hormonas sexuales y respuesta inmune

7/28/2019 Hormonas Sexuales y Respuesta Inmune

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Sex Hormones and Immunoregulation

Written by MM Faas, P de Vos & BN Melgert

Tuesday, 12 July 2011 00:00

The sexual dimorphism in immune responses in humans is well known; females have more

vigorous cellular and humoral immune responses, they are more resistant to many infections,

and they suffer a higher incidence of autoimmune diseases as compared with males [reviewed

in Reference 1].

Moreover, in women disease expression appears to be affected by their reproductive status.

Patients with immune-based diseases, such as multiple sclerosis (MS), asthma or systemic

lupus erythematosus (SLE), may have exacerbations during specific periods of the menstrualcycle or during pregnancy [2-4]. The differences in immune responses between the sexes and

the reproductive phases in women are accompanied by variations in sex hormones. Therefore,

these variations in levels of sex hormones have been suggested to cause the different immune

responses. The actions of sex hormones, however, are extremely complex. In this overview, we

will therefore discuss what is known about the effects of sex hormones on the function of the

different immune cells in isolation. Moreover, we will also discuss briefly how sex hormones

affect immune responses in complex situations like models of immune-mediated diseases

related to specific and non-specific immune responses.

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Sex hormones

Three classes of sex hormones exist: androgens (mainly testosterone), estrogens (which ismainly 17beta-estradiol in the ovarian cycle), and progesterone. In males, plasma testosterone

concentrations are relatively stable throughout life, although testosterone production declines

with age. In females, the production of sex hormones 17beta-estradiol and progesterone

fluctuates during the menstrual cycle. In response to pituitary luteinizing hormone (LH) and

follicle stimulating hormone (FSH), fluctuations in sex hormone concentrations in the menstrual

cycle include increasing 17beta-estradiol, but low progesterone plasma concentrations in the

follicular phase and high plasma 17beta-estradiol and progesterone concentrations in the luteal

phase (see also Fig. 1).

If pregnancy occurs, luteolysis is prevented and 17beta-estradiol and progesterone levels

remain high. When the ovarian follicles are depleted later in female life (after menopause) sex

hormone concentrations drop to low levels. Hormone replacement therapy (HRT) and the use of

oral contraceptives (OCC) increase (synthetic) estrogen and progesterone concentrations.

Immune system

There are two arms of the immune system: the nonspecific (innate or natural) immune system

and the specific (acquired or adaptive) immune system. The nonspecific immune response is

the first line of defense against infections. It recognizes structures specific for microbes. The

effector cells of the nonspecific immune response are monocytes, macrophages, granulocytes

(neutrophils, eosinophils and basophils), dendritic cells and natural killer (NK) cells. These cellsattack microbes that have entered the body. They do so by phagocytosing the microbe

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(neutrophils, monocytes and macrophages), by lysis of infected cells (NK cells), or by producing

cytokines to enhance nonspecific immune and specific immune responses (all cells). Dendritic

cells are (together with monocytes and macrophages) the most important antigen presenting

cells. They take up foreign antigens (including viruses or pathogens), process the antigens,

present antigen peptides in the context of MHC II molecules on their surface and present themto the specific immune system mainly helper T lymphocytes.

T lymphocytes and B lymphocytes are the cellular components of the specific immune

response. Within the T lymphocyte population, cytotoxic T lymphocytes (Tc cells) can directly

kill foreign or infected cells. The helper T lymphocytes (Th cells) provide help to other immune

cells by producing cytokines. These Th cells can be divided into 5 subsets, i.e. the Th1 subset

producing interferon (IFN) gamma to promote cellular immune responses, the Th2 subset

producing mainly interleukin (IL)-4, IL-13 and IL-5 to provide optimal help for humoral immuneresponses, the Th17 subset producing IL-17, which plays a crucial role in autoimmunity and

allergen-specific immune responses and the regulatory T cell (Treg) subset that is in the centre

of immunoregulation and is capable of suppressing both Th1- and Th2-mediated specific

immune responses. A Th9 subset has also been described. This population has only been

studied in vitro and it is unclear whether this is a real subset or an adapted Th2 population [5].

Receptors for sex hormones on immune cells

Sex hormones are steroid hormones. Due to their lipophilic nature, steroid hormones can

diffuse across the cell membrane; classical steroid hormone receptors can thus be found

intracellularly and have direct genomic effects [6]. More recently, also non-genomic effects of

steroid hormones have been described, which are most likely regulated via more recently

described membrane receptors for steroid hormones [7,8]. An alternative explanation is that by

their lipophilic nature, sex steroids can alter membrane properties by integrating into the

membrane, thereby changing the function of the immune cells [9].

Classical intracellular estrogen receptors are present in human monocytes [10-16], human

neutrophils [17], human dendritic cells [18], murine peripheral NK cells [19], human Tc

lymphocytes and B lymphocytes [20,21]. There is no evidence that classical intracellular

progesterone receptors are expressed on resting lymphocytes [22-28], monocytes [24],

neutrophils [29], NK cells, B lymphocytes, Treg cells and dendritic cells. Various studies,

however, demonstrated that activated lymphocytes, for instance lymphocytes during pregnancy,

can upregulate progesterone receptors [25-28,30,31]. More recently membrane-bound

progesterone receptors have been shown to be present on resting lymphocytes [8,32].Androgen receptors have long been considered not to be present on T lymphocytes [20,33].

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More recent studies, however, have demonstrated testosterone receptors in Th lymphocytes in

mice [34] and membrane-bound testosterone receptors on lymphocytes, which are different

from the classical intracellular testosterone receptors [35]. B-lymphocytes do express

intracellular androgen receptors [36]. Androgen receptor expression was also found in murine

macrophages [37] and androgen receptor mRNA was found in human macrophages [38]. Thereare no reports about the presence of androgen receptors on human monocytes, neutrophils, NK

cells, dendritic cells or Treg cells.

Influence of estrogen, progesterone and testosterone on immune cells

The most obvious effects of sex hormones on the immune response are the effects of thesehormones on the numbers of circulating immune cells. In the peripheral blood, about 65% of the

leukocytes are granulocytes (90% neutrophils), 5-10% is monocytes, and 30% are lymphocytes

(85-90% T lymphocytes and 10-15% B lymphocytes). Sex hormones have been shown to affect

these cell numbers by affecting proliferation or apoptosis of the cells or by recruitment of new

cells from the bone marrow [39,40]. Although total white blood cell counts did not differ between

males and females, an increase in white blood cells counts was observed in the luteal phase

(and during pregnancy) as compared with the follicular phase of the ovarian cycle [40-43]. This

may be largely due to an increase in granulocyte numbers in these reproductive conditions

[42,44-47]. This suggests a role for progesterone and/or estrogen in increasing the numbers of

granulocytes. In addition, various studies point to a decrease of monocyte numbers in thepresence of estrogen, as shown by increased numbers of monocytes in males and menopausal

women as compared with women in the follicular phase of the ovarian cycle [14,48]. However,

the presence of estrogen together with progesterone may increase monocyte numbers as

monocyte numbers are increased in the luteal phase and during pregnancy as compared with

the follicular phase. Whether sex hormones also affect B and T lymphocyte numbers remains to

be established. Conflicting results have been published [41,42,46,49-56]. Treg cell numbers

may be modulated by sex hormones, since it has been shown that both estrogen [57,58] and

testosterone [59] increase Treg cells numbers.

Cells of the nonspecific immune system

Monocytes

One of the functions of monocytes is ingesting and killing micro-organisms by a process ofphagocytosis. A few studies have indicated that sex hormones may affect this function of

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monocytes. For instance, numbers of Fc receptors on monocytes, which are involved in the

binding and phagocytosis of Ig coated particles, are increased on monocytes from females as

compared with males [60]. In addition, it has been shown that androgens may decrease the

number of Fc receptors on monocytes in certain patient groups [61], while animal studies have

shown that estrogen is capable of enhancing clearance of IgG coated red blood cells [62].Another important function of monocytes is to direct immune responses by the production of

cytokines. Cytokines mostly studied in this respect are: tumor necrosis factor (TNF)-alpha,

IL-1beta, IL-12, and IL-6.

TNF-alpha

TNF-alpha has pleiotropic actions and has emerged as an especially important mediator in

pro-inflammatory responses and activation of T cells [63]. Various observations suggest that

sex hormones may influence monocyte TNF-alpha production: in males endotoxin-stimulated

monocytes produce more TNF-alpha as compared to females [48,64,65]. Whether this is due to

direct effects of high levels of testosterone in males remains uncertain since in vitro studies

showed no effect of testosterone upon monocyte TNF-alpha production [66]. Furthermore,

endotoxin-stimulated monocytes of women in the luteal phase produce more TNF-alpha as

compared to monocytes of women in the follicular phase [7,42,67]. Although this suggests a

role for the female sex hormones in increasing monocyte TNF-alpha production, hormone

replacement therapy (HRT) in postmenopausal women and OCC use did not affect TNF-alphaproduction by monocytes [68,69]. These observations indicate that also other factors, apart from

estrogen and progesterone, may affect monocyte TNF-alpha production.

Various papers describe in vitro experiments in which stimulated monocytes were incubated

with estrogen or progesterone. The results are conflicting and vary from a down regulation of

endotoxin-induced TNF-alpha production by estrogen at both physiological and

supraphysiological levels [64,70] to no effect of either estrogen or progesterone upon

TNF-alpha production in stimulated monocytes [16,68,71-73].

