Immunological and Hormonal Aspects of Normal Pregnancy

Pregnancy has a significant effect on the immune system, in order to maintain the fetal-maternal allograft, which is not rejected despite displaying paternal histocompatability antigens [12]. While there is no overall immunosuppression during pregnancy, control or tolerization of anti-fetal T cells is critical [13]. Clinical improvement usually occurs in patients with immunological disorders such as rheumatoid arthritis [RA] when they become pregnant [14]. Clinical improvement occurs as well in psoriatic arthritis and Graves' disease. On the other hand, systemic lupus erythematosus (SLE) may flare during pregnancy.

The trophoblast does not express the classical major histocompatibility complex (MHC) class Ia or II which are needed to present antigenic peptides to cytotoxic cells and T helper cells, respectively. Instead HLA-G, a non-classical MHC Ib molecule is expressed which may be a ligand for the natural killer (NK) cell receptor so protecting the fetus from NK cell damage; it may also activate CD8+ T cells that may have a suppressor function. Human trophoblasts also express the Fas ligand abundantly, thereby contributing to the immune privilege in this unique environment possibly by mediating apoptosis of activated Fas expressing lymphocytes of maternal origin [15].

T cell subset studies in pregnancy are discrepant, as peripheral blood CD4+ and CD8+ cell levels have been variously reported to decline, remain unchanged and increase during pregnancy. Although, the distinction between Th1 (T cell helper 1) and Th2 (T cell helper 2) immune responses in humans remains less clear than in the mouse the general agreement is that in pregnancy there is a bias towards a Th2 response [16]. This seems to be achieved by the fetal/placental unit producing Th2 cytokines, which inhibit Th1. Th1 cytokines are potentially harmful to the fetus as, for example, interferon alpha is a known abortifacient.

Table 2. Immunological and hormonal features of pregnancy

Clinical: Improvement in Graves' hyperthyroidism Rheumatoid arthritis

Psoriatic arthritis and other autoimmune diseases Trophoblast: HLA G expression

Fas ligand expression Lymphocytes: Th2 response

Th2 cytokines produced by the fetal/placental unit Hormones: Progesterone increase - reduction in B cell activity Oestrogen increase - fall in autoantibody levels

Cortisol, 1, 25-vitamin D and norepinephrine all affect the immune response

Sex steroids are powerful negative regulators of B cell activity. Oestrogen alone is effective in reducing B cell lymphopoiesis in pregnancy. Although progesterone is not effective on its own, it reduced the amount of oestrogen required for suppression by up to 90% in a mouse pregnancy model. The high concentrations of oestrogen produced in normal pregnancy almost certainly contribute to the fall in autoantibody levels observed in pregnant patients with autoimmune thyroid disease (AITD). Despite the fall in autoantibodies, there are no significant changes reported in the number of B cells in the circulation in normal human pregnancy. While progesterone may favour Th2 cells, evidence has indicated that oestrogen delivers a negative signal to B cell function during pregnancy and this showed a slow reversal in the postpartum period. In keeping with these observations, autoantibody titres and inflammation fall throughout pregnancy as observed in all autoimmune diseases investigated [17]. However, after most pregnancies, there is a marked increase in many different types of autoantibody secretion and an exacerbation of autoimmune diseases in the months after delivery. Recent data suggests that cortisol, norepinephrine and 1,25-dihydroxyvitamin-induced inhibition and subsequent rebound of interleukin-12 (IL-12) and tumour necrosis factor-a (TNFa) production may represent a major mechanism by which pregnancy and postpartum alters the course of or susceptibility to various autoimmune disorders [18]. Table 2 summarises relevant immunological changes in gestation.

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