The persistence of anticardiolipin antibodies is associated with an increased risk of the presence of lupus anticoagulant and anti-beta2-glycoprotein I antibodies.

OBJECTIVE: We studied antiphospholipid antibodies (aPL) in blood samples from a cohort of individuals followed for thrombosis to determine whether the persistent presence of anticardiolipin antibodies (aCL) is associated with a greater likelihood of having lupus anticoagulant and/or anti-beta2-glycoprotein I antibodies (LA/abeta2GPI). METHODS: Blood samples from 353 individuals who had been tested for aCL on at least two occasions were tested for abeta2GPI and LA. Two groups were defined: aCL-persistent, who tested aCL-positive on at least two occasions, and aCL non-persistent, who tested aCL-positive on fewer than two occasions. Multivariate logistic regressions were performed using LA/abeta2GPI, LA and abeta2GPI as outcome variables and the percentage of aCL-positive tests as the predictor variable, adjusted for age, gender, family history of cardiovascular disease (CVD), systemic lupus erythematosus (SLE), smoking and number of venous (VT) and arterial thromboses (AT). RESULTS: Sixty-eight (19%) individuals were aCL persistent and 285 (81%) were aCL non-persistent. LA/abeta2GPI was found in 36 (53%) of the aCL persistent group and 38 (13%) of the aCL non-persistent group. The two groups were similar for age, gender and smoking. Family history of CVD, SLE, VT and AT were more frequent in the aCL persistent group. Multivariate analyses revealed that odds ratios for LA/abeta2GPI, LA and abeta2GPI were 1.34 [95% confidence interval (CI) = 1.22-1.47], 1.36 (95% CI = 1.24-1.50) and 1.47 (95% CI = 1.31-1.65) respectively for each 10% increase in aCL-positive tests vs 0% positive tests. CONCLUSION: Persistence of aCL positivity is associated with an increased risk of LA/abeta2GPI.

Differential display analysis of oxygen-mediated changes in gene expression in first trimester human trophoblast cells.

Physiologic or pathologically induced periods of exposure to relatively low levels of oxygen during pregnancy affect the expression and function of certain genes in the placenta. In this study, the differential display technique was utilized to identify genes that are regulated in cultured cytotrophoblast cells by exposure to low levels of oxygen. Using this approach, four genes, which have been designated HRF-1, HRF-2, HRF-6, and HRF-8, were cloned and partially characterized. Northern blot analysis showed that clones HRF-1 and HRF-2 were downregulated in response to exposure to low levels of oxygen, whereas expression of HRF-6 and HRF-8 was increased. DNA sequencing and sequence analysis revealed that HRF-1 may represent an alternatively spliced or tissue-specific form of the Kruppel family zinc finger protein znfp104 gene. Clone HRF-2 showed a high degree of identity with exons 9, 10 and 11 of N33, a gene that is located within a homozygously deleted region of metastatic prostate cancer. Clones HRF-6 and HRF-8 did not exhibit significant sequence identity with known sequences in GenBank and may represent novel genes. None of these genes have previously been shown to be present in trophoblast cells, nor have their expressions been shown to be regulated by oxygen. This study demonstrates that the differential display technique is a novel and effective method to analyse oxygen-mediated changes in gene expression in trophoblast cells.

Functional interaction between the integrin antagonist neutrophil inhibitory factor and the I domain of CD11b/CD18.

Neutrophil inhibitory factor (NIF) is a hookworm-derived glycoprotein ligand of the integrin CD11b/CD18 that inhibits human neutrophil function (Moyle, M., Foster, D. L., McGrath, D. E., Brown, S. M., Laroche, Y., De Meutter, J., Stanssens, P., Bogowitz, C. A., Fried, V. A., Ely, J. A., Soule, H. R., and Vlasuk, G. P. (1994) J. Biol. Chem. 269, 1008-10015). Here, we present evidence that recombinant NIF (rNIF) associates with the approximately 200-amino acid residue I domain of CD11b/CD18 and that this interaction is essential for inhibition of neutrophil function by NIF. First, radiolabeled rNIF binds to a recombinant glutathione S-transferase fusion protein that contains the CD11b I domain. This high affinity interaction has a partial dependence on divalent cations. The association of rNIF with the CD11b I domain is specific because 125I-rNIF does not bind either a glutathione S-transferase fusion protein that contains the I domain of the integrin CD11a/CD18 or recombinant glutathione S-transferase without the I domain. Second, the CD11b I domain fusion protein effectively competes with CD11b/CD18 on human neutrophils for 125I-rNIF binding. Third, the CD11b I domain fusion protein blocks the inhibition of certain neutrophil functions by rNIF, including adhesion of neutrophils to human endothelial cell monolayers and adhesion-dependent release of hydrogen peroxide from neutrophils. Specificity is demonstrated by the inability of the CD11a I domain fusion protein to block either rNIF binding to neutrophils or rNIF activity. Fourth, rNIF blocks the interaction between neutrophils and fibrinogen, a CD11b/CD18 ligand that is also thought to bind the I domain of CD11b. In contrast, rNIF does not appear to block the binding of factor X to CD11b/CD18 on neutrophils. These results suggest that CD11b/CD18 has multiple distinct binding sites for its cognate ligands, including, but not limited to, the I domain. NIF interferes with the binding of a subset of these CD11b/CD18 ligands in a highly selective manner.