IL-1beta

Production of IL-1beta, which mediates a wide variety of immune responses, also shows

differences in different reproductive stages. In the luteal phase an increased IL-1beta plasma

concentration and an increased frequency of IL-1beta-producing monocytes after endotoxinstimulation was demonstrated as compared to the follicular phase [42,74,75]. This suggests a

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potentiating effect of estrogen and/or progesterone on monocyte IL-1beta production. However,

also other mechanisms may be present since in males a higher frequency of IL-1beta-producing

monocytes after endotoxin stimulation was demonstrated as compared with females in the

follicular phase [48]. The effect of testosterone upon monocyte IL-1beta production in vitro was

also studied by us and others. Although we showed that incubation of whole blood withphysiological concentrations of testosterone increased monocyte IL-1beta production [66],

Morishita et al [76] did not find this.

IL-12

IL-12 is mainly produced by monocytes and macrophages and plays an important role in theinduction of cell-mediated immunity; i.e. together with IFN gamma it is a major inducer of Th1

differentiation [77]. IL-12 is thus an important cytokine that links the nonspecific immune system

to the specific immune system. We have shown no differences in IL-12 production after

LPS-stimulation when comparing monocytes from the luteal phase with those from the follicular

phase in women [42]. In men, however, the IL-12 production by monocytes after LPS

stimulation was increased as compared with women [42,48]. This may suggest that

testosterone stimulates monocyte IL-12 production. Indeed, physiological levels of testosterone

increased IL-12 production by LPS-stimulated monocytes in vitro [66], while no effect of

estrogen on LPS-stimulated IL-12 production was found [43]. However, others found a

decreasing effect [78] or an increasing [71] effect of estrogen on stimulated IL-12 production;progesterone did not affect the production of IL-12 in vitro [43,78].

IL-6

IL-6 stimulates B lymphocyte and T lymphocyte differentiation and activates macrophages and

NK cells, while it also possesses anti-inflammatory properties. It is generally thought that IL-6production is decreased by estrogen. Indeed, plasma IL-6 levels are increased after menopause

[79-82] and decreased by HRT treatment [18,81,83]. However, no variations in plasma IL-6

levels or spontaneous leukocyte IL-6 production during the menstrual cycle [7,67,84-88] were

found. Whether the production of IL-6 after LPS is stimulation is also influenced by estrogen is

unclear. No difference [86,89], an increase [88] or a decrease [65] in IL-6 production was found

between the follicular and luteal phase when whole blood was stimulated with LPS. Moreover,

stimulated IL-6 production was either decreased [90] or not affected [69,91] by the estrogenic

compound in HRT.

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The effects of gender and reproductive condition upon monocyte functions are obvious. The

most consistent effects are: plasma IL-6 levels appear to be decreased by estrogens;

LPS-stimulated TNF-alpha and IL-1beta productions are increased in males as compared to

females, and these are also increased in the luteal phase as compared to the follicular phase of

the ovarian cycle; LPS-stimulated IL-12 production is only increased in males and not affectedby the ovarian cycle. These differences in monocyte function may play a role in the differences

in immune responses between sex and reproductive condition. Whether these differences are

due to direct effects of sex hormones remains uncertain, since in vitro experiments in which

monocytes were incubated with sex hormones revealed conflicting results upon monocyte

cytokine production. Such conflicting results may be due to differences in experimental setup.

For instance incubations with sex hormones are performed using whole blood, peripheral blood

mononuclear cells or isolated monocytes.

Macrophages

Macrophages are tissue-residing cells derived from monocytes [92]. In these tissues they stand

guard against foreign invaders and alert the adaptive immune system with signals and through

antigen presentation. In order to maximize their effector functions, macrophages need to be

activated and the type of activation determines its effector functions [93]. Presently, two major

macrophage activation states have been described: the classically activated state and the

alternatively activated state [93]. The first one is associated with increased generation of oxygenradicals and cell killing to remove invading microorganisms and the second one with increased

expression of phagocytic receptors to remove cell debri and increased tissue remodeling to

reconstruct the tissue during wound healing. In addition, macrophages with a nonactivated,

anti-inflammatory phenotype have been described, these are called the immunosuppressive

macrophages [93]. These producers of IL-10 are important in controlling inflammation and

collateral damage associated with excessive inflammation [93]. Sex hormones have been found

to affect these activation states and effector functions in macrophages and their effects are

reviewed below.

Classically activated macrophages: Macrophages become classically activated after exposure

to IFN gamma or microbial products like LPS and they upregulate mechanisms to destroy

microorganisms [93]. As the classically activated phenotype has been known for the longest

time, most studies investigating effects of sex hormones on macrophage activation have studied

this phenotype. Many studies have described upregulation of inducible nitric oxide (NO)

synthase (iNOS) and NO production, increased production of proinflammatory cytokines and

increased cell surface expression of Toll-like receptor (TLR)4 in macrophages [94-99] after

treatment with estrogens. This may lead to enhanced killing of microorganisms and thus to

increased resistance to extracellular bacteria and infections in the presence of estrogen [100].Progesterone on the other hand was found to inhibit NO production, TLR4 expression and

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proinflammatory cytokine production [101-104], counteracting the effects of estrogens. The net

effect on classical activation of macrophages therefore seems to depend on the ratio of these

two hormones, though this has not been studied yet to the best of our knowledge.

