Immunological puzzle related to recurrent miscarriage: Overview

The maternal immune-system must be modified in order to tolerate the semi-allogeneic conceptus. Because maternal alloreactive lymphocytes are not depleted, local mechanisms have to play a key role in altering the immune response. Both humoral and cellular immunity are affected. Th1/Th2 cytokine balance is not essential to have normal pregnancies. Alloreactive Th1 cells must be regulated, for instance, by regulatory T cells. Animal and human experiments showed that Treg number and/or function are diminished in spontaneous abortions. Miscarriage can be prevented by transfer of Treg from normal pregnant mice. Treg at the maternal-fetal interface avoid fetal allo-rejection by means of the creation of a "tolerant" microenvironment characterized by expression of IL-10, TGF-β, HO-1 and IDO, rather than diminishing the Th1 cytokines. Treg or CTLA-4 expression on Treg enhances IDO expression. T-regFoxp3+ can increase placental HO-1. In turn, HO-1 may lead to up-regulation of TGF-β, IL-10 and CTLA-4. The role of progesterone, β-HCG and hPGH and their relation to uNK cell and Treg activity are discussed. A new linking between trophoblast apoptosis, Treg, aPL and NK cell is also raised. Finally, a relationship between HLA-haplotypes and HLA-G molecule, Babs, NK cells, Th1/Th2/Th3/Tr1/Treg balance, aPL and cytotoxic TCD8+, CD4+ is discussed. © 2009 Bentham Science Publishers Ltd.