Alterations in T-cell signal transduction molecules associated with recurrent spontaneous pregnancy loss.
Clinical evidence suggests that cell-mediated immunity is altered during pregnancy and that failure to suppress the maternal immune response can lead to placentation failure, resulting in partial or total rejection of the fetus. In contrast to women experiencing recurrent spontaneous abortions (RSA), normal uncomplicated pregnancies are associated decreased T-cell proliferation and production of Th1 cytokines and increased T-cell apoptosis. This study addresses a circulating factor in normal pregnancy that may mediate these events. Sera were obtained from three groups: pregnant women who have uncomplicated term deliveries (Group 1, n = 8), pregnant women with a history of RSA, who subsequently abort (Group 2, n = 10), and age-matched non-pregnant female controls (Group 3, n = 8). Pregnancy sera were obtained between 10 and 12 weeks of gestation. Using chromatography, a CD3-zeta inhibitory factor (or analogous fraction) was isolated from each patient within each group and incubated with cultured T-cells, Jurkat and HUT-78 cells. Apoptosis was assayed by a cell-death ELISA and IL-2 production by cytokine-specific ELISA. Apoptosis regulatory proteins and signaling molecules were analyzed by western immunoblotting. Group 1 material induced a significant increase in apoptosis versus Groups 2 and 3. No significant apoptosis was observed between Groups 2 and 3. Material from Group 1 resulted in an increase in the bax expression compared to Groups 2 and 3 (P < 0.001), while no significant differences were observed in the expression of bcl-2. IL-2 secretion was inhibited 2.8-fold by material from Group 1 compared to Groups 2 and 3. Group 1 material decreased the expression of CD3-zeta, JAK3 and STAT5 compared to Groups 2 and 3 (as defined by densitometric units). Circulating materials from normal pregnancies are associated with increased lymphoid apoptosis, possibly through increased bax, and diminished production of the Th1 cytokine, IL-2. Our findings indicate that women experiencing RSA fail to suppress CD3-zeta and JAK3, suggesting a deficiency in this circulating factor that induces their suppression in normal pregnancy.
Taylor
Douglas D
DD
Department of Obstetrics and Gynecology, University of Louisville, School of Medicine, 511 S. Floyd Street, MDR 420, Louisville, KY 40202, USA. ddtaylor@louisville.edu
Gercel-Taylor
Cicek
C
D000026:Abortion, Habitual / Q000276:immunology* / Q000378:metabolism*; D000328:Adult; D017209:Apoptosis; D017252:CD3 Complex / Q000378:metabolism; D045744:Cell Line, Tumor; D002850:Chromatography, Gel; D004268:DNA-Binding Proteins / Q000378:metabolism; D020964:Embryo Loss / Q000276:immunology* / Q000378:metabolism*; D005260:Female; D006801:Humans; D007376:Interleukin-2 / Q000378:metabolism; D053616:Janus Kinase 3; D008894:Milk Proteins / Q000378:metabolism; D011247:Pregnancy; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D050799:STAT5 Transcription Factor; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism
D017252:CD3 Complex; C121704:CD3 antigen, zeta chain; D004268:DNA-Binding Proteins; D007376:Interleukin-2; D008894:Milk Proteins; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; D011505:Protein-Tyrosine Kinases; C507933:JAK3 protein, human; D053616:Janus Kinase 3