The stimulation of Toll-like receptors (TLRs) on macrophages triggers production of the cytokine tumor necrosis factor (TNF). TNF production occurs within 1 h of TLR stimulation and is sustained for 1 d. Here we document a function for the TNF family member 4-1BB ligand (4-1BBL) in sustaining TLR-induced TNF production. TLR signaling induced 4-1BBL, and 4-1BBL interacted with TLRs on the macrophage surface. The influence of 4-1BBL on TNF production was independent of its receptor (4-1BB) and did not require the adaptors MyD88 or TRIF. It did not influence TLR4-induced activation of transcription factor NF-kappaB (an early response) but was required for TLR4-induced activation of transcription factors CREB and C/EBP (a late event). Transient TLR4-MyD88 complexes appeared during the first hour after lipopolysaccharide stimulation, and TLR4-4-1BBL interactions were detected between 2 h and 8 h after lipopolysaccharide stimulation. Our results indicate that two different TLR4 complexes sequentially form and selectively control early and late TNF production.

Pre-conceptional NK cell abnormalities were predictive of spontaneous abortion with normal fetal karyotype.

High NK cell activity at 6-7 GW correlates with subsequent abortion with normal chromosomes.

25OBJECTIVE: Some women exhibit a gradual decline in antithrombin activity during 26 the late stage of pregnancy. This retrospective study was performed to better 27 characterize the laboratory features and water metabolism of such women with 28 pregnancy-induced antithrombin deficiency (PIATD). 29 METHODS:Among 1493 women who gave birth to a singleton infant at our institution, 30 114 women who developed PIATD and/or pregnancy-induced hypertension (PIH) were 31 reviewed with respect to perinatal changes in laboratory variables (hematocrit value, 32 fibrinogen, fibrinogen degradation product, D-dimer, uric acid, aspartate 33 aminotransferase, lactate dehydrogenase) and body weight. PIATD was defined as a 34 gradual decline in antithrombin activity to ≤ 65% of normal activity levels. One 35 hundred and fourteen women with neither PIATD nor pregnancy-induced hypertension 36 (PIH) and matched for the cesarean delivery rate were selected as a control group. 37 RESULTS:Of the 81 women who developed PIH, 19 (23.4%) also developed PIATD. 38Thirty-three women developed PIATD in the absence of PIH. Coagulation-fibrinolysis 39 was significantly more enhanced and the postpartum reduction in the hematocrit value 40 was significantly larger in women with PIATD, irrespective of the presence or absence 41 of hypertension, than in women without PIATD. The postpartum decrease in body 42 weight was significantly smaller in women with PIATD, irrespective of the presence or 43 absence of hypertension, than in women without PIATD. Some women develop a gradual decline in antithrombin (AT) activity during the late 54 stage of pregnancy, even in the absence of hypertension [9, 16]. This decline in AT 55 activity continues until the day of or one day after delivery, and a prompt normalization 56 of AT activity occurs postpartum in such patients with pregnancy-induced AT deficiency 57 (PIATD) [9]. Because AT is the most important molecule for the anti-coagulation of the 58 circulating blood, delivery delays may be dangerous in women with PIATD. Indeed, 59the risk of developing pulmonary embolism increases in women with known risk factors 60for PIATD, such as preeclampsia [6, 17, 18] or multi-fetal pregnancy [2, 6, 10,[16][17][18]. 61Further, women with PIATD are at risk of developing acute fatty liver of pregnancy [2, 62 9]. Indeed, the risk of developing acute fatty liver of pregnancy is reportedly high in 63 women with a known risk factor for PIATD, such as preeclampsia or multi-fetal 64 pregnancy [11]. Because a profoundly decreased AT level is seen in women with acute 65 fatty liver of pregnancy at the time of presentation [2] and because the risk of a perinatal 66 elevation in aspartate aminotransferase increases as the antenatal AT activity decreases 67[9], the monitoring of AT activity in women who exhibit a gradual decline in AT activity 68 may help to avoid the development of acute fatty liver of pregnancy. These 69 observations suggest that women with PIATD might constitute a high-risk pregnancy 70 group, although th...

Congenital and acquired thrombophilia are associated with an increased risk of pregnancy-associated venous thrombosis and fetal loss. Two hundred eighty-nine patients with a history of recurrent spontaneous abortion were subjected to screening examinations for the etiology of these abortions. Endocrine abnormality (28.0%), uterine abnormality (10.4%), autoimmune diseases (1.4%), antiphospholipid antibody syndrome (4.5%), and balanced type chromosome translocation (4.2%) were found as underlying causes of recurrent abortions, and the remaining 55.0% of the 289 patients were classified as having an unexplained etiology. Congenital thrombophilia such as protein C (PC) deficiency, protein S (PS) deficiency, antithrombin deficiency, and factor V Leiden mutation was not frequently detected; only one patient had PS deficiency. A reduced factor XII activity was found at a frequency of 4.2%. The frequency of methylene tetrahydrofolate reductase gene C677T mutation in recurrent aborters (0.38) was the same as that found in a fertile control group. Although the prevalence of anti-beta2-glycoprotein I antibody (abeta2-GPI) syndrome was very low (1.7%), patients with a high titer of immunoglobulin G (IgG) class abeta2-GPI, despite anticoagulation therapy, experienced severe fetomaternal complications in subsequent pregnancies. The rate (13.8%) of positive tests for serum IgA class abeta2-GPI in patients with unexplained etiology was higher than that in the controls (0%) (P < .05). We conclude that congenital thrombophilia is rare in Japanese patients who had experienced consecutive spontaneous abortions.