Objectives: Biased Th1 immunity to trophoblast and defective Th2 cytokine production by decidual T cells have been associated with RPL. The underlying genetic mechanisms remain to be elucidated. Our preliminary studies did not show association of polymorphisms of the IFNG gene and the TNFA promoter region with Th1 immunity to trophoblast. Because IL-1 may influence either Th1 or Th2 immune response, in the present study, we investigated whether polymorphisms of the IL1B and IL1RN genes influence Th1 immunity to trophoblast in women with RPL. Design: A case control study was performed in Caucasian women with a history of three or more pregnancy loss from the Center for Reproductive Medicine of our hospital. Patients were grouped into Th1(+) and Th1(−) subgroups depending upon IFN-γ production by their trophoblast-stimulated PBMC in vitro as evidence of Th1 immunity to trophoblast. Caucasian women with a history of two or more successful pregnancies and no pregnancy loss were recruited as fertile controls. Materials and Methods: Diallelic polymorphisms of the IL1B gene at positions −511 and +3953 were analyzed using PCR-restriction fragment length polymorphism (RFLP) methods and tandem repeat polymorphism of the IL1RN gene was analyzed by PCR and gel electrophoresis. IFN-γ production by trophoblast-stimulated PBMC was determined by ELISA. Data were statistically analyzed by Fisher’s Exact Test or by Kruskal-Wallis one way ANOVA and Mann-Whitney rank sum Test. Results: The frequency of IL1B-511 allele 1 was significantly increased in the Th1(+) RPL group (allele n=96) compared to fertile controls (allele n=122) (76% vs. 51.6%; P =0.0002), compared to the Th1(−) RPL group (allele n=92) (76% vs. 60.8%; P =0.028). An increased frequency of this allele was confirmed in a second Th1(+) RPL group (allele n=84), compared to fertile controls (67.8% vs. 51.6%; P =0.022). These changes correlated with an increased frequency of the homozygotes for IL1B-511 allele 1 in the two Th1(+) RPL groups compared to fertile controls ( P =0.0023). No significant difference in the allelic frequencies of IL1B+3953 and ILRN gene polymorphisms was observed between all the study groups. The high level IFN-γ production by trophoblast-stimulated PBMC was associated with IL1B-511 allele 1 in women with RPL ( P <0.05). Conclusions: These results suggest that polymorphism of the IL1B promoter region may influences Th1 immunity to trophoblast in women with RPL and IL-1 may be involved in the regulation of Th1/Th2 cytokine production in human reproduction.</P>
Fertility and Sterility – Elsevier
Published: Sep 1, 2000
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