Like progesterone, androgens have also been found to reduce classical activation by inhibiting

TLR4 expression and oxygen radical formation [105-107], and this may explain the increasedsusceptibility of men for infections [108-110]

Alternatively activated macrophages: Macrophages become alternatively activated after

exposure to IL-4 and/or IL-13 and they adopt a phenotype intent on taking up apoptotic cells

and cell debri and reconstructing damaged tissues. This phenotype has been discovered

relatively recently and the effects of sex hormones have not been studied much in relation to

alternative activation. The few studies published that did investigate sex hormones and

alternative activation showed increased alternative activation of macrophages after treatmentwith either progesterone or estrogen and decreased alternative activation after treatment with

androgens [111,112].

Immunosuppressive macrophages: This subset is the least-known of the subsets and little to no

data are available about the effects sex hormones have on this phenotype. One study did

investigate IL-10 production by macrophages from hemorrhaged mice treated with estrogens or

androgens and found reduced production by estrogen and increased production by androgen

[113]. These findings are again in line with the anti-inflammatory effects usually found for

androgens.

Dendritic cells

Dendritic cells are also tissue-residing cells derived from monocytes [92]. Immature dendritic

cells reside in the tissues. They may be activated by microbial products or inflammatory

cytokines after which they differentiate into mature dendritic cells [114], while migrating to lymph

nodes to present antigen to naive T cells. In human dendritic cells, derived from monocytes in

vitro, both estrogen and progesterone upregulated IL-10 production by mature and immaturedendritic cells [115,116]. These hormones also increased apoptosis of dendritic cells [116]. On

the other hand, neither progesterone, nor estrogen affected the phenotype of mature and

immature dendritic cells [115] or the T cell stimulatory capacity [116]. Although analysis of

subpopulations of dendritic cells is still difficult, it has been shown recently that progesterone

inhibited IFN gamma production by plasmacoid dendritic cells [117]. Since IFN gamma is

necessary to fight viruses and also primes antiviral responses of the specific immune system,

progesterone may therefore inhibit antiviral responses [117].

Neutrophils

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Neutrophils play a key role in the first-line defense against invading pathogens by phagocytosis,

the release of anti-microbials and the generation of neutrophil extracellular traps [118].

Therefore, they need to be able to respond to chemotactic stimuli to get to the place of actionand they need to be able to produce those anti-microbial factors. Studies have shown that

progesterone enhanced chemotactic activity of neutrophils, while estrogens decreased this

activity [119]. Various groups have also investigated the effects of progesterone and estrogen

on free radical production by neutrophils. This has been shown to be increased [120],

decreased [121] or not affected [122] by estrogen or progesterone incubations in vitro. Sex

hormones also affect NO production via NOS activity. NO production by neutrophils was found

to have anti-inflammatory effects since it prevented neutrophil adhesion to the endothelium

[123]. NO-synthase in neutrophils varies with reproductive condition: increased NO synthase

expression was observed in vivo in the luteal phase as compared with the follicular phase and

in postmenopausal women on estrogen therapy as compared with untreated postmenopausalwomen [124]. This is in line with in vitro results showing that estrogen upregulated NOS

expression in neutrophils in vitro [124,125].

Taken together, it appears that both sex and reproductive condition affect neutrophil function. In

general, estrogen has anti-inflammatory effects on neutrophils, while progesterone has

pro-inflammatory effects on these cells. Therefore, sex hormones can affect nonspecific

immune responses in vivo by modulating neutrophil function.

NK cells

There are various reports on the effects of the reproductive condition and gender sex on the

main function of NK cells, i.e. their ability to lyse other cells. Various studies have shown a

negative association of the lysing activity of NK cells with estrogen or progesterone levels: an

increased potency to lyse other cells was found in postmenopausal women and in males ascompared to females with a regular menstrual cycle and women on OCC [126,127]. In addition,

exposure to OCC caused a reduction in NK-activity as compared to non-users [126,128,129],

while NK cell activity was decreased in postmenopausal women using HRT [130]. Indeed, in

vitro studies have directly demonstrated that estrogen decreased the potency of NK cells to lyse

other cells [131,132], while no effect of progesterone on NK cell activity was demonstrated

[132,133]. Unfortunately, the suppressive effect of estrogen on NK cell activity is not always

observed during the menstrual cycle, since results vary from no difference between follicular

and luteal phase, as well as highest NK cell activity in follicular phase, periovulatory phase or

luteal phase [126,127,134-136]. Such different results may be due to different time points in the

ovarian cycle of measuring the NK cell activity.

