Why did your mother reject you? Immunogenetic determinants of the response to environmental selective pressure expressed at the uterine level.

Problem: Maternal "rejection" of the implanted conceptus is considered to account for a significant proportion of miscarriages (abortions) in both humans and animals. Our understanding of mechanisms has been limited, and hence, explanations for nonrejection have remained largely speculative. Losses, when they occur, could represent either random accidental failure of protective mechanisms or a more purposeful discrimination.

From the decidual cell internet: trophoblast-recognizing T cells.

The mammalian fetus has been perceived, paradoxically, as a successful allograft, a successful tumor, and a successful parasite. Success depends on fetal trophoblast cells, which form the interface with the mother. The maternal immune system is involved in the success of pregnancy and in its failure.

Cytokine-dependent abortion in CBA x DBA/2 mice is mediated by the procoagulant fgl2 prothrombinase [correction of prothombinase].

Spontaneous resorption in the CBA x DBA/2 model is attributed to NK cells, macrophages, and Th1-type cytokines. In vivo depletion of NK cells by anti-asialoGM1 Ab or macrophage depletion by silicon dioxide treatment reduced abortion rates, which could no longer be boosted by injecting TNF-alpha (which activates NK cells) or IFN-gamma (which activates macrophages). TNF-alpha + gamma-IFN coadministration aborted >80% of the embryos whether or not NK cells or macrophages had been depleted or estradiol + progesterone was injected to correct potential reduction in ovarian function by cytokines.

Murine T cell determination of pregnancy outcome: I. Effects of strain, alphabeta T cell receptor, gammadelta T cell receptor, and gammadelta T cell subsets.

Problem: T cells bearing alphabeta T cell receptor (TcR) and gammadelta TcR are present at the fetomaternal interface, and the latter, which express surface activation markers, can react with fetal trophoblast cell antigens. What is the role of these cells?

Method: Using stress-abortion-prone DBA/2-mated CBA/J and abortion-resistant C57/B16 mice, alphabeta, gammadelta, and CD8+/- T cell subsets were measured in spleen and uterine decidua. The effect of immunization against abortion and administration of anti-TcR antibody in vivo was examined.

Decidua-associated suppressor cells in abortion-prone DBA/2-mated CBA/J mice that release bioactive transforming growth factor beta2-related immunosuppressive molecules express a bone marrow-derived natural suppressor cell marker and gamma delta T-cell receptor.

The decidua of allopregnant mice contains a novel population of Thy1 Lyt1 CD4 CD8 asialoGM1- non-B small lymphocytic suppressor cells that release transforming growth factor (TGF) SS2-related suppressor molecules. The "null" phenotype of this cell population is similar to some bone marrow-derived natural suppressor cell (NSC) populations, and the latter may release TGF(beta)s. We now report that the TGF beta2-producing suppressor cells in the uterine decidua of DBA/2-mated CBA/J female mice-linked to prevention of abortions-are inactivated effectively by 1E5/B5.

Soluble receptors neutralizing TNF-alpha and IL-1 block stress-triggered murine abortion.

Problem: In several models of abortion in rodents, the success or failure of the implanted embryos is determined by a balance between pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha), interleukin-2, interleukin-1 (IL-1), and gamma-interferon, and cytokines that counteract the former, such as interleukin-10 and transforming growth factor-beta 2 (TGF-beta 2)-related suppressor factor. Stress can trigger abortions in susceptible strains of mice and is thought to reflect the pathogenesis of some types of miscarriage in human pregnancy. In mice, stress increases levels of the abortogenic cytokine TNF-alpha and decreases the suppressive activity of TGF-beta 2-related factor via a neurotransmitter substance P (SP)-dependent pathway.

Stress triggered abortions are associated with alterations of granulated cells into the decidua.

Problem: Stress is known to be abortogenic in animals and humans. An increased decidual release of cytokines such as TNF-alpha and reduction in TGF-beta 2-related immunosuppressive activity has been proposed as the triggering mechanism. Substance P release by nerves in endometrium/decidua has been found to be the key neurotransmitter in this pathway.

Regulation of abortion by gamma delta T cells.

Problem: T cells are present at the feto-maternal interface, but their function during pregnancy has not been fully elucidated. T cells bearing gamma delta T-cell receptor (TCR) may be particularly important, as some subsets can react to trophoblast cells by producing cytokines, such as interleukin-2 (IL-2).

