Proteins hitherto linked with tumors may help fetuses evade immune rejection from their mothers, scientists reported this week in the Journal of Immunology. These findings provide a new explanation for a curious scenario -- why mothers don't attack fetal tissue -- and may even present additional clues for other unanswered questions in biology, according to the authors.
Not only could further research into these proteins shed light on both pregnancy, cancer, and immunity, the fact that fetuses are genetically distinct from their mothers makes them interesting models on transplantation, coauthor Lucia Mincheva-Nilsson at Umeå University in Sweden told The Scientist.
The proteins in question include the MHC class I chain related proteins A and B (MICA and MICB), which are up-regulated in cancer, infections, and autoimmune disorders. Membrane-bound MICA and MICB trigger immune responses by binding to the NK cell receptor known as NKG2D on white blood cells, while soluble MIC proteins released by some tumors appear to suppress immune activity.
Mincheva-Nilsson and her colleagues found that human placentas express mRNAs for MICA and MICB. Immunoelectron microscopy determined MIC protein expression was located in the outermost fetal component of the placenta -- known as the syncytiotrophoblast -- both on cell membranes and in microvesicles structurally similar to exosomes.
Enzyme-linked immunosorbent assay (ELISA) experiments revealed that serum from pregnant women possessed hundreds-fold higher levels of soluble MIC proteins than serum from non-pregnant women, and analyses of cultured placenta cells confirmed they released soluble MIC.
What's more, NKG2D expression in the white blood cells of pregnant women was reduced approximately 55% when compared to non-pregnant women -- comparable to the down-regulation of NKG2D expression due to tumor-secreted soluble MIC. Pregnancy serum caused an eight to 10-fold decline in NKG2D expression in incubated white blood cells from non-pregnant women, while such serum treated with antibodies against the MIC proteins did not, suggesting soluble MIC is the main factor behind the reduction. White blood cells treated with pregnancy serum also showed a significant drop when it came to in vitro killing ability when mixed with human leukemia cells.
Mincheva-Nilsson said she plans to examine whether these proteins play roles in pathologies of human pregnancy, such as infertility, miscarriages, or endometriosis. Studying mutations or polymorphisms of the MIC proteins for any changes in immunological activity in pregnancy is also important, Gil Mor at Yale University, who did not participate in this study, told The Scientist. Mincheva-Nilsson added that 3.5% of certain East Asian populations lacked MICA and MICB, but other ligands of NKG2D exist, such as the ULBP proteins, which her team also plans to investigate in pregnancy.
Veronika Groh at the Fred Hutchinson Cancer Research Center, who did not participate in this study, told The Scientist research should investigate whether down-modulating NKG2D has more profound immune suppressive effects by in turn negatively affecting the function of other receptors, as recent work has shown can occur.
However, Jeffrey Platt at the Mayo Clinic College of Medicine, who did not participate in this study, disagreed with some of the researchers' conclusions, noting that pregnant women do experience immune responses toward their fetuses. He suggested an alternative explanation: The MIC proteins help prevent the "maternal immune responses that do arise in response to the fetus from getting out of control," he told The Scientist.
Mor added that he does agree with the conclusions, which suggest a new model of pregnancy may be in order, where the maternal immune system and placenta are not antagonists, but instead work together to fight infection.
While tumors may have adapted this mechanism from placentas, "tumors are more ancient than mammals, dating back at least to the dinosaurs, so maybe placentas have hijacked a tumor mechanism," Mincheva-Nilsson speculated.
Links within this article
L. Mincheva-Nilsson et al. "Placenta-derived soluble MHC class I chain-related molecules down-regulate NKG2D receptor on peripheral blood mononuclear cells during human pregnancy: A possible novel immune escape mechanism for fetal survival." Journal of Immunology, March 15, 2006.
L.B. Schultz. "A new paradigm in immune surveillance." The Scientist, September 22, 2003.
T.P. Toma. "Ligand hides tumors from attack." The Scientist, October 17, 2002.
M. Fogarty. "Researchers find a eukaryotic mRNA policing system," The Scientist, April 29, 2002.
T. Toma. "Finding virus-infected cells," The Scientist, March 7, 2001.
J.D. Coudert et al. " Altered NKG2D function in NK cells induced by chronic exposure to NKG2D ligand-expressing tumor cells" Blood, September 1, 2005.