25 Unique Skin Immunology of theLower Female Genital Tract with Age

M. A. Farag# Springer

Paul R. Summers

Introduction

It has been long recognized that the genital tract must

be able to defend against significant microbial exposures.

In this area of medicine, old theories that may have even

acquired some attributes of folklore must be revised

to include new knowledge. Through the last century,

popular ideas regarding mechanisms of microbial

defenses in the genital tract have reflected the medical

thinking of each era. In the time of antisepsis of the

early twentieth century, lactic acid from the lactobacillus

was proposed as the chief regulatory vaginal antiseptic.

Subsequently, the possibility of antiseptic action from

hydrogen peroxide-producing lactobacilli was considered,

although little hydrogen peroxide would be expected to be

produced in the naturally anaerobic environment of the

vaginal lumen. With the influence of the more recent

antibiotic era, research interest has focused upon bacter-

iocins, unique but relatively weak lactobacillus-derived

antibiotics. Theories of microbial defense have evolved

further in the current, more enlightened era of immuno-

logy. Rapid advances in the area of immunology have now

disclosed complex immune defenses in the genital epithe-

lium that do have a significant antimicrobial impact,

moderated by estrogen.

From the immune standpoint, the lower genital tract

has the following competing roles: (1) to facilitate the

various aspects of reproduction and (2) to simultaneously

prevent the access of locally resident microbes to the upper

genital tract and to the peritoneal cavity. To facilitate a

primary function in reproduction, the immune responsive-

ness of the lower female genital tract is blunted. Ovulation,

fertilization, pregnancy, labor, and delivery of the infant are

all mediated by immune mechanisms that may not be

optimal for microbial defense. A blunted humoral immune

response may be compensated by an active innate or cell-

mediated response. For example, sperm may be highly

immunogenic. If sperm are detected by the humoral im-

mune system, the development of antisperm antibodies

can reduce fertility [1]. It is important for the vaginal

immune system to identify potential pathogens, but not

e, K. W. Miller, H. I. Maibach (eds.), Textbook of Aging Skin, DO

-Verlag Berlin Heidelberg 2010

to target sperm or the fetus, or to disrupt the immune

mechanisms of fertility.

Microbial and immune events in the female urethra

mirror the status of the vaginal vestibule [2]. The immune

function and microbial flora of the vaginal vestibule and

urethra change in a parallel fashion in response to the

effects of aging and hormone cycles. Hormone changes

alter the morphology and mucosal defenses. Menopausal

decline in innate immune defenses in the vaginal mucosa

allows colonization with potential uropathogens and

increases the risk for bladder infection.

Humoral Immunity

The humoral immune system associated with vaginal

mucosa is unique. Mucosal surfaces outside the genital

tract develop in conjunction with lymphoid tissue that

predominantly produces IgA. At other body sites, IgA

may have a significant role in mucosal defense against

microbes. With the absence of associated lymphoid tissue,

vaginal mucosa releases only limited quantities of any

category of immunoglobulin at all stages of life. IgG is

present in vaginal secretions. The relatively small amount

of IgG is serum-derived as well as locally produced in the

vaginal and cervical mucosa [3]. With the relative absence

of a local source of IgA, more IgG than IgA is detected in

vaginal secretions [4]. The converse is true for mucosal

surfaces elsewhere in the body.

Cervical secretions have a higher concentration of IgA

than vaginal secretions [5]. This finding is consistent with

the presumed protective role of cervical mucus to prevent

ascent of microbes into the endometrial cavity. The con-

centration of IgA in vaginal secretions declines by 90% after

hysterectomy so the upper genital tract may be assumed to

be the primary source of the small quantity of IgA that is

present in the vaginal lumen [6]. It is reasonable to assume

a similar decline in lower genital tract immunoglobulins

after the menopause, with the minimal production of

cervical mucus and vaginal secretions at that time in life.

Cervical secretion of IgG and IgA into the vaginal pool

I 10.1007/978-3-540-89656-2_25,

254 25 Unique Skin Immunology of the Lower Female Genital Tract with Age

varies during the menstrual cycle with the highest levels

prior to ovulation during the proliferative phase, but with

an 80% decline at the time of ovulation [7]. The limited

amount of immunoglobulin in vaginal secretions may

lower the risk for the development of antisperm antibo-

dies. It is reasonable to speculate that sperm survival may

be enhanced in some fashion by the further decline in

immunoglobulins around the time of ovulation.

