Deficiency of monoclonal non-specific suppressor factor beta (MNSFB) promotes pregnancy loss in mice.

Maternal immune tolerance to the semi-allogenic fetus is required for successful pregnancy in mammals. Monoclonal nonspecific suppressor factor beta (MNSFB) is an immunosuppressive factor present in uterine epithelial and stromal cells, as well as in macrophages and T cells. Although the functional neutralization of MNSFB using specific antibodies against it lead to failed embryo implantation in mice, the exact role of MNSFB at the fetal-maternal interface remains unclear. The present study generated conditional heterozygous Mnsfb-deficient (Mnsfb(+/) (-) ) mice using the LoxP/Cre system. Western-blot analyses showed that uterine MNSFB protein in Mnsfb(+/-) mice was remarkably down-regulated compared to that in the wild-type (Mnsfb(+/+) ) mice. The litter size of female Mnsfb(+/-) mice was significantly reduced, which corresponded to developmental failure of embryos beyond Day 11 of pregnancy. The expression level of MNSFB protein was also lower in the failing compared to the normal embryos. An aberrant interaction between the embryos of Day-4 pregnant wild-type mice and endometrial stromal cells of female Mnsfb(+/-) mice was observed in vitro. The uterine Day-5 abundance of P53, BAX, and BCL-G in pregnant Mnsfb(+/-) mice was significantly decreased compared to that of wild-type mice, whereas the expression of P27 and tumor necrosis factor alpha (TNFA) was elevated. By comparison, the levels of MNSFB and BAX proteins in human decidual tissues obtained from recurrent spontaneous miscarriage patients were significantly reduced compared to those obtained from legal medial abortion, highlighting the involvement of MNSFB in the pathogenesis of recurrent spontaneous miscarriage. Together, these results demonstrated that a deficiency in MNSFb is associated with pregnancy loss, probably through reduced P53 and/or increased TNFA production at the fetal-maternal interface.

The IL-27 receptor (WSX-1) is an inhibitor of innate and adaptive elements of type 2 immunity.

Although previous studies have investigated the role of IL-27/WSX-1 interactions in the regulation of Th1 responses, little is known about their role in regulating Th2-type responses. Studies presented in this work identify a direct role for IL-27/WSX-1 interactions in the negative regulation of type 2 responses independent of effects on type 1 cytokines. WSX-1-/- mice infected with the gastrointestinal helminth Trichuris muris displayed accelerated expulsion of parasites and the development of exaggerated goblet cell hyperplasia and mastocytosis in the gut due to increased production of Th2 cytokines. Enhanced mast cell activity in the absence of WSX-1 was consistent with the ability of wild-type mast cells to express this receptor. In addition, IL-27 directly suppressed CD4+ T cell proliferation and Th2 cytokine production. Together, these studies identify a novel role for IL-27/WSX-1 in limiting innate and adaptive components of type 2 immunity at mucosal sites.

IL-10 mediates suppression of the CD8 T cell IFN-gamma response to a novel viral epitope in a primed host.

Priming to Ag can inhibit subsequent induction of an immune response to a new epitope incorporated into that Ag, a phenomenon referred to as original antigenic sin. In this study, we show that prior immunity to a virus capsid can inhibit subsequent induction of the IFN-gamma effector T cell response to a novel CD8-restricted antigenic epitope associated with the virus capsid. Inhibition does not involve Ab to the virus capsid, as it is observed in animals lacking B cells. CD8-restricted virus-specific T cell responses are not required, as priming to virus without CTL induction is associated with inhibition. However, IL-10(-/-) mice, in contrast to IL-10(+/+) mice, generate CD8 T cell and Ab responses to novel epitopes incorporated into a virus capsid, even when priming to the capsid has resulted in high titer Ab to the capsid. Furthermore, capsid-primed mice, unable to mount a response to a novel epitope in the capsid protein, are nevertheless able to respond to the same novel epitope delivered independently of the capsid. Thus, inhibition of responsiveness to a novel epitope in a virus-primed animal is a consequence of secretion of IL-10 in response to presented Ag, which inhibits local generation of new CD8 IFN-gamma-secreting effector T cells. Induction of virus- or tumor Ag-specific CD8 effector T cells in the partially Ag-primed host may thus be facilitated by local neutralization of IL-10.

A subset of patients with recurrent spontaneous abortion is deficient in transforming growth factor beta-2-producing "suppressor cells" in uterine tissue near the placental attachment site.

PROBLEM: To determine if patients with unexplained recurrent miscarriage have a deficiency of decidual immunosuppressor cells that produce transforming growth factor beta type 2, as has been found in mice with abortion due to rejection and/or trophoblast failure. METHODS: Decidual biopsy specimens were taken as near to the placental attachment site as possible under ultrasound guidance from first trimester legal termination (control) patients with recurrent miscarriage and non-viable pregnancy, and from patients with sporadic missed abortion. The tissue was tested for TGF beta-2+ suppressor cells by in situ hybridization, immunohistochemistry, and analysis of supernatants. RESULTS: TGF beta-2-related suppressor molecules similar but not identical to those identified in pregnant mice were released by decidual lymphoid cells. Fifty percent of 14 recurrent miscarriage patients showed a lack of suppressor cells and 59% were subnormal in comparison to 20 controls and 5 sporadic miscarriage patients, where 80-85% of the patients had detectable suppressor cells. CONCLUSIONS: Suppressor cell deficiency is compatible with a role for rejection and/or trophoblast failure in some patients with recurrent miscarriage. Presence of suppressor cells in most patients with missed abortion (4/5) is compatible with an alternative cause of fetal death, similar to findings reported in genetic fetal death mice.

Disminución de linfocitos T supresores y activación de monocitos y neutrófilos durante la reacción inmediata del asma-inducida por ejercicio / Lymphocyte T supressors dicrease and monocyte and neutrophil activation during the early reaction of exercise induced asthma

Durante la broncoconstricción inducida por el ejercicio (AIE) en individuos asmáticos se producen cambios cuantitativos y cualitativos de los leucocitos en sangre periférica. Para estudiar la participación de células inmunes y accesorias de la reacción inflamatoria en el AIE, analizamos las modificaciones de las subpoblaciones de linfocitos T y de la expresión de los antígenos de histocompatibilidad clase II (la) en monocitos, además de la participación de los receptores para el tercer factor del complemento (C36) mediante su expresión en monocitos y su adhesión y consecuente activación en neutrófilos. Se estudió 20 pacientes asmáticos alérgicos, de los cuales 11 presentaron broncoconstricción después de una prueba de ejercicio estandarizada. En todos los individuos estudiados se produjo, 5 min después del ejercicio, un aumento significativo de los leucocitos sanguíneos totales y de los neutrófilos, linfocitos y monocitos. Los basófilos y eosinófilos aumentaron sólo en los AIE (+). También este grupo presentó eosinófilos más altos desde el nivel inicial. En los individuos con AIE (+) el aumento inicial de los linfocitos a los 5 min se produce a expensas de los linfocitos T supresores (CD8) los que luego comienzan a disminuir hasta alcanzar valores significativamente menores que el inicial a los 60 min después del ejercicio. Esto lleva a un aumemto de la relación CD4/CD8 a nivel periférico, que es simultáneo con el aumento en la expresión de los antígenos Ia en monocitos observados en los AIE (+). Además en estos pacientes se encontró un aumento en la expresión de los receptores C3b en monocitos y en la producción de radical superóxido por neutrófilos estimulados con zimusán y complemento, desde el momento que se inicia la broncoconstricción hasta los 60 min después del ejercicio. Estos hallazgos sugieren que en los asmáticos con AIE (+) se producen cambios en las células inmunocompetentes que pudieran estar relacionados con la participación de células inflamatorias y su eventual manifestación como hiperactividad bronquial

DiGeorge syndrome with hypogammaglobulinaemia: a patient with excess suppressor T cell activity treated with fetal thymus transplantation.

A male infant with DiGeorge syndrome had hypogammaglobulinaemia with a normal number of B cells. CD3(+) T cells were reduced and the CD4(+)/CD8(+) ratio was reversed. Proliferative responses of T cells to mitogens and to allogeneic cells were low. The pokeweed mitogen (PWM)-induced B cell differentiation assay revealed a higher than normal suppressor T cell activity. This suggests that some T cells had differentiated into functionally mature cells resulting in an imbalance of regulatory T cell functions and that excess suppressor activity might play a role in hypogammaglobulinaemia. Fetal thymus transplantation improved both cellular and humoral immunity. The patient's susceptibility to viral and bacterial infections, proliferative response of T cells and serum Ig concentration returned to normal. The excess suppressor activity seen before transplantation disappeared. Hypocalcaemia did not improve. These results show that fetal thymus transplantation was effective not only in reconstituting cellular immunity but also in normalizing the imbalance of regulatory T cell functions in this patient with DiGeorge syndrome.