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Another important function of NK cells is cytokine production. The cytokine repertoire of

peripheral NK cells is mainly type 1 cytokines (IFN gamma) [137,138]. Although there are many

studies into cytokine production of uterine NK cells during pregnancy, little is known aboutcytokine production by peripheral NK cells in relation to reproductive condition or separate

effects of sex hormones on peripheral NK cells. During pregnancy, induced IFN gamma

production of peripheral NK cells was found to be decreased, however, no effect of the

menstrual cycle upon IFN gamma production of NK cells was found [139]. This suggests that

during pregnancy other mechanisms rather than sex hormones affect IFN gamma production by

NK cells.

Effect of sex hormones on the nonspecific immune response in vivo

Acute immune actions, which are part of the innate immune system, appear to work favorably

for women as compared to men. In general, men are more susceptible to viral, bacterial, fungal

and parasitic infections (with the exception of sexually transmitted diseases) then women

[140,141]. They also have a higher risk of developing more severe disease [142]. This may be

due to the effects of androgens and estrogens on the innate immune cells. As described above,

in general androgens have been shown to suppress innate immune cell function, resulting in

suppression of the resistance to infections [105], whereas estrogens were found to stimulateinnate immune cells, which can promote resistance to infections [143]. The effects of androgen

and estrogen on non-specific immune responses are also obvious from the fact that male sex is

a significant risk factor for the development of sepsis. This is supported by many animal models

of endotoxemia and bacterial challenge in which females demonstrate better survival when

subjected to severe sepsis than males [142]. In males infections can more easily progress to

damaging inflammation, hence the increased susceptibility for sepsis. More on the mechanisms

can be read in some excellent reviews on the subject [144-146].

Wound healing also differs between males and females [147]. Recent studies have suggested

that the male genotype is a strong risk factor for impaired wound healing in the elderly

[148-150]. These sex effects are mediated by estrogens and androgens, since wound healing

increases after estrogen treatment [151] and after deprivation of androgens after castration of

male mice [152]. The striking acceleration of wound regeneration after androgen deprivation

was associated with a reduced inflammatory response [152]. Although exact mechanisms by

which sex hormones affect wound healing are not clear yet, it seems likely that the effects are,

at least partly, mediated by the effects of sex hormones on the nonspecific immune response.

For instance, the effects of sex hormones on the macrophage subsets may be important in

wound healing, since a subset switching of macrophages is essential in wound healing[153,154]. The types of macrophages present in wounds determine whether chronic

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inflammation will occur or whether proper healing is started [111]; classically activated

macrophages are needed in the first stage, whereas alternatively activated macrophages have

been found important in the wound healing stage. Both estrogen and progesterone have been

found to promote wound healing by enhancing alternative activation of macrophages and failure

to switch was associated with chronic inflammation of wounds [111].

Cells of the specific immune system

Cytotoxic T lymphocytes (Tc)

Sex hormones have been described to affect Tc lymphocyte function (reviewed by Grossman et

al., Reference 155). Many studies (vitro and in vivo) have shown that both estrogen and

progesterone suppress cell-mediated immune responses [155]. Although the exact mechanisms

are unclear, estrogen and progesterone inhibited proliferation of Tc lymphocytes (or Tc

lymphocyte cell lines) after stimulation with mitogenic substances [156-159]. In addition, both

hormones have also been shown to increase apoptosis in activated Tc lymphocytes [160]. Only

a few studies have evaluated the role of sex hormones on Tc lymphocyte cytolytic activity. One

study suggested that cytolytic activity of Tc lymphocytes in the uterine endometrium is

depressed by estrogen and progesterone [161] and another study suggested that progesteronedecreased cytolytic activity of these lymphocytes from the decidua [162]. Also, cytotoxicity in

peripheral Tc lymphocytes was decreased by estrogen [162].

Helper T lymphocytes (Th)

The main function of Th lymphocytes is cytokine production. As indicated above, Thlymphocytes can be subdivided in Th1, Th2, Th9, Th17 and Treg. The effects of sex hormones

on these subtypes will be discussed below.

Th1 subtype: The most important cytokine produced by Th1 cells is IFN gamma. Although

various studies have evaluated the effects of sex hormones on IFN gamma production, it

remains elusive whether there are direct effects of sex hormones on lymphocyte IFN gamma

production. Increased IFN gamma production [163] as well as similar IFN gamma production

[48] by stimulated male lymphocytes as compared to female lymphocytes was found.Furthermore, no effect of the menstrual cycle upon induced IFN gamma production was found

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[46], while induced IFN gamma was decreased in HRT-treated postmenopausal women as

compared to untreated postmenopausal women [130]. Others, however, found no effect of

synthetic hormones on lymphocyte IFN gamma production [90,164]. These in vivo results are in

line with in vitro experiments in which neither progesterone, estrogen nor testosterone altered

IFN gamma production [66,163,165].

