Why Don't Women Mount A Immune Attack On The Foetus?

This is one of the oldest puzzles that have confounded Immunologists. The father, and thus the foetus, often contain major histocompatibility antigens that are distinct from those carried by the pregnant woman. Yet, the foetus is almost never immunologically attacked by the maternal immune system. There are several reasons for this.

The placenta is of foetal origin. The outermost layer of the placenta, called the trophoblast, is poor in both MHC Class I & Class II antigens, thus reducing the risk of attack by maternal T cells. However, not expressing MHC Class I antigens does open up the trophoblast to attacks from Natural Killer (NK cells). It does express a weakly antigenic MHC Class I molecule called HLA-G. This interacts directly with the two main inhibitory receptors on NK cells- KIR-1&2, and thus keeps the NK cells at bay.

Secondly, the placental tissue produces an enzyme called IDO- indoleamine 2,3 dioxygenase. This degrades the tryptophan contained in T cell proteins, and makes these T cells less likely to become activated.

Thirdly, it is thought the specific T cells that the mother does have against major and minor paternal antigens become temporarily anergic to these antigens. This tolerance disappears after the baby is delivered.

Fourthly, regulatory T cells such as CD4 CD25 T-reg cells may play a part by suppressing Th1 responses in particular. Thus, cytokines such as IL-4, IL-10 & TGF-beta predominate in the placenta, which steer the T-cell response away from the more stridently inflammatory Th1 phenotype to Th2 and T-reg phenotypes.

The foetus is not the only "tissue" that's exempt from immune attacks. There are three other sites in the body- namely the brain, the anterior chamber of the eye, and the testes, which are normally sequestered from the immune system. They are thus "immunologically previleged". The brain and the anterior chamber of the eye lack lymphatics, and the brain is also separated physically by the blood brain barrier. This sequestration does occasionally break down, resulting in autoimmune conditions such as multiple sclerosis, but in general, this phenomenon of immune previlege explains why HLA-matching is not required for transplants in these regions such as corneal grafts, and also why such grafts are quite long-lived.

No such tolerance exists outwith pregnancy. When organs such as kidney, etc are transplanted into the (MHC matched) female of the species from the male, the female's T-lymphocytes recognise the foreign proteins translated from genes on the Y chromosome of the male, and attacks them, thus increasing risk of graft failure. This does not happen with female--> male transplants, as both have common proteins translated from the mRNA transcripts of the X-chromosome. This phenomenon is known as H-Y, and explains why a solid organ or bone marrow transplant from female to male is more likely to succeed than a male to female transplant, although modern immuno-suppressive regimes have narrowed the gap.