Disruption of vaginal immunoglobulin homeostasis

can be harmful. Electrical loop excision of the cervical

transformation zone (LEEP) may allow an unregulated

humoral immune response at that site. Serum antisperm

antibodies have been identified in women who are sexu-

ally active while the cervical LEEP site is healing [8].

Innate Immunity

The innate immune system has major importance in

preventing invasion of potentially pathogenic microbes

normally found in the lower genital tract and on the

perirectal skin. During the reproductive years, an active

innate immune response compensates somewhat for the

blunted humoral and cell-mediated immune response in

the lower female genital tract (> Table 25.1). Sexually

transmitted diseases develop when sexually acquired

pathogens have the ability to evade these standing

defenses [9]. Human beta defensins (HBD) 1, 2, 3 and 5,

secretory leukocyte protease inhibitor (SLPI), elafin, and

mannose binding lectin (MBL) have been demonstrated

in vaginal secretions [9]. The highest concentration of

SLPI is in the cervical mucus plug, although it is expressed

in secretions throughout the female genital tract. SLPI

blocks the action of various destructive enzymes that

may be released by pathogens. Elafin is an important

protein that inhibits inflammation-related tissue damage

by blocking elastase, which may be released by activated

neutrophils. Elafin also has antimicrobial activity. Leuko-

cytes and vaginal epithelial cells are the main sources of

. Table 25.1

Important characteristics of the cervical transformation

zone during the reproductive years

High concentration of elements of cell-mediated immunity

to interact with viruses and to prevent ascent of bacteria

into the upper genital tract and peritoneum

Macrophages are involved in cervical ripening prior to labor

Macrophages and granulocytes are involved in cervical

dilation during labor

defensins [10]. Defensins are antibiotic substances that

are active against various bacteria and yeast. Surfactant

proteins in vaginal mucosal secretions (SP-A, SP-D) pro-

tect against viral infections, including HIV-1 and herpes

simplex virus (HSV) [11]. Human neutrophil peptides

(HNP 1–3) also suppress HSV in vaginal secretions [12].

These secretory products of the innate immune system are

considered to be estrogen dependent, since many are the

result of local mucosal metabolism, and the secretory fluid

that contains these substances requires estrogen stimu-

lation. Menopause results in a decline in the mucosal-

dependent elements of the innate immune system.

Minor congenital defects in the innate immune system,

such as polymorphisms which result in deficiency of man-

nose binding lectin (MBL), increase the risk of symptomatic

infection [13]. MBL provides a target for complement

activation by binding to the cell surface of pathogenic

microbes. MBL is produced mainly in the liver and most

likely arrives in the vaginal secretions as a transudate from

the blood stream. MBL is a significant factor in vaginal

mucosal defense against pathogens, although the MBL

level in vaginal secretions is much lower than the level

normally found in the systemic circulation. It is not clear

whether MBL is produced by vaginal mucosal cells.

During the reproductive years, toll-like receptors (TLRs)

1, 2, 3, 5, and 6 are expressed in vaginal mucosal cells. TLR

1, 2, and 5 mainly target bacteria. TLR 3 is directed against

virus, and TLR 6 controls fungi [9]. The expression of TLRs

is estrogen-dependent. This may explain the pre-pubertal

and possibly post menopausal increased mucosal suscep-

tibility to pathogens such as streptococcus or Neisseria

gonorrhea.

Cell-Mediated Immunity

Langerhans cells are abundant in vaginal and cervical mu-

cosa [14]. In the lower female genital tract, T cells and

Langerhans cells are most prevalent in the normal cervical

transformation zone, so the cervical transformation zone

is assumed to be the major site for cell-mediated immune

reactions in this area of the human body [15]. The likely

immune consequences of excision of this important area

by extensive LEEP or cervical cone biopsy have not been

determined (> Table 25.1). If the human skin is consid-

ered to be a major immune organ, then the cervix should

be considered to have special immune function in that

organ. Chronic cervicitis, often detected on cervical biop-

sy in asymptomatic women is actually a misnomer, as

the normal cervical transformation zone is a site of signif-

icant immune activity in normal health. Pathogenic

. Table 25.2

Characteristics of the lower female genital tract under the

influence of estrogen

Innate immunity TLR 1, 2, 3, 5, 6 HBD 1, 2, 3, 5 SLPI MBL

SP-A SP-D etc.