Th2 subtype: As estrogen has been shown to enhance humoral immune responses [166] it

seems likely that it would also affect Th2 cytokine production. IL-4 is released predominantly by

Th2 lymphocytes. In males and after menopause IL-4 production is similar to fertile women

[163,167,168], suggesting no effect of sex hormones on the production of IL-4. In contrast to

this suggestion the production of IL-4 was significantly increased in Th cells in the luteal phase

as compared with the follicular phase of the ovarian cycle [46]. This may be due to increased

progesterone concentrations in the luteal phase, since one study demonstrated an increase inIL-4 production by Th lymphocytes after incubation with progesterone [165]. Synthetic

hormones, such as in OCC or HRT, have not been found to affect IL-4 production by

lymphocytes [90,163,168].

Interleukin-10 (IL-10), another Th2 type cytokine was not produced differently by lymphocytes of

both males or postmenopausal women and premenopausal women [48,163]. In addition, during

the menstrual cycle IL-10 production by lymphocytes after stimulation is stable [46,169],

suggesting no effect of sex hormones on IL-10 production. Results with oral contraceptives,which do not influence IL-10 production [164] and in vitro experiments, which showed no effect

of estrogen, progesterone or testosterone on IL-10 production [66,163,165] after polyclonal

stimulation of whole T lymphocyte populations, corroborate this suggestion.

Th17 and Th9 subtype: Unfortunately, at this time no data exist showing an effect of sex

hormones on the Th17 or Th9 subtype. Apart from pregnancy, in which the number of Th17

cells does not differ from non-pregnant individuals, also no data are available on the effect of

the reproductive condition on Th17 or Th9 cells [170].

Treg subtype: Numbers of Treg cells appear to be influenced by estrogen [57,58] and

testosterone [59], but not much is known whether Treg cells function is also under control of sex

hormones. Human data are scarce at this moment. One study showed that estrogen increases

suppressive function of Treg cells [57]. This potentiating of suppressive function by estrogen

has been confirmed in mice studies. Estrogen increased Foxp3 expression in mice Treg cells in

vitro [58,171,172]. Foxp3 is a transcription factor present in Treg cells that controls the

development and function of Treg cells [171,172]. An increase in this factor by estrogen thus

suggests that estrogen increases Treg cell function. In vivo studies in mice corroborated this

suggestion: estrogen treatment upregulated Foxp3 expression together with Treg cell function in

mice [58,173].

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B lymphocytes

The main function of B lymphocytes is the production of antibodies. Effects of sex on B cell

function can therefore be derived from differences in plasma levels of antibodies. Females have

higher serum levels of total IgM and IgG as compared to males [174-178] with no changes

during the menstrual cycle [52,179]. During OCC use immunoglobulin levels and

immunoglobulin production are unaltered as compared to females not taking OCC [180,181],

but others found immunoglobulin levels to be decreased [182] or even increased [183] in

females using OCC as compared to females not using OCC. The higher serum levels of

immunoglobulin in females may suggest a stimulating effect of female sex hormones or an

inhibiting effect of testosterone upon this parameter or both. Indeed, in vitro studies, haveshown that estrogen induced polyclonal activation of human B cells and increased IgG and IgM

production by PBMCs [184,185]. Testosterone inhibited immunoglobulin IgG and IgM

productions [186]. It has also been shown that estrogen increased and testosterone decreased

autoantibody production by PBMC in patients with SLE [187,188]. Animal data have shown that

estrogen also induced a switch in antibody isotype. In mice treated with estrogen, autoantibody

production was increased and the antibodies were mainly of the IgG isotype [189,190]. Present

evidence to date thus points towards an important role for estrogen and testosterone in antibody

production.

In conclusion, there are obvious effects of sex hormones on lymphocytes. As described above,

both female sex hormones seem to inhibit Tc cytotoxicity, while estrogen and testosterone also

affect humoral immunity: estrogen upregulates (auto)antibody production and testosterone

inhibits (auto)antibody production. Whether sex hormones also affect lymphocyte cytokine

production remains to be established. More recently, it has been shown that sex hormones also

affect Treg: estrogen both increased Treg cell numbers and Treg cell function.

Effects of sex hormones on specific immune responses in vivo

The effects of sex hormones on the immune response in vivo can be studied using immune

disease models and study the effects of gender, reproductive condition and sex hormone

treatment on the incidence and course of the disease. The ability to mount more vigorous

cell-mediated and humoral immune responses in women increases their chances of developing

unwanted Th1, Th2, Th9, and Th17-mediated responses to self-antigens or otherwise

innocuous compounds such as allergens. The result is increased incidences of autoimmunediseases like multiple sclerosis (MS) and allergic diseases like asthma in women. Until recently

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these self-reactive and allergen-reactive processes were primarily thought to be associated with

Th1 cells and Th2 cells, but with the discovery of Th17 and Th9 cells, the disease mechanisms

appear to be far more complex [191]. Unfortunately, little to no data is available about the

effects of sex hormones on these new subsets in the context of autoimmune diseases and

asthma. Therefore, we will shortly discuss the effects of sex hormones on the development andcourse of MS as an example of a Th1-mediated disease and asthma as a Th2-mediated

disease and keep Th17 and Th9 out of this context for the moment.

