Monkeys with excellent reproductive histories were immunized with the laminin peptides YIGSR, RGD, IKVAV, and YD, a control sequence with no known biological function. Sera from the YIGSR-immunized monkey became toxic, causing neural tube defects in whole rat embryo cultures, and this monkey experienced fetal loss after immunization. Sera from the RGD-immunized monkey also became embryotoxic in culture after immunization, but this monkey appeared to become infertile as she failed to initiate a pregnancy for at least 2 years after immunization. In contrast, embryos cultured on sera from the IKVAV-or YD-immunized monkeys were predominantly normal and both monkeys completed successful pregnancies. Antibody levels to the respective peptides or to laminin were not predictive of embryotoxicity, but antibody binding to homogenized yolk sacs as well as to yolk sacs of cultured embryos was associated with sera embryotoxicity and reproductive outcomes in vivo. These observations suggested that the laminin sequences YIGSR and RGD may play a role in immune-mediated reproductive failure by reacting directly with embryonic tissue and could provide a basis for identifying individuals at risk for both spontaneous abortion and infertility.Immune dysfunction has been implicated in recurrent pregnancy loss (1). For example, isolated T cells from recurrent aborters were found to secrete embryotoxic cytokines in response to trophoblast cells (2), while a direct role of autoantibodies in fetal loss has been implicated for women with autoimmune diseases, such as systemic lupus erythematosus (3) and herpes gestationis (4). Anti-phospholipid autoantibodies particularly have been associated with spontaneous abortions (5), but their presence alone could not predict poor pregnancy outcomes (6). Therefore, there has been a need to identify specific autoantibodies responsible for reproductive failure and to establish their mechanisms of pathogenicity (7).Anti-laminin autoantibodies were detected in the sera of some monkeys with histories of reproductive failure, and sera from these monkeys caused neural tube defects in cultures of whole rat embryos (8). When monkeys with excellent reproductive histories were immunized with intact murine laminin, their sera became embryotoxic, again causing neural tube defects in rat embryo cultures, and these monkeys subsequently failed to reproduce (9). When pregnant mice were injected with heterologous anti-laminin antibodies, they spontaneously aborted (10). However, sera from lamininimmunized rats were not consistently embryotoxic and sera anti-laminin antibody levels were not predictive of embryotoxicity (11). These toxic and nontoxic sera were found to recognize different epitopes on Western blots of enzymedigested laminin, suggesting that antibodies to only certainThe publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact. laminin epitopes were r...