Humoral

immunity

Very low IgA very low IgG IgG > IgA

Cell-mediated

immunity

Depressed Th1 tendency for enhanced

Th2

TLR toll like receptor; HBD human beta defensin; SLPI secretory leuko-

cyte protease inhibitor; MBL mannose binding lectin; SP surfactant

proteins

. Table 25.3

Characteristics of the lower female genital tract in the

absence of estrogen

Innate immunity Decreased expression of TLRs decrease

in all secretory products

Humoral

immunity

Further decline in IgA with decreased

cervical secretions

Cell-mediated

immunity

Decline in langerhans cell count decline

in cytokine responsiveness estrogen-

associated suppression of Th1 response

is eliminated

Unique Skin Immunology of the Lower Female Genital Tract with Age 25 255

microbes can activate cervical inflammation, but the pres-

ence of numerous immune cells is actually physiologic.

The increased vulnerability of the relatively fragile transi-

tional epithelium in the transformation zone may require

better standing defenses to prevent ascending infection.

During the reproductive years, and to a greater extent

during pregnancy, estrogen down-regulates antigen pre-

senting cells. This results in a shift toward a Th2 immune

response [16, 17]. Although this has not been studied with

specific reference to the female lower genital tract, a Th2

response down-regulates the defensins and other secretory

products of the innate immune system [18]. This relative

immune compromise is presumed to be important for

normal fertility and pregnancy. However, there are conse-

quences, such as an increased risk for allergic contact der-

matitis, as well as increased susceptibility to yeast, viruses,

and other pathogens. Sexually transmitted diseases typically

have mechanisms to avoid cell-mediated immunity [19].

The abundant macrophages and granulocytes in the

cervical transformation zone are regulated by hormone

changes of pregnancy. Reflecting the immune suppression

of pregnancy, the number of macrophages in the cervical

transformation zone declines in early pregnancy, and then

increases in preparation for labor. Macrophages are

involved in cervical ripening just prior to the onset of

labor, and macrophages and granulocytes have a signifi-

cant role in cervical dilation [20].

TLR toll like receptor; HBD human beta defensin; SLPI secretory leuko-

cyte protease inhibitor; MBL mannose binding lectin; SP surfactant

proteins

Immune Changes with Age

Innate immune defenses of the vaginal mucosa are com-

promised with aging. Estrogen influences the expression

of TLRs in vaginal mucosa [21, 22] (> Tables 25.2 and> 25.3). This loss of TLR expression increases the risk for

colonization with pathogens. The post menopausal lack of

epithelial cell maturation results in loss of vaginal surface

barrier function. Pathogens can invade the more readily

traumatized fragile epithelium Estrogen deficiency leads

to a decline in mucosal secretions that contain the anti-

microbial constituents of the innate immune system.

The neutral vaginal pH after the menopause reflects loss

of the acid defense as well as a significant decline in

vaginal mucosal metabolic ability.

Cell-mediated immunity is estrogen and age depen-

dent. Langerhans cells are most prevalent in vulvar skin

during the reproductive years [23]. Estrogen receptors

on dendritic cells moderate the maturation of functional

dendritic cells from precursor cells [24]. There is a decline

in Langerhans cell function with aging, as well as a decre-

ased Langerhans cell count by approximately 50% [25, 26].

A decreased response to cytokines is also characteristic

of aging [18]. The immunologically active cervical trans-

formation zone is gradually eliminated by the aging

process of squamous metaplasia.

Antigen presenting cells are still present in the vaginal

mucosa after menopause [27]. Post menopausal estrogen

replacement can reactivate deficient vaginal mucosal cell-

mediated immune function. Asthma is a good example of

the estrogen effect upon cell-mediated immunity. Asthma

is influenced by the estrogen-related shift of cell-mediated

immunity from a Th1 to a Th2 environment. Asthma is

more prevalent in males than females prior to puberty, but

higher in females with the rise in estrogen after puberty

[28]. Asthma may become less severe after menopause

following the decline in Th1 suppression [29]. Hormone

replacement therapy after menopause may make asthma

worse [30]. Similarly, post menopausal estrogen replace-

ment may restore a Th2 environment that favors vaginal

colonization with yeast.

256 25 Unique Skin Immunology of the Lower Female Genital Tract with Age

Conclusion

Lower female genital tract immune defenses are complex

and are not yet completely understood. Clearly, the immune

system plays a major role in regulating vaginal microflora,

but unfortunately, many pathogens have mechanisms to

evade the immune defenses. Estrogen promotes the innate

system, but suppresses the cell-mediated response in the

lower genital tract. Humoral immunity appears to play

only a small role in this portion of the female body. Immune

function during the reproductive years reflects a balance

between the need to protect against infection and the

requirements of reproduction.

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