Multiple sclerosis (MS)

MS is an autoimmune disease characterized by a Th1 and Th17-mediated chronic inflammatorydemyelinating process of axons in the central nervous system and is more common in women

than in men [191,192]. In 80% of the cases, MS starts with a relapsing/remitting phenotype and

may become progressive after several years [193]. Changes in MS symptoms have been

related to reproductive status. About 40% of women with relapsing/remitting MS have reported

an increase in symptoms in the time preceding menstruation when both estrogen and

progesterone levels have dropped [194,195]. In contrast, in the third trimester of pregnancy

when estrogen and progesterone levels are highest, the rate of relapse significantly reduces,

only to increase again post-partum when hormone levels have dropped [196,197]. Little data

exists on the effects of OCC and HRT use. Two studies have reported an improvement of MS

symptoms in women using OCC [194,195] and one study reported an improvement in mostwomen using HRT during menopause [198].

The effects of sex hormones on MS development have been tested quite extensively in a model

of MS called experimental autoimmune encephalitis (EAE), as reviewed by Van den Broek et

al., recently [199]. The role of estrogen in MS and EAE is complex and seems to be

dichotomous: on the one hand it appears to increase the risk of developing the disease, while

on the other hand high concentrations were found to be beneficial on the clinical manifestations

of EAE. Most of the studies have focused on the protective effects of sex hormones in thecourse of the disease. There may be different mechanisms by which estrogen affects MS. The

protective effect of high concentrations of estrogen may be due to an increase of the

anti-inflammatory IL-10 production of specific T cell clones directed against proteins of the

myelin sheath [200]. Also the homing of destructive Th1 and Th17 cells into the central nervous

system was limited by estrogen [201]. Furthermore, Treg cell function and numbers were found

increased by high levels of estrogen and these can limit the expansion of Th1 effector cells

[57,58,202,203]. A regulatory B cell mediated protection has also been shown [204]. Finally, the

effect of estrogen may also be mediated through decreased numbers of macrophages and

dendritic cells in the central nervous system [205].

Progesterone also has protective effects on experimental MS [206-209] as it attenuated diseaseseverity and reduced the inflammatory response. The high progesterone and estrogen during

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pregnancy may thus explain the improvement of MS signs during pregnancy [210]. It was

speculated that the Th2-promoting effects of progesterone [199] may be responsible for tipping

the Th1/Th2 balance in a protective direction, but no formal evidence for this hypothesis exists.

The neuroprotective effects of progesterone were accompanied by increased IL-10 production

and increased infiltration of B cells, possibly regulatory B cells, and cytotoxic T cells into thespinal cord [207].

Administration of androgen significantly delayed onset and progression of EAE and its

protective effects are postulated to be responsible for the reduced susceptibility of men for MS

[211-213]. Both castration of male mice and treatment of female mice with androgens showed

similar results. Androgen was found to inhibit infiltration of Th1 cells into the spinal cord [214] as

well as reduce the expression of Th1 cytokines [212] and increase the production of

anti-inflammatory cytokine IL-10 [199].The effects of female sex hormones on Th1 inflammation in the context of EAE all point at

protection against disease. This may explain why women remit during pregnancy, but it fails to

explain why women are at risk of developing MS in the first place. This particular question

needs more research. The effects of androgens on EAE development are consistent with what

is found in men: androgens inhibit EAE development, which is why men are less susceptible to

the disease.

Asthma

Like autoimmune diseases, asthma is also more prevalent among women in the reproductive

stages of life than men [215,216]. Asthma is a common chronic inflammation of the airways,

which is characterized by a Th2 polarization with an overabundance of eosinophils, mast cells,

and activated Th2 lymphocytes in the lungs and increased levels of IgE in serum.

There is substantial support for a role of female sex hormones in the development of asthma,

starting with the fact that the prevalence of asthma and other atopic conditions is higher in boys

than girls before puberty and reverses to a higher prevalence in girls and women after puberty

when female sex hormone levels have increased [217].

Also other observations suggest a link between female sex hormones and the development of

asthma since an earlier menarche increases the risk of developing asthma in females [218,219].

As described above for MS, the effects of estrogen on asthma also appear to be dichotomous.Although it may increase the incidence of asthma, estrogen also appears to be beneficial, since

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30% to 40% of menstruating female asthmatics experience perimenstrual asthma worsening

with increased symptoms and a greater likelihood of hospitalization [220,221]. Since estrogen

levels are low perimenstrually, this suggests a protective effect of estrogen on asthma. Indeed,

most of the limited number of case reports and studies investigating OCC use suggest a small

beneficial effect on perimenstrual asthma and mild asthma in general among women[218,220,222]. With the Th2 dominance during pregnancy, one would expect an increase in

asthma severity in pregnant women with asthma. However, this does not seem to be the case in

women with mild asthma: in an equal number of women symptoms worsen, stay the same, or

decrease with pregnancy. Only in women with severe asthma, symptoms may increase with

pregnancy [223]. After menopause asthma incidence declines in women as compared to men

and younger women, but not in women who receive HRT to treat symptoms of menopause

[224-228].

