Obstetric Topic 04. Immunology of pregnancy

I. Immunologic Problem of Pregnancy

The fetus is semi-allogeneic: it expresses paternal antigens but is normally not rejected by the mother.
Pregnancy requires local immune tolerance at the maternal-fetal interface while preserving maternal defense against infection.
Medawar's paradox: implantation and placental invasion expose fetal tissues to the maternal immune system, yet pregnancy is maintained.
Pregnancy is not generalized immunosuppression → immune responses are remodeled in a tissue- and pathogen-specific manner.

Decidua/placenta: anatomical and immunologic interface between mother and fetus.
Major decidual immune cells: uterine NK cells, macrophages, T cells including Treg, dendritic cells and few B cells.
Uterine NK cells: regulate trophoblast invasion and spiral-artery remodeling; they are mainly regulatory, not classically cytotoxic.
Macrophages: phagocytosis, tissue remodeling and immune regulation.
Treg cells: suppress harmful maternal anti-fetal responses and support tolerance.

Extravillous trophoblasts do not express classical HLA-A/HLA-B or HLA class II in the usual pattern.
They express non-classical HLA-C, HLA-E, HLA-F and HLA-G → interact with maternal NK-cell receptors and limit cytotoxicity.
HLA-G and local cytokines support controlled trophoblast invasion, placentation and fetal growth.

Adaptive immunity: increased regulatory/Treg activity and relative reduction of harmful cytotoxic responses.
Th1/Th2 model: successful pregnancy was classically associated with a relative Th2 predominance; current view emphasizes a dynamic Th1/Th2/Th17/Treg balance.
Innate immunity remains functional → protects the mother against infection and contributes to placentation.
Estrogen and progesterone: modulate immune-cell recruitment, differentiation and cytokine production.
Placental separation and trophoblast HLA expression → reduce direct maternal recognition of fetal antigens.

Immune development begins early but remains functionally immature at birth.
Granulocytes: appear in fetal liver/spleen from about 8 weeks.
T cells and B cells: detectable from about 8 weeks; fetal immune responses remain limited.
Fetal immunoglobulin production is low because the intrauterine environment is relatively antigen-free; IgM is the main antibody produced in utero.
Maternal IgG crosses the placenta via FcRn-mediated transport, mainly from the 2nd trimester and increasingly in the 3rd trimester.
Preterm infants receive less transplacental IgG → increased susceptibility to infection.
IgM, IgA, IgD and IgE do not cross the placenta in clinically significant amounts.

Maternal IgG is protective, but pathogenic IgG can cross the placenta → hemolytic disease of the fetus/newborn and neonatal lupus.
Abnormal immune tolerance or placentation may contribute to miscarriage, preeclampsia, fetal growth restriction and preterm birth.
Exam sequence: semi-allogeneic fetus → placental/trophoblast interface → HLA and Treg-mediated tolerance + regulated uNK activity → pregnancy maintenance with preserved infection defense.