Th2 immune deviation induced by pregnancy: The two faces of autoimmune rheumatic diseases
Introduction
Pregnancy is a condition in which profound immune-endocrine changes occur. Hormonal modifications during pregnancy are regulated by the feto-placental unit and depend on interactions between mother and fetus [1]. Hormones mainly involved in these modifications are progesterone, corticosteroids and estrogens.
Progesterone is the crucial hormone during the first part of pregnancy and the precursor of some fetal hormones. It also has other functions, some of which are still partially unknown. It has a placental origin, since it is secreted by the corpus luteum during the first 6–8 weeks of gestation. During physiological pregnancy progesterone levels are 4–6 times higher than those out of gestation. Deoxicorticosterone, one of its metabolites, is found in concentrations 1000 times higher than that out of pregnancy, but the physiologic role of this hormone is still not known [1].
Estrogen concentration is also significantly increased during pregnancy reaching levels 3–8 times higher compared to normal levels [1]. This increase results from a unique interchange between mother and fetus. The fetus uses the pregnenolone produced by the placenta, in order to produce adrenal dehydroepiandrosterone and dehydroepiandrosterone sulphate. These hormones are metabolized to androstenedione and testosterone at the level of the placenta. Finally they are rapidly converted to estrone and estradiol and released into maternal circulation [1].
The physiological increase of cortisol, progesterone, estradiol and testosterone during the third trimester of pregnancy seems to lead to Th2 cytokine polarization both at the systemic level and at the feto-maternal interface [2], [3]. Therefore, the suppression of the immune response mediated by Th1 cytokines seems to be essential for fetal survival.
Elevated levels of Th2 cytokines, such as IL-10, have been found in the placenta and amniotic fluid during the third trimester of pregnancy [4]. It has been also demonstrated that during pregnancy IL-6 serum levels gradually increase in maternal circulation and even more during labor [5]. TNF-α serum levels do not vary during pregnancy, whereas those of the TNF-α soluble receptors increase probably in order to protect the fetus from the dangerous effects of TNF-α [6].
It is known that glucocorticoids inhibit IL-1, TNF-α, IFN-γ and IL-2 production and that they stimulate IL-10, IL-4 and IL-13 synthesis confirming a modulatory effect on the balance between anti-inflammatory/immunosuppressive responses during pregnancy [7].
At physiological concentration progesterone stimulates IL-4 (Th2 cytokine) synthesis, whereas estradiol stimulates TNF-α production (Th1 cytokine). On the contrary, at pharmacological levels, such as those observed during the second part of pregnancy, progesterone inhibits TNF-α secretion and stimulates IL-10 production in T lymphocyte clones, leading to an increased humoral immune response [8].
Autoimmune rheumatic diseases (ARD) affect young females in their childbearing age. Over the last decades, the improvement of survival rate as well as quality of life in patients affected with ARD have led to an increased number of pregnancies observed during the course of such diseases.
It is worthy to note that some autoimmune diseases, such as systemic lupus erythematosus (SLE), which are mainly mediated by Th2 cytokines, tend to occur or relapse during pregnancy [9], [10], whereas Th1 mediated diseases, such as rheumatoid arthritis (RA), tend to improve [11].
Most of the available data on disease and obstetric outcome of patients with ARD during pregnancy regard SLE which is the ARD most frequently observed during pregnancy because it generally affects young females in their childbearing age.
Data regarding pregnancy outcome in other ARD such as RA, ankylosing spondylitis, Sjögren Syndrome, undifferentiated connective tissue diseases, systemic sclerosis, polymyositis-dermatomyositis and systemic vasculitis, are limited mainly because most of them are rare and their onset is after the age of 40 [12], [13].
This review is focused on the disease course, gestational outcome and management of patients with SLE and RA during pregnancy.
Section snippets
Systemic lupus erythematosus and pregnancy
SLE is an autoimmune disease which affects various organs and tissues inducing inflammation and damage.
Rheumatoid arthritis and pregnancy
RA is an articular and systemic chronic inflammatory disease leading to joint damage and to consequent severe anatomic and functional alterations.
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