IL-4-producing NK T cells are biased towards IFN-γ production by IL-12. Influence of the microenvironment on the functional capacities of NK T cells

NK T cells are an unusual T lymphocyte subset capable of promptly producing several cytokines after stimulation, in particular IL-4, thus suggesting their influence in Th2 lineage commitment. In this study we demonstrate that, according to the cytokines present in the micro environment, NK T lymphocytes can preferentially produce either IL-4 or IFN-γ. In agreement with our previous reports showing that their IL-4-producing capacity is strikingly dependent on IL-7, CD4⁻ CD8⁻ TCRα β⁺ NK T lymphocytes, obtained after expansion with IL-1 plus granulocyte-macrophage colony-stimulating factor, produced almost undetectable amounts of IL-4 or IFN-γ in response to TCR/CD3 cross-linking. However, the capacity of these T cells to produce IFN-γ is strikingly enhanced when IL-12 is added either during their expansion or the anti-CD3 stimulation, while IL-4 secretion is always absent. A similar effect of IL-12 on IFN-γ production was observed when NK T lymphocytes were obtained after expansion with IL-7. It is noteworthy that whatever cytokines are used for their expansion, IL-12 stimulation, in the absence of TCR/CD3 cross-linking, promotes consistent IFN-γ secretion by NK T cells without detectable IL-4 production. Experiments in vivo demonstrated a significant up-regulation of the capacity of NK T cells to produce IFN-γ after anti-CD3 mAb injection when mice were previously treated with IL-12. In conclusion, we provide evidence that the functional capacities of NK T cells, which ultimately will determine their physiological roles, are strikingly dependent on the cytokines present in their microenvironment.     

Detection rate and intratumoral virus load of human herpesvirus-8 in immunodeficiency-related B-cell lymphoid malignancies

Human herpesvirus-8 (HHV-8), associated with Kaposi's sarcoma, primary effusion lymphoma, and Castleman's disease, has been found in circulating B-cells and might have a causative role in B-cell malignancies associated with immunodeficiency syndromes. We determined the rate of detection and intratumoral virus load of HHV-8 by means of a semiquantitative approach in post-transplant lymphoproliferative diseases (PTLDs), AIDS-related non-Hodgkin's lymphomas (NHLs), including both Burkitt's lymphomas (BLs) and large cell lymphomas (LCLs), as well as in control groups consisting of follicular hyperplasias (FHs) and HIV-negative LCLs. HHV-8 sequences were detected at a similar rate in HIV-negative PTLDs (24%), HIV-negative LCLs (22%) and HIV-negative FHs (17%). The detection rate was significantly higher in HIV-positive BLs (73%), HIV-positive LCLs (67%), and HIV-positive FHs (65%) supporting the view of an epidemiological link between HHV-8 and HIV infections. The viral load was 10² genome copies per cell in the single case of primary effusion lymphoma included in the LCL group while it was 10⁻³ copy per cell (median value; range: 10⁻⁴–10⁻¹) in all the other HHV-8-positive samples. No significant difference of viral load was found according to HIV status. The virus loads of PTLDs and HIV-positive LCLs were significantly higher than those observed in HIV-positive BLs and FHs, suggesting, to some extent, that the degree of immunodeficiency may influence HHV-8 replication. However, with the exception of the single case of primary effusion lymphoma studied, the low intratumoral load of HHV-8 strongly argues against a direct causative agent of the virus in the occurrence of PTLDs and AIDS-related NHLs. J. Med. Virol. 53:277–281, 1997. © 1997 Wiley-Liss, Inc.     

Developmental regulation of the serpin,protease nexin I,localization during activity-dependent polyneuronal synapse elimination in mouse skeletal muscle

