Thinking outside the box: Mechanisms of environmental selective pressures on the outcome of the materno-fetal relationship

PROBLEM: Study of mechanisms causing spontaneous abortion of the vascularized placenta have focused primarily on the feto-maternal immunological relationship within the pregnant mother. The Th1 cytokines such as tumor necrosis factor (TNF)-alpha + interferon (IFN)-gamma derived in part from natural killer (NK) and NKgammadeltaT cells have been implicated in causing abortion via up-regulation of the novel prothrombinase fgl2 at the feto-maternal interface; Th2/3 cytokines such as interleukin (IL)-10, progesterone-induced blocking factor (PIBF), and TGF-beta2 derived from gammadeltaT cells stimulated by embryo antigens in the context of the OX-2 (CD200) tolerance signal have been viewed as counteracting the Th1 effect. These mechanisms are distinct from those causing and preventing occult pregnancy loss during the periimplantation phase of pregnancy prior to development of a vascularized placenta. Spontaneous abortions in the CBA/J x DBA/2 can be boosted by injecting TNF-alpha + IFN-gamma, but the boosted abortion rates can range from less than or equal to 30 to > 80%, depending on the loss rate in uninjected mice, and this is not explainable by the endogenous level of these cytokines. Furthermore, there is a poor correlation between Th1/Th2,3 cytokine ratios and abortion rates. Could there be a third factor involved, and if so, what might this mean? METHODS: Known precipitants of recurrent abortion in mice were reviewed with particular attention to stress and endotoxin absorption. The effect of antagonizing the response to bacterial lipopolysaccharide (LPS) (endotoxin) was tested. Data on environmental selective pressures were considered (i.e. thinking outside the 'box' which typifies the conventional approach to thinking about materno-fetal interactions). RESULTS: Th1 cytokine-triggered abortions appear to depend on availability/presence of LPS. CONCLUSIONS: Environmental selective pressures are implicated in eliminating 'genetically weaker' embryos in early pregnancy.