbers and activity might increase in the periovulatory period.

Monocyte numbers increase during the luteal phase,
while their IL-1 and TNF production develop in opposing
fashion
Results on NK cell number and activity have been
conflicting, with
reports
of increase/decrease
Prigione.
Autoimmune
reviews, 2012 in both

Introduction
Immune
system in
female
reproductive
tract
Menstrual
cycle and
female
immune
system
Take home
messages

In the case of autoimmune conditions, SLE and MS

appear to worsen premenstrually, while RA worsens
during menstruation
Prigione. Autoimmune reviews, 2012

Journal of Reproductive Immunology, 1999

Introduction
Immune
system in
female
reproductive
tract
Menstrual
cycle and
female
immune
system
Take home
messages

Characterization of
immunoglobulins and cytokines
in human cervical mucus:
influence of exogenous and
endogenous hormone
RD Franklin, WH Kutteh

This study sought to determine the effect of

exogenous hormones on reproductive tract
immunity in women on OCP and to
compare the results with respects to
naturally cycling women

Introduction
Immune
system in
female
reproductive
tract
Menstrual
cycle and
female
immune
system

The peak concentration of IgA and IgG occurred

approximately one day before the estradiol peak
just
before ovulation

Take home
messages
Franklin. J Reprod Immunol, 1999

Introduction
Immune
system in
female
reproductive
tract
Menstrual
cycle and
female
immune
system
Take home
messages

Introduction
Immune
system in
female
reproductive
tract
Menstrual
cycle and
female
immune
system
Take home
messages

Introduction
Immune
system in
female
reproductive
tract
Menstrual
cycle and
female
immune
system
Take home
messages

Distribution of T cells at different sites of the lower

reproductive tract during various stages of menstrual
cycle

Normal fluctuations in the thickness of the

cervicovaginal epithelium during the menstrual
cycle ARE NOT accompanied by alterations in the
distribution, type, or absolute numbers of immune
cells in the genital tract
Ma et al. Clin Immunol, 2001

Introduction
Immune
system in
female
reproductive
tract
Menstrual
cycle and
female
immune
system
Take home
messages

1. Immune response in the female reproductive

tract must deal with potential bacterial and
viral pathogens, allogeneic spermatozoa and
immunologically distinct fetus
2. Immunoglobulins in the cervical mucus
reached peak levels before ovulation
3. Changes in the concentration of
immunoglobulin in cervicovaginal secretions
are not due to changes of the immune cells
population in the genital tract at different
time of cycles

THANK YOU

THANK YOU