A sphingosine-1-phosphate receptor 1 agonist inhibits tertiary lymphoid tissue reactivation and hypersensitivity in the lung.

Hypersensitivity pneumonitis is characterized by pulmonary accumulation of B-cell-rich tertiary lymphoid tissues (TLTs), which are alleged sites of amplification for antigen-specific responses. The sphingosine-1-phosphate receptor 1 (S1P1) regulates key mechanisms underlying lymphoid tissue biology and its chemical modulation causes lymphocyte retention in lymph nodes. Given the putative immunopathogenic impact of lymphocyte accumulation in TLTs, we investigated whether or not chemical modulation of S1P1 caused lymphocyte retention within TLTs in a model of hypersensitivity pneumonitis. Mice were exposed subchronically to Methanosphaera stadtmanae (MSS) in order to induce an hypersensitivity pneumonitis-like disease. MSS exposure induced B-cell-rich TLTs surrounded by S1P1-positive microvessels. Upon MSS rechallenge, the S1P1 agonist RP001 prevented the pulmonary increase of CXCL13, a chief regulator of B-cell recruitment in lymphoid tissues. This was associated with a complete inhibition of MSS rechallenge-induced TLT enlargement and with a 2.3-fold reduction of MSS-specific antibody titers in the lung. Interference with TLT reactivation was associated with a 77% reduction of neutrophil accumulation and with full inhibition of protein-rich leakage in the airways. Thus, an S1P1 agonist hinders TLT enlargement upon antigenic rechallenge and inhibits key pathognomonic features of experimental hypersensitivity pneumonitis.

Electrophysiological and molecular identification of hepatocellular volume-activated K+ channels.

Although K+ channels are essential for hepatocellular function, it is not known which channels are involved in the regulatory volume decrease (RVD) in these cells. We have used a combination of electrophysiological and molecular approaches to describe the potential candidates for these channels. The dialysis of short-term cultured rat hepatocytes with a hypotonic solution containing high K+ and low Cl- concentration caused the slow activation of an outward, time-independent current under whole-cell configuration of the patch electrode voltage clamp. The reversal potential of this current suggested that K+ was the primary charge carrier. The swelling-induced K+ current (IKvol) occurred in the absence of Ca2+ and was inhibited with 1 microM Ca2+ in the pipette solution. The activation of IKvol required both Mg2+ and ATP and an increasing concentration of Mg-ATP from 0.25 through 0.5 to 0.9 mM activated IKvol increasingly faster and to a larger extent. The KCNQ1 inhibitor chromanol 293B reversibly depressed IKvol with an IC50 of 26 microM. RT-PCR detected the expression of members of the KCNQ family from KCNQ1 to KCNQ5 and of the accessory proteins KCNE1 to KCNE3 in the rat hepatocytes, but not KCNQ2 and KCNE2 in human liver. Western blotting showed KCNE3 expression in a plