Microbiology and Immunology

WORLD OF MICROBIOLOGY AND IMMUNOLOGY Reproductive immunology

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REPLICA PLATING•seeLABORATORY TECHNIQUES IN

MICROBIOLOGY

RReproductive immunologyEPRODUCTIVE IMMUNOLOGY

Pregnant women experience many physiological changes

before implantation of the early embryo (blastocyst) takes

place. Ovulation, copulation, and fertilization directly or indi-

rectly induce dramatic changes in uterine physiology that

resemble classical inflammationat the mucosal surfaces of the

female reproductive tract, and it is quite likely that these

changes impact the maternal immune systemwell before the

blastocyst implants in the uterus. Consequently, the outcome

of the immune response differs during pregnancy, when com-

pared to outcomes in nonpregnant women. Thus, the uterus

may be preconditioned to accept the blastocyst.

Blastocyst implantation is a crucial point in the process

of reproduction because it is the moment of highest sponta-

neous embryo loss for humans. It is characterized by the inva-

sion of trophoblastic cells in the maternal decidua, a mucosal

tissue derived from the endometrium. Antigenically, the fetus

and placenta have half of the histocompatibilitygenes because

of the paternal origin of the conceptus. The reasons why the

fetus and placenta are accepted by the maternal immune sys-

tem are still largely unknown. It is, however, a harmonic equi-

librium among maternal cells of the immune system.

Originally, British immunologist Peter Medawar proposed

three broad hypotheses to explain the paradox of maternal

immunological tolerance to the fetus: (a) physical separation

of mother and fetus; (b) antigenic immaturity of the fetus; and

(c) immunologic inertness of the mother. At the present time,

several factors have been included in the mechanisms of fetal

protection: (1) general aspecific immunosuppression due to

hormonal and proteic patterns of pregnancy, (2) reduced fetal

immunogenicity by alteration of expression of fetal MHCanti-

gens by placental trophoblast cells, (3) IgG production toward

paternal lymphocyte antigens and toward maternal lympho-

cytes (blocking antibodies), also called trophoblast-lympho-

cyte cross-reactive antigens (TLX) for their cross reactivity

with antigens of the trophoblast. These blocking antibodies

could bind and protect fetal antigens from maternal lympho-

cytes, and (4) modification of the cellular mediated response

driven by cytokines. Cytokines are produced in the feto-pla-

cental unit and have a positive activity on the development of

pregnancy.

Spontaneous human fetal loss is a significant clinical

problem. Studies on recurrent spontaneous abortion syn-

dromes are dominated by suggestions of immunologic causa-

tion. This evidence includes genetic (epidemiological)

analyses, anatomical, physiological, and evidence for cytokine

dysregulation linked to inappropriate activation of the innate

and adaptive immune systems during human pregnancy.

However, it is difficult to discriminate whether abnormalities

of pregnancies are causes or effects of immune dysfunction.

Autoimmunityis defined as the pathologic condition

where humoral or cellular immune response is also directed

against self-antigens, leading to severe and debilitating clini-

cal conditions. Systemic autoimmune conditions such as

systemic lupus erythematosus (SLE) are associated with

higher risk for pregnancy loss. In the general population,

about 15% of clinical pregnancies are spontaneously aborted,

and about 50% of fertilized eggs fail implantation as a blasto-

cyst. The higher rate of fetal loss in women with SLE occurs

in association with antiphospholipid antibodies (aPL), which

are also associated with miscarriage in otherwise healthy

women. Clinical relevance is also given to lupus anticoagulant

(LAC), anticardiolipin antibodies (aCL), and antinuclear anti-

bodies (ANA). These are associated with several medical con-

ditions the description of which is beyond the aim of this

article.

Association of LAC with recurrent miscarriage has been

described in the past twenty years. The lupus anticoagulant

test (LAC) is a clotting time test used to detect women’s anti-

bodies against components of the blood clotting system, such

as negatively charged phospholipidsor prothrombin. These

antibodies cause a prolongation in the clotting time.The aCL

test measures 3 different species of antibodies to the phospho-

lipid cardiolipin. This test is essentially an antiphospholipid

antibodytest, with all features similar to those of the aPL.

ANA are antibodies against one or more elements within a

biological cell, involved in the machinery of translating

genomic message into proteins. These antibodies can destroy

cells, and their effect usually leads to SLE.

When the immune system is the cause of miscarriage,

the mother has a 30% chance of having a successful pregnancy

without intervention after three miscarriages, a 25% chance

after four miscarriages, and a 5% chance after five miscar-

riages. More epidemiological studies report a 90% chance of

failure in untreated patients, whereas, in the presence of aPL,

a 70% chance of reproductive failure was reported. Prevalence

of LA in women with recurrent miscarriage has been quoted in

a range between five and fifteen percent of fetal loss.

Pathogenesis of fetal loss in the presence of aPL includes the

presence of extensive infarction and necrosis in the placenta

due the recurrent thrombosis of the placental vascular bed. In

particular, intraluminal thromboses of the uterine spiral arter-

ies and necrotizing decidual vasculopathy, histologically char-

acterized by fibrinoid necrosis, atherosis, and intimal

thickening have been observed.

Among immune system causes of miscarriage are the

inability to properly detect fetal antigens and the lack of pro-

ducing blocking antibodies. Another cause is maternal pro-

duction of anti-sperm antibodies (IgG and IgA).

Endometriosis is a disease in which abnormal endome-

trial tissue grows in the abdomen and other places in the body.

It causes internal bleeding, inflammation, scarring, severe pain,

fatigue, and sometimes infertility. Endometriosis is related to

the functional deficit of NK cells and cytoplasmic granules of

cytotoxic lymphocytes (CTL) that allow the development of

autoantibodies. In premature ovarian failure, autoantibodies

against ovarian tissue and against gonadothropin receptors

have been found. Oocyte reduction has been detected in

women affected with premature ovarian failure.

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