The self- /non-self-theory has pitfalls, and pregnancy is the main one for opponents. Antonio Countinho sees the immune system as: (a) networks, including anti-self natural autoantibodies12 and idiotype/anti-idiotype antibodies/T-cells. This has been relatively poorly studied in allopregnancy, despite reports13,14 that might be relevant to effects of intravenous immunoglobulins (IVIG) for recurrent spontaneous abortions (RSA). Matzinger’s ‘danger theory’15 stems from discussions on pregnancy with Robert Schwab (June 16, 1998 New York Times). For her, it implies that the immune system does not function by self /non-self, but instead reacts

to ‘danger’ signals such as inflammation, apoptosis, and bleeding. Thus, healthy foetuses are not rejected, simply because they do not send alarm signals. However, should Src inhibitor they become infected, the mother, in clearing infection, also rejects the foetus. ‘The danger model’ predicted an important role for antigen presenting cells (APCs) in turning tolerance on or off, and specific ‘danger receptors’, subsequently identified as Toll-like receptors. It offers an apparently elegant, though tautological, explanation

of allopregnancy INK128 as ‘it does not elicit danger’. Polly Matzinger states further: ‘reproduction cannot be a danger’…. ‘it does not make evolutionary sense’. This also explains why a conceptus still thrives in a pre-immunised host, as grafting produces micro wounds and local bleeding, while the foetus does not seem to do so. Danger was enunciated before the 1989–1991 papers describing implantation as requiring local inflammation and ignores that invasion is accompanied by apoptosis,16 local bleeding and in equids there are zones of quasi rejections in the placenta with a massive maternal lymphocytic infiltrate.17 Rebamipide It is also difficult to explain by the danger model why, in murine abortion,18 some foetuses are rejected, whereas in the same mother, others are not, both being not infected.

However, CBA × DBA/2 embryos can be rescued by pre-culture in CSF-conditioned medium before transfer to a CBA foster mother, suggesting that these embryos are not fully ‘normal’.19 Danger might explain why the CBA × DBA/2 system is environmentally dependent,20 although surprisingly, the LPS content of faeces does not correlate with abortion.21 Danger, however, does not explain why CBA × DBA/2 and DBA/2 × CBA matings are seen differentially (gene imprinting experiments of A. Paldi) and why immunisation against paternal MHC antigens corrects ‘danger’,22 even how immunisation permits pregnancy in case of donkey embryos implanted in mare (the donkey in horse pregnancy).15 Finally, Matzinger did not envisage alloantigen-specific mechanisms regulating only the anti-foetal reactions. Moreover, what she describes is exactly opposite to some cases of infections, such as local, e.g. uterine Listeria.