During vertebrate neuromuscular development, all muscle fibers are transiently innervated by more than one neuron. Among the numerous factors shown to potentially influence the passage from poly- to mononeuronal innervation, serine proteases and their inhibitors appear to play important roles. In this regard, protease nexin I (PNI), a potent inhibitor of the serine protease, thrombin, is highly localized to the neuromuscular junction (NMJ). In turn, thrombin is responsible for activity-dependent synapse elimination both in an in vitro model, and in vivo. In the present study, we used a monospecific anti-PNI polyclonal antibody to study the developmental kinetics of PNI expression in mouse leg skeletal muscle. By using immunoblotting, we detected PNI at embryonic day 16 (E16), as a 48-kDa band. This 48-kDa PNI band became prominent in leg muscle extracts at postnatal day 5 (P5) and remained so in extracts from adult muscle. In contrast, a higher molecular weight immunoreactive PNI band, which was sodium dodecyl sulfate– and β-mercaptoethanol–resistant, was first detected at E16, increased at birth (P0), and then decreased at P15, i.e., after the wave of polyneuronal synapse elimination had occurred in these muscles. The results of an enzyme-linked immunosorbent assay, measuring active, complexed, and truncated PNI, correlated with Western blot data. We used immunocytochemistry to probe the localization of PNI at the NMJ and found that PNI was present in the cytoplasm of myotubes at E16, but neither then nor at birth did it colocalize with acetylcholine receptors. PNI became localized at NMJs by P5 and increased by P15, after which it remained stably concentrated there in the adult. Finally, we studied the gene expression of PNI mRNA, by using Northern blotting, and showed that PNI mRNA was present in skeletal muscle and remained stable throughout the time-course studies, suggesting that developmental regulation of muscle PNI occurs principally at the translational and/or post-translational levels. These results suggest that the localization of PNI, through a binding site or “receptor” may play an important role in differentiation and maintenance of synapse. J. Comp. Neurol. 397:572–579, 1998. © 1998 Wiley-Liss, Inc.     

Effects of radiofrequency versus neurotoxic cingulate lesions on spatial reversal learning in mice

Mice with radiofrequency (RF) lesions of the posterior (PC) or anterior (AC) cingulate cortex were trained on spatial discrimination reversal learning in a T-maze. The results were compared with those obtained in an earlier study after ibotenic acid (IBO) cingulate lesions. PC-RF lesions facilitated the initial discrimination and first reversal, whereas they retarded subsequent reversals; in contrast, PC-IBO lesions yielded a deficit on the initial discrimination and first reversal, but had no effect on subsequent reversals. AC-IBO, but not AC-RF lesions, precluded the formation of a learning set across reversals. These data suggest that cingulum transection, which accompanies RF but not IBO lesions, can mask or even antagonize the specific effects of cingulate damage. Consequently, inferences made from the effects of conventional lesions to assess and distinguish the functions of the two cingulate areas appear subject to caution. Hippocampus 7:355–360, 1997. © 1997 Wiley-Liss, Inc.     

Heterotaxy-neural tube defect and holoprosencephaly occurring independently in two sib fetuses

We report on two sib fetuses, products of a consanguineous union, who had multiple and apparently unrelated malformations. The first fetus, a female, had trilobed lungs, a single cardiac ventricle, asplenia, situs ambiguus of the liver, and a lumbosacral meningomyelocele. The brain of this fetus was normal. The second fetus, a male, had bilobed lungs, a single cardiac ventricle, situs solitus of the abdominal organs and spleen, and a semilobar holoprosencephaly. The occurrence of these malformations in sibs of different sexes and the parental consanguinity suggest a recessive mutation in a gene responsible for both heterotaxy and midline defects, including holoprosencephaly. Am. J. Med. Genet. 84:373–376, 1999. © 1999 Wiley-Liss, Inc.     

Facial anomalies in D-2-hydroxyglutaric aciduria

D -2-hydroxyglutaric aciduria is a rare autosomal recessive organic aciduria with variable clinical expression. The biochemical defect is still unknown, and genetic heterogeneity has been suggested. Here, we report on facial anomalies in two unrelated cases of D -2-hydroxyglutaric aciduria presenting with epileptic encephalopathy. In a review, we found that minor facial anomalies have been mentioned in three patients. A flat face with a broad nasal bridge and external ear anomalies were present in our patients and in reported cases. We suggest giving consideration to D -2-hydroxyglutaric aciduria as a cause of minor facial anomalies in epileptic encephalopathy of unknown origin. Am. J. Med. Genet. 86:124–129, 1999. © 1999 Wiley-Liss, Inc.     

