Systemic alterations of the maternal inflammatory and immune system occur during pregnancy. These changes alone are unlikely to be responsible for the acceptance of the fetal semiallograft. Numerous local events at the maternal-fetal interface appear to be more important. The alterations of the maternal inflammatory and immune systems are subtle enough for no significant increase of infections or malignancy to be apparent. However, 75% of women with rheumatoid arthritis are clinically improved during pregnancy. The effects of pregnancy on polymorphonuclear cells are not likely to be responsible because cell function actually appears enhanced in vivo, despite the fact that pregnancy serum is suppressive in vitro. There is no clear evidence for reduction of monocyte/macrophage function during pregnancy, either in vivo or in vitro. It is unlikely that modulation of B cell phenotype or function is responsible because no suppression is noted, either in vivo or in vitro. Selected products of B cells, immune complexes, appear to be reduced during pregnancy. In patients, the reduction in the concentration of complexes may be due to adsorption by the placenta. The importance of this reduction as a causative factor in the improvement of women with rheumatoid arthritis during pregnancy remains to be determined. Natural killer cell cytotoxicity is decreased during pregnancy. This may in part be due to the release of progesterone induced blocking factor. It is also possible that circulating factors, capable of inhibiting IL-2 release or IL-2 function in vivo, might be responsible. Natural killer cytotoxicity can be normalized by incubation with IL-2. It is unclear how the reduction of natural killer cell activity might systemically affect inflammation or immunity in vivo during pregnancy. In vivo delayed type hypersensitivity appears somewhat reduced during pregnancy. This observation appears consistent with the improvement of rheumatoid synovitis, which is also thought to be T cell mediated. T cell function, measured in vitro, generally appears normal. However, most recent studies have employed mitogens, such as PHA, which is not physiological. Subtle defects involving antigen processing or antigen presentation might be missed in this system. These observations suggest that circulating factors might be important in modulating the cell mediated immune system, in vivo, during pregnancy. While anti-HLA-DR antibodies eluted from the human placenta may be effective therapy in patients with rheumatoid arthritis, their occurrence is too infrequent to account for the improvement seen in afflicted patients. Cortisol in physiological concentrations found during pregnancy is capable of reproducing the suppressive effects of pregnancy serum on T cell activation. Of the other non-specific factors, PAPP-A may also contribute to the suppressive effects of pregnancy serum. Pregnancy associated α2-glycoprotein, α-fetoprotein and the placental proteins appear less important or not relevant. Although studies in recent years have examined circulating cells in order to understand better the systemic effects of pregnancy on the inflammatory and immune systems, it appears that circulating non-specific factors are important. How important these factors are in the maternal acceptance of the fetal semiallograft may be a totally different issue.
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