Method: We depleted T cells bearing the gamma delta receptor by injecting monoclonal antibodies (mAb) into females of the abortion-prone animal model CBA x DBA/2.

Immunosuppressive properties of monoclonal antibodies and human polyclonal alloantibodies to the R80K protein of trophoblast.

Problem: The R80K protein on human trophoblast is antigenically polymorphic, and in all placentae of successful pregnancies, the protein is covered by maternal alloantibody. Alloantibody eluted from human placenta has been shown to inhibit killing by human NK cells. Do those antibodies to R80K that inhibit NK killing also affect the murine abortion models?

Methods: We made three murine monoclonal antibodies to conserved epitopes, on human R80K, all of which also reacted with the homologous murine molecule.

Inhibition of immunoprotective CD8+ T cells as a basis for stress-triggered substance P-mediated abortion in mice.

The embryo expresses paternal antigens foreign to the mother and therefore has been viewed as an allograft. The maternal immune system responds to paternal antigens on the "graft", and these responses are thought to protect pregnancy. However, pregnancy can be aborted by stress, which stimulates local production of TNF-alpha and inhibits TGF-beta 2-producing natural suppressor cell (NS) activity via a neurotransmitter substance P-dependent pathway.

Transforming growth factor-beta 2-related-decidual suppressor factor is not related to TJ6 protein.

Transforming growth factor (TGF)-beta 2-related-decidual suppressor factor (DSF) and TJ6 protein are both immunosuppressive molecules present in murine and human pregnancy. Treatment of mice with either anti-TJ6 or anti-TGF-beta 2 neutralizing antibodies results in increased fetal loss. Western blots of supernatants from pregnant mouse decidua probed with anti-TJ6 (soluble form) showed a doublet at a similar molecular size as when the blot was probed with anti-TGF-beta 2 antibody.

Psycho-neuro-cytokine/endocrine pathways in immunoregulation during pregnancy.

Problem: Some mammalian pregnancy failure is thought to occur by immunological or immunologically modifiable mechanisms. The original model wherein spontaneous abortion was proposed to represent rejection of the conceptus as an allograft has been supplanted by a model of maternal paraimmunological natural effector cell toxicity to fetal trophoblast more closely related to tumor rejection. The problem is to integrate current information concerning the role of immunological, paraimmunological, endocrinological, and stress-triggered neural factors that determine whether or not abortion will occur.

Stress-induced murine abortion associated with substance P-dependent alteration in cytokines in maternal uterine decidua.

Stress is known to induce abortions, but underlying mechanisms are unknown. Both alloimmunization and injection of antibody to the asialoGM1 determinant of natural killer cells have been shown to prevent stress-triggered abortion in mice. DBA/2J-mated CBA/J female mice were used to investigate the influence of stress during early gestation on systemic hormone levels and on cytokines in the decidua that are thought to be relevant to abortion in nonstress-related murine abortion.

Stress-triggered abortion: inhibition of protective suppression and promotion of tumor necrosis factor-alpha (TNF-alpha) release as a mechanism triggering resorptions in mice.

Problem: Stress adversely affects pregnancy outcome and has been implicated as an abortogen in both animals and humans. However, the mechanisms whereby stress aborts are largely unknown. Alloimmunization can prevent stress-triggered abortion, and immunization is known to increase transforming growth factor-beta 2 (TGF-beta 2)-related suppressive activity.

[Membranoproliferative glomerulonephritis in non-Hodgkin's lymphoma nad myeloproliferative syndrome--a causal relationship?].

A pathogenetic relationship is postulated for the development of membranoproliferative glomerulonephritis type I in non-Hodgkin's lymphoma (B-cell lymphoma of low-grade malignancy) and myeloproliferative syndrome, which we have observed in eight patients. This hypothesis is supported by the fact that chronic lymphatic leukaemia and immunocytoma are often associated with immunodysregulative phenomena, and by the immunohistological and ultrastructural findings in the kidney, especially the frequent electron-microscopic finding of cryoglobulins, which results in the membranoproliferative type of immune-complex glomerulonephritis, an expression of a disturbance in immune balance. The pathogenetic mechanism may involve cryoglobulins themselves as immune complexes; it is also possible that monoclonal cryoglobulins combine with an antigen to form immune complexes or lead to in situ formation of immune complexes.