This Article Full Text Full Text (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kauma, S. W. Articles by Nilkaeo, A. Search for Related Content PubMed PubMed Citation Articles by Kauma, S. W. Articles by Nilkaeo, A.

Placental Fas Ligand Expression Is a Mechanism for Maternal Immune Tolerance to the Fetus¹

Departments of Obstetrics/Gynecology (S.W.K., N.H.) and Microbiology/Immunology (S.W.K., T.F.H., A.N.), Virginia Commonwealth University/Medical College of Virginia, Richmond, Virginia 23298

Address all correspondence and requests for reprints to: Dr. Scott Kauma, Departments of Obstetrics/Gynecology and Microbiology/Immunology, Virginia Commonwealth University/Medical College of Virginia, Box 980034, Richmond, Virginia 23298.

Fas ligand (FasL) is a peptide that plays an important immunoregulatory role in limiting the host immune response. Several studies have shown that the expression of FasL in the anterior chamber of the eye and the testis allows these tissues to be immunoprivileged sites. Immunotolerance is achieved by binding of FasL to its receptor (Fas) on activated immune cells, which results in cell apoptosis. To determine whether FasL has a role in maternal immune tolerance to the fetus, we looked for the expression of FasL in the human placenta. Immunoperoxidase staining localized FasL to both syncytiotrophoblast and cytotrophoblast in placental villi and chorionic extravillous trophoblast. Western analysis demonstrated FasL in placental villi and a human first-trimester trophoblast cell line (ED₂₇). In contrast, Fas was colocalized to CD45 (leukocyte common antigen) positive cells found in maternal decidua. When isolated peripheral blood lymphocytes were induced to express Fas with phytohemagglutinin (PHA) and interleukin-2 (IL-2) and then cocultured with trophoblast, 30% of the lymphocytes underwent apoptosis, as determined by the in situ death (TUNEL) assay. Neutralizing antibodies to FasL inhibited apoptosis by 40% in these studies. In contrast, activated lymphocytes cocultured with non-FasL-expressing fibroblasts or unactivated non-Fas-expressing lymphocytes cocultured with ED₂₇ trophoblast showed little evidence of apoptosis. These findings suggest that FasL expressed by fetal trophoblast cells can induce apoptosis in activated lymphocytes there by providing a mechanism for maternal immune tolerance to the fetus.

This article has been cited by other articles:

				A. Kaponis, A. Skyrlas, N. Zagorianakou, I. Georgiou, V. Passa, E. Paraskevaidis, and G. Makrydimas Coelomic cells show apoptosis via Fas/FasL system: a comparative study between healthy human pregnancies and missed miscarriages Hum. Reprod., May 1, 2008; 23(5): 1159 - 1169. [Abstract] [Full Text] [PDF]

				V. Minas, U. Jeschke, S.N. Kalantaridou, D.U. Richter, T. Reimer, I. Mylonas, K. Friese, and A. Makrigiannakis Abortion is associated with increased expression of FasL in decidual leukocytes and apoptosis of extravillous trophoblasts: a role for CRH and urocortin Mol. Hum. Reprod., September 1, 2007; 13(9): 663 - 673. [Abstract] [Full Text] [PDF]

				L. K. Harris, R. J. Keogh, M. Wareing, P. N. Baker, J. E. Cartwright, J. D. Aplin, and G. S. J. Whitley Invasive Trophoblasts Stimulate Vascular Smooth Muscle Cell Apoptosis by a Fas Ligand-Dependent Mechanism Am. J. Pathol., November 1, 2006; 169(5): 1863 - 1874. [Abstract] [Full Text] [PDF]

				B. Selam, U. A. Kayisli, G. E. Akbas, M. Basar, and A. Arici Regulation of FAS Ligand Expression by Chemokine Ligand 2 in Human Endometrial Cells Biol Reprod, August 1, 2006; 75(2): 203 - 209. [Abstract] [Full Text] [PDF]

				S. L. Straszewski-Chavez, V. M. Abrahams, and G. Mor The Role of Apoptosis in the Regulation of Trophoblast Survival and Differentiation during Pregnancy Endocr. Rev., December 1, 2005; 26(7): 877 - 897. [Abstract] [Full Text] [PDF]

				G. W. Wolkersdorfer, C. Marx, J. Brown, S. Schroder, M. Fussel, E. P. Rieber, E. Kuhlisch, G. Ehninger, and S. R. Bornstein Prevalence of HLA-DRB1 Genotype and Altered Fas/Fas Ligand Expression in Adrenocortical Carcinoma J. Clin. Endocrinol. Metab., March 1, 2005; 90(3): 1768 - 1774. [Abstract] [Full Text] [PDF]

				L. Frangsmyr, V. Baranov, O. Nagaeva, U. Stendahl, L. Kjellberg, and L. Mincheva-Nilsson Cytoplasmic microvesicular form of Fas ligand in human early placenta: switching the tissue immune privilege hypothesis from cellular to vesicular level Mol. Hum. Reprod., January 1, 2005; 11(1): 35 - 41. [Abstract] [Full Text] [PDF]

				S. V. Ashton, G. St. J. Whitley, P. R. Dash, M. Wareing, I. P. Crocker, P. N. Baker, and J. E. Cartwright Uterine Spiral Artery Remodeling Involves Endothelial Apoptosis Induced by Extravillous Trophoblasts Through Fas/FasL Interactions Arterioscler. Thromb. Vasc. Biol., January 1, 2005; 25(1): 102 - 108. [Abstract] [Full Text] [PDF]

				S. L. Straszewski-Chavez, V. M. Abrahams, E. F. Funai, and G. Mor X-linked inhibitor of apoptosis (XIAP) confers human trophoblast cell resistance to Fas-mediated apoptosis Mol. Hum. Reprod., January 1, 2004; 10(1): 33 - 41. [Abstract] [Full Text] [PDF]

				V. M. Abrahams, S. L. Straszewski-Chavez, S. Guller, and G. Mor First trimester trophoblast cells secrete Fas ligand which induces immune cell apoptosis Mol. Hum. Reprod., January 1, 2004; 10(1): 55 - 63. [Abstract] [Full Text] [PDF]

				U. A. Kayisli, B. Selam, O. Guzeloglu-Kayisli, R. Demir, and A. Arici Human Chorionic Gonadotropin Contributes to Maternal Immunotolerance and Endometrial Apoptosis by Regulating Fas-Fas Ligand System J. Immunol., September 1, 2003; 171(5): 2305 - 2313. [Abstract] [Full Text] [PDF]

				D. R Balkundi, J. A Ziegler, J. F Watchko, C. Craven, and M. Trucco Regulation of FasL/Fas in Human Trophoblasts: Possible Implications for Chorioamnionitis Biol Reprod, August 1, 2003; 69(2): 718 - 724. [Abstract] [Full Text] [PDF]

				B. Selam, U. A. Kayisli, J. A. Garcia-Velasco, G. E. Akbas, and A. Arici Regulation of Fas Ligand Expression by IL-8 in Human Endometrium J. Clin. Endocrinol. Metab., August 1, 2002; 87(8): 3921 - 3927. [Abstract] [Full Text] [PDF]

				S. Aschkenazi, S. Straszewski, K. M.A. Verwer, H. Foellmer, T. Rutherford, and G. Mor Differential Regulation and Function of the Fas/Fas Ligand System in Human Trophoblast Cells Biol Reprod, June 1, 2002; 66(6): 1853 - 1861. [Abstract] [Full Text] [PDF]

				B. Selam, U. A. Kayisli, N. Mulayim, and A. Arici Regulation of Fas Ligand Expression by Estradiol and Progesterone in Human Endometrium Biol Reprod, October 1, 2001; 65(4): 979 - 985. [Abstract] [Full Text] [PDF]

				D. Ait-Azzouzene, S. Caucheteux, F. Tchang, J. Wantyghem, R. Moutier, A. Langkopf, M.-C. Gendron, and C. Kanellopoulos-Langevin Transgenic Major Histocompatibility Complex Class I Antigen Expressed in Mouse Trophoblast Affects Maternal Immature B Cells Biol Reprod, August 1, 2001; 65(2): 337 - 344. [Abstract] [Full Text] [PDF]

				S. Wongweragiat, R. F. Searle, and J. N. Bulmer Expression of Fas/Fas Ligand by Decidual Leukocytes in Hydatidiform Mole Biol Reprod, March 1, 2001; 64(3): 784 - 789. [Abstract] [Full Text]

				V. D. Dixit and N. Parvizi Pregnancy Stimulates Secretion of Adrenocorticotropin and Nitric Oxide from Peripheral Bovine Lymphocytes Biol Reprod, January 1, 2001; 64(1): 242 - 248. [Abstract] [Full Text]

				N. S. Fedarko, B. Fohr, P. G. Robey, M. F. Young, and L. W. Fisher Factor H Binding to Bone Sialoprotein and Osteopontin Enables Tumor Cell Evasion of Complement-mediated Attack J. Biol. Chem., May 26, 2000; 275(22): 16666 - 16672. [Abstract] [Full Text] [PDF]