A small number of investigations in animal models have tried to elucidate how female sex

hormones affect asthma. The few studies published have focused little on mechanisms but

rather on inflammatory and allergic endpoints like airway hyperresponsiveness, IgE levels and

eosinophils. Yet these studies failed to come up with conclusive proof of the effects of female

sex hormones on asthma development because they reported both inhibition and aggravation of

airway inflammation by estrogen and progesterone [229-234]. The effects of testosterone on the

other hand are clear: testosterone has been shown to suppress Th2 inflammation in the lungs

[235,236]. In addition, in an interesting study by Okuyama et al. it was shown that sex

differences in airway inflammation are not only caused by the hormonal environment during

inflammation, but also by intrinsic differences between male and female immune cells [237].These intrinsic differences between males and females are probably partly due to local

regulation of airway inflammation by macrophages and not by T cells [238,239].

Results from these animal models show that the influence of female sex hormones on Th2-type

inflammations is most likely a complex interplay of estrogens, progesterone and their receptors.

To be able to tease out their effects we need to understand which parts of the Th2 immune

response cascade are different between males and females to identify the most likely targets for

the modulation by sex hormones. The effects of androgens are clearer showing inhibition ofTh2-type inflammation, which explains the reduced susceptibility of men.

Conclusions

The aim of this review was to describe the effects of sex hormones, both female (estrogen and

progesterone) as well as male sex hormones (testosterone), on immune responses in humans.Available evidence from animal studies suggests that sex hormones regulate immune

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responses in vivo (as reviewed in Reference 1). Since clinical data on human immune

responses are largely lacking, we focused on the effects of sex hormones on isolated human

immune cells and on human data of effects of sex and reproductive condition on two immune

mediated diseases (MS and asthma) as well as on experiments studying the role of sex

hormones in animal models for these data.

In the past, the effects of gender and the reproductive condition upon the specific immune

response have gained much more attention then the effects on the nonspecific immune

response. It is now much clearer that there are also important effects of sex hormones on cells

of the nonspecific immune response. This should not be surprising, since many reproductive

processes, such as ovulation and menstruation, are regulated by nonspecific immune

responses. Ovaries therefore have an interest in regulating the nonspecific immune response.

Sex hormones regulate nonspecific immune responses, by affecting monocyte, macrophage,granulocyte and NK cell numbers, but also by affecting the function of these cells.

Many studies have been performed on the effects of sex hormones on the specific immune

response. At present, evidence points towards an important role for estrogens and testosterone

in the humoral response i.e. (auto)antibody production; estrogen increases, while testosterone

decreases antibody production. Sex hormones also have prominent effects on the cellular

immune response, by affecting T lymphocytes. Numbers of T lymphocytes are decreased in

males and female sex hormones appear to inhibit T cell proliferation and cytotoxicity of Tclymphocytes. Th cells are also affected by female sex hormones: progesterone induces Th2

development and estrogen seems to increase the number and function of regulatory T cells.

Unfortunately, in vivo studies on the effects of sex hormones on immune responses in humans

are largely lacking. Although the female preponderance in autoimmune diseases has been

known for many years, the mechanisms for this are not clear. Effects of the reproductive

condition and sex hormone treatment on symptoms of autoimmune diseases and asthma are

not consistent. This may amongst others be due to a lack of standardization how and whensymptoms are scored and what sex hormone treatment is given (combination of

progesterone/estrogen treatment, duration of treatment, amount of hormones given). Such a

lack of standardization is also seen in animal models. Therefore in order to get more insight into

the effects of sex hormones on immune responses and immune based diseases, it is important

to standardize experiments and not only study effects of sex hormones separately but also in

combination and in different concentrations and for different time periods.

It is obvious from this review that we have decades worth of research, which have alreadytaught us a lot about how sex hormones influence the immune system. However, with every

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new discovery more questions emerge. For instance, the recent discovery of Th9, Th17 and

Treg subsets make us wonder how sex hormones affect these subsets. Future research should

focus on these subsets, but also on how these hormones work together in more complicated

set-ups than isolated cells. This is not an easy task, but with the ever-expanding research tools

and the increased interest in sex differences in disease development and management weshould be able to move forward in this challenging field.

Author(s) Affiliation

MM Faas - Immunoendocrinology, Division of Medical Biology, Department of Pathology and

Medical Biology, University Medical Centre Groningen and University of Groningen

P de Vos - Immunoendocrinology, Division of Medical Biology, Department of Pathology and

Medical Biology, University Medical Centre Groningen and University of Groningen

BN Melgert - Department of Pharmacokinetics, Toxicology and Targeting, University Center forPharmacy, University of Groningen, Groningen, The Netherlands

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