Norbert Gleicher

Activity of natural killer cells in normal pregnancy and edema-proteinuria-hypertension gestosis

Natural killer cytotoxicity of peripheral blood lymphocytes in normal pregnancy and edema-proteinuria-hypertension (EPH) gestosis was investigated and compared to natural killer cytotoxicity in lymphocytes of normal nonpregnant control donors. These lymphocytes were also compared for their ability to respond to interferon treatment in vitro. Natural killer activity was found to be only slightly decreased in normal pregnant women but was found to be increased in patients with EPH gestosis. Interferon treatment of peripheral lymphocytes caused strong enhancement of natural killer activity in lymphocytes of normal pregnant women but resulted in only weak activities in lymphocytes from patients with EPH gestosis. We consequently concluded that pre-natural killer lymphocyte subpopulations from patients with EPH gestosis have already been activated by a presently still unknown stimulator.

Autoantibodies in Normal and Abnormal Pregnancy

ABSTRACT: Abnormal autoimmune function has been associated with reproductive failure for decades. In fact, all medical conditions historically associated with pregnancy loss (and on occasion infertility) are now recognized to have an autoimmune etiology. It is therefore quite surprising that only less than a decade ago a correlation between the presence of abnormal autoantibodies and pregnancy loss was reported for the first time. Since reproductive failure, similar to other abnormal autoimmune states, is not a monoclonal event, we have established that affected patients demonstrate polyclonal autoantibody abnormalities including a variety of nonorganospecific as well as organspecific autoantibody groupings. For example, patients with repeated pregnancy loss will exhibit abnormal levels of anti‐phospholipid antibodies (PA).

Autoantibodies and pregnancy history in a healthy population.

OBJECTIVEnOur purpose was to determine whether the presence of autoantibodies is associated with pregnancy history in healthy adults.nnnSTUDY DESIGNnAntibodies against phospholipid, histone, and nucleotide antigens were determined in 102 male and 99 female subjects. The effects of age, sex, marital status, and pregnancy history on antibody positivity were assessed.nnnRESULTSnWomen showed higher levels of autoantibodies, but differences were not statistically significant in this sample. Age was not associated with antibody positivity in men. In women age was associated with positivity for (1) immunoglobulin G antibodies (p = 0.009), (2) antihistone antibodies (p = 0.024), and (3) more than one antibody (p = 0.020). Immunoglobulin M antibodies were more common in unmarried than married females (p = 0.020). In contrast, the prevalence of immunoglobulin G antibodies was increased in married women, although differences did not reach statistical significance (p = 0.167). Gravidity and history of fetal loss were not associated with increased antibody positivity. In subjects in whom follow-up data were available, positive antibody titers were not associated with subsequent adverse pregnancy outcome.nnnCONCLUSIONSnIn this population autoantibodies are not associated with adverse pregnancy outcome. However, an increased prevalence of immunoglobulin M in unmarried women and immunoglobulin G in married women suggests that a switch from immunoglobulin M to immunoglobulin G autoantibodies is associated with marriage, as a result of either exposure to semen or trophoblast antigens.

The Biology of Immune Complexes and Their Possible Role in Pregnancy

The formation of antigen-antibody complexes, which are then phagocytized, is, of course, a crucial component in the body’s normal defense against pathogens and other foreign substances. Physiologic immune responses are designed to eliminate or neutralize antigens and thus protect the host. Under some circumstances, however, immune complexes (ICs) may induce inappropriate activation or inactivation of either humoral or cellular immunologic effectors. The humoral mechanism most often involved in IC pathogenicity is the complement (C) system. The cellular mechanism that usually mediates IC-induced injury is the polymorphonuclear cell, which interacts with the IC, resulting in the release of hydrolytic and lysosomal enzymes that produce inflammation and tissue injury. Research has recently clarified many factors involved in the formation, removal, and localization of ICs, and the mechanisms of IC-induced biologic functions as well as inflammatory reactions. Immune complexes have assumed the role of regulatory factors in immune responses because they can interact with antigen receptor-bearing lymphocytes and subpopulations of T and B cells, as well as with unclassified lymphocytes and macrophages having Fc and C receptors. Additionally, as IC-mediated activities and immunopathologic consequences become clearly established, and as new techniques for demonstrating ICs in tissues and biologic fluids are developed, considerable evidence substantiates the primary pathogenic significance of ICs in a variety of animal and human diseases, including infectious, autoimmune, and neoplastic disorders. Immune complexes may form as a result of or during normal pregnancy, probably via the following main circumstances: First, ICs can result from the normal immune response of the mother against paternal histocompatibility and blood group antigens as well as other fetal antigens that covertly pass the placenta in the form of fetal cells and perhaps soluble antigens and enter the maternal circulation. Of course, due to transplacental passage of maternal IgG antibodies, such ICs may also form in the fetus. Second, in situations where the mother has an autoimmune disease, eg, systemic lupus erythematosus (SLE), IgG maternal autoantibodies may enter the fetal circulation and form ICs with circulating or tissue-fixed fetal antigens.

The complexes in pregnancy

Abstract Seventeen patients during the third trimester of pregnancy with associated immune complex disease and/or immune complex state and their infants cord blood were investigated for the presence of immune complexes. In comparing maternal levels of immune complex in normal third-trimester pregnancies to the study group, no statistical significant difference was noted. However, levels in cord blood were significantly lower (p

Fetal and Maternal Red Cell Immune Adherence (RCIA) Receptors

ABSTRACT: The addition of autologous serum to mixtures containing human red cells, from pregnant and nonpregnant females, and sheep red cells resulted in the formation of mixed aggregates containing both human and sheep red cells. In contrast, no aggregate formation occurred when autologous cord serum was addded to mixtures containing cord red cells and sheep red cells. Heat inactivation of the adult serum or the presence of 0.15 M EDTA prevented the formation of mixed aggregates. These observations indicated that the mixed aggregates occurred through the complement‐dependent red cell immune adherence (RCIA) phenomenon. The addition of untreated cord serum to mixtures containing inactivated adult serum restored the formation of mixed aggregates, indicating that the cord serum contained sufficient complement for RCIA. Natural antibody against sheep red cells was present in adult sera but was absent in cord sera.

Introduction—The Worldwide Collaborative Observational Study and MULTI‐Analysis on Allogeneic Leukocyte Immunotherapy for Recurrent Abortion

The concept of immunotherapy with allogeneic leukocytes has become increasingly controversial, especially as some of the theoretical considerations in support of such treatment have been questioned. Initially, the hypothesis was that increased sharing of histocompatiblity antigens (HLA) between partners predisposes to recurrent pregnancy loss (it was proposed that such immunogenetic compatibility prohibits the proper activation of immunologic processes essential for pregnancy maintenance). The concept of activation failure was also supported by the hypothesis that mixed lymphocyte cultures in affected couples were hyporesponsive and could be properly activated through immunotherapy of the female that would involve further exposure to (paternal) antigens through leukocyte immunization. However, mixed lymphocyte culture has also proven to be an unreliable marker of either miscarriage risk or treatment success.I Stripped of these theoretical arguments in support of leukocyte immunotherapy, proponents of such treatment correctly argued that the mere facts that neither HLA typing nor mixed lymphocyte cultures were predictive of repeated miscarriage risk did not necessarily indicate that the concept of leukocyte immunization in itself was mistaken. In a number of studies a claim was made that leukocyte immunotherapy was effective since pregnancy success increased with such therapy. Opponents of such therapy were not convinced by the presented data in support of improved pregnancy outcome and therefore strongly argued against the clinical use of leukocyte immunization. It was at that stage that the American Society for Reproductive Immunology (ASRI) stepped in. Recognizing that prospectively randomized studies of sufficient sample size were probably years away from providing convincing answers, the ASRI decided to pursue the second-best option. Through the ASRIs Ethics Committee, a worldwide collaborative study was established (Dr. Coulam-designed) that was to reevaluate and reanalyze all available data in regard to leukocyte immunization (and related techniques). This effort was undertaken not only because of its obvious scientific merits but also because of its immediate clinical implications. The ASRI felt that NORBERT GLEICHER, M.D.

Reproductive Immunology News

The NICHD once again has provided the AJRI with grant summaries of projects in reproductive immunology awarded grant funding for fiscal year 1983. In each issue of Volume 6, we will feature descriptions of some of those grants. The information given in each summary was provided in the grant applicaiton by the principal investigator. n n n nThe Editorial Board of the AJRI would like to thank the NICHD for its cooperation in regard to this feature of the Reproductive Immunology News section of the Journal It is their hope that continuing to publish this information will continue to facilitate increased communication among investigators in the field of reproductive immunology.

Rheumatic heart disease diagnosed during pregnancy: a 30-year follow-up.

One hundred one patients originally diagnosed as having rheumatic heart disease (RHD) during the years 1945–1948 were reevaluated in 1975 to determine the natural history of the disease. Twenty patients (19.8%) showed no sign of RHD. Of the patients with confirmed RHD, 56 (70.0%) had their original lesion confirmed, while 23 (28.8%) had developed additional valvular involvement. Pure mitral stenosis resulted in significantly lower mortality than all other valvular lesions, and congestive heart failure was the leading cause of death. Nineteen patients underwent cardiac surgery; the mortality in this group (52.6%) was not significantly higher than that in the overall RHD group (38.8%). False diagnosis of RHD during pregnancy is common. A more thorough evaluation of the “cardiac murmur of pregnancy” is advocated.

Fertility Control in the Female Patient with Medical Disease

Fertility control for the female patient with medical disease has attracted only limited attention in the medical literature. It has been stated in conjunction with cardiac disease that the occurrence of a medically contraindicated pregnancy represents the failure of the medical community to appropriately counsel and treat the patient with cardiac disease.1 The same applies to any other medical disorder affecting a female during her reproductive years. Although standard medical texts frequently refer to advice concerning termination of pregnancy in medically contraindicated pregnancy situations, only very limited reference is generally made to the far more important aspects of preconceptional counseling. Appropriate family planning advice to the female with medical disease is important in reference to the contraindication of pregnancy and, more often, in reference to a particular choice of contraceptive in view of a specific disease situation. Furthermore, appropriately controlled medical care in very early gestational stages may be particularly important with certain disease states in order to prevent early injury to the fetus. Consequently, the availability of planned conception to many patients with medical disease will improve both maternal and fetal outcomes.