Splenogonadal fusion limb defect syndrome: Report of five new cases and review

Splenogonadal fusion (SGF) is a rare congenital malformation in which the spleen is abnormally connected to the gonad. SGF may occur as an isolated condition or may be associated with other malformations, especially with terminal limb defects in what is called splenogonadal fusion limb defect (SGFLD) syndrome. In this article, we report on 5 new cases of SGFLD and we review the 25 cases reported since 1889. Most cases reviewed here have a combination of severe limb and oro–mandibular defects, suggesting that SGFLD may be related to the broader group of Hanhart complex. In addition, several cases have limb malformations and facial anomalies, which suggest that SGFLD overlaps with both femur–fibula–ulna dysostosis and femoral–facial syndrome. The hypothesis of a vascular disruptive event, occuring between the 5th and the 7th weeks of gestation, could explain the limb defects, the mandibular hypoplasia, and the fusion of the spleen to the gonad observed in SGFLD. However, this heterogenous and polytopic condition could also be the consequence of a primary field defect. All the cases to date reported have been sporadic and the recurrence risk is probably low. However, a recent case of Roberts syndrome with SGF was reported that suggests careful examination of chromosomal status. Am. J. Med. Genet. 86:347–358, 1999. © 1999 Wiley-Liss, Inc.     

Hypoxia‐Induced Loss of Synaptic Transmission Is Exacerbated in Hippocampal Slices of Transgenic Mice Expressing C‐Terminal Fragments of Alzheimer Amyloid Precursor Protein

To investigate the possible involvement of β‐amyloid (Aβ) in disrupting neuronal function during ischemia, we examined whether overexpression of C‐terminal fragments of β‐amyloid precursor protein (β‐APP) in transgenic (Tg) mice is capable of altering the capacity of hippocampus slices to recover synaptic transmission after transient hypoxic episodes. Recovery of synaptic transmission was monitored in area CA₁ of perfused hippocampal slices prepared from both control and Tg mice. The results obtained indicate that hippocampal slices prepared from Tg mice exhibited a much lower level of recovery in synaptic transmission following reoxygenation. This reduction in the capacity of Tg slices to recover from hypoxia‐induced impairment of synaptic transmission in the hippocampus does not appear to be related to pre‐existing alterations in either functional or biochemical properties of glutamate receptors in Tg mice. The present results provide the first experimental evidence that overexpression of the C‐terminal fragment of APP exacerbates functional damage of hippocampal neurons after hypoxic episodes. Hippocampus 1999;9:201–205. © 1999 Wiley‐Liss, Inc.     

Retrospective analysis of Schlafen11 (SLFN11) to predict the outcomes to therapies affecting the DNA damage response

Background The absence of the putative DNA/RNA helicase Schlafen11 (SLFN11) is thought to cause resistance to DNA-damaging agents (DDAs) and PARP inhibitors.Methods We developed and validated a clinically applicable SLFN11 immunohistochemistry assay and retrospectively correlated SLFN11 tumour levels to patient outcome to the standard of care therapies and olaparib maintenance.Results High SLFN11 associated with improved prognosis to the first-line treatment with DDAs platinum-plus-etoposide in SCLC patients, but was not strongly linked to paclitaxel–platinum response in ovarian cancer patients. Multivariate analysis of patients with relapsed platinum-sensitive ovarian cancer from the randomised, placebo-controlled Phase II olaparib maintenance Study19 showed SLFN11 tumour levels associated with sensitivity to olaparib. Study19 patients with high SLFN11 had a lower progression-free survival (PFS) hazard ratio compared to patients with low SLFN11, although both groups had the benefit of olaparib over placebo. Whilst caveated by small sample size, this trend was maintained for PFS, but not overall survival, when adjusting for BRCA status across the olaparib and placebo treatment groups, a key driver of PARP inhibitor sensitivity.Conclusion We provide clinical evidence supporting the role of SLFN11 as a DDA therapy selection biomarker in SCLC and highlight the need for further clinical investigation into SLFN11 as a PARP inhibitor predictive biomarker.Subject terms: Tumour biomarkers, Tumour biomarkers     

X-linked mental retardation with neonatal hypotonia in a French family (MRX15): Gene assignment to Xp11.22-Xp21.1

Linkage analysis was performed in a family with non-specific X-linked mental retardation (MRX 15). Hypotonia in infancy was the most remarkable physical manifestation. The severity of mental deficiency was variable among the patients, but all of them had poor or absent speech. Significant lod scores at a recombination fraction of zero were detected with the marker loci DXS1126, DXS255, and DXS573 (Zmax = 2.01) and recombination was observed with the two flanking loci DXS164 (Xp21.1) and DXS988 (Xp11.22), identifying a 17 cM interval. This result suggests a new gene localization in the proximal Xp region. In numerous families with non-specific X-linked mental retardation (MRX), the corresponding gene has been localized to the paracentromeric region in which a low recombination rate impairs the precision of mapping. © 1996 Wiley-Liss, Inc.