Alterations in humoral immune responses associated with recurrent pregnancy loss.

OBJECTIVE: To investigate the reactivity of maternal antibodies with endometrium-derived antigens and to correlate their association with recurrent pregnancy loss (RPL). DESIGN: Prevalence study. SETTING: Academic research center. PATIENT(S): Nulliparous women (n = 10), women with RPL (n = 15), pregnant women (n = 8), and multiparous women with a normal obstetric history (n = 20). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Reactive antibodies were analyzed by Western immunoblot techniques and quantitated by densitometry. RESULT(S): Antibodies from women with RPL and multiparous women recognized antigens ranging from 10-120 kd on normal endometrium and endometrial tumors. Antibodies from most women with RPL (10/15) and from multiparous women (15/20) recognized 65-kd and 80-kd proteins in normal endometrium. Antibodies from women with RPL recognized 21-kd and 28-kd antigens (12/15 and 13/15, respectively) in endometrial tumors at a significantly greater rate (than did antibodies from multiparous women (5/20 and 8/20, respectively). Women with RPL had significantly lower levels of asymmetric IgG compared with controls. CONCLUSION(S): Recurrent pregnancy loss may be linked with the failure to elicit asymmetric IgG and a unique immunologic recognition of endometrial antigens.

Immune recognition of endometrial tumor antigens induced by multiparity.

OBJECTIVE: The risk of developing endometrial cancer is reduced with increasing parity. The purpose of this study was to investigate the possibility that maternal immunization against fetal antigens might be elicited during pregnancy and, if so, to characterize antigens reactive with this immune response. METHODS: Sera were obtained from nulliparous (n = 9) and multiparous women (n = 14). Cellular proteins were isolated from normal endometrium and cultured cells from early (HEC-1A) and late (KLE and RL95-2) stage endometrial cancers. These were separated by SDS-PAGE and those proteins reactive with each individual's serum were assessed by Western immunoblot. Reactive proteins were isolated from KLE tumor cells by immunoaffinity columns. Three commonly recognized proteins were identified, separated, and processed for internal microsequencing. RESULTS: Sera from multiparous women, used as primary antibodies, recognized multiple bands on endometrial tumors, ranging from 10 to 120 kDa. Several antigens were commonly recognized by the sera of multiparous women. The three commonly recognized proteins, normally expressed by fetal tissues, were identified as cystatin A (10 kDa), epidermal fatty acid binding protein (18 kDa), and keratin 10 (54 kDa). Nulliparous women failed to recognize these antigens. CONCLUSION: These findings suggest that certain antigens expressed by the fetus and/or the placenta immunize women during pregnancy. This immune response may protect these women from developing endometrial cancer and explain epidemiologic findings. Future studies will explore the utility of these reexpressed fetal antigens as possible targets for active immunotherapy.

Induction of immune responses to ovarian tumor antigens by multiparity.

OBJECTIVE: Because epidemiologic data indicate a reduction in ovarian cancer risk with increased parity, the occurrence of maternal immunization against ovarian tumor-associated antigens during pregnancy was investigated. METHODS: Sera were obtained from nulligravid and multiparous women and from men. Cellular proteins were isolated from four ovarian tumor cell lines as well as from normal ovaries. These proteins were separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and the presence of cellular proteins reactive with each individual's serum was assessed by Western immunoblot. Tumor-reactive antibodies from two multiparous women were used to prepare immunoaffinity columns for the isolation of reactive proteins from ovarian tumor cells. These immunoaffinity-purified antigens were transferred electrophoretically to nitrocellulose membranes, stained with Ponceau S, and identified by amino acid sequencing. RESULTS: Western immunoblot analysis of the cellular proteins from four established ovarian tumor cell lines using sera from multiparous women as the primary antibody indicated that these samples recognized multiple bands on ovarian tumors, ranging from 30 to 150 kD. Two commonly recognized proteins were isolated and subjected to microsequencing, which identified the 56-kD band protein as elongation factor-1 alpha and the 38-kD protein as nucleophosmin/B23 protein. Both of these proteins play integral roles in cell growth. CONCLUSION: These findings suggest that certain antigens expressed by the fetus immunize women during pregnancy. This immune response may protect these women from the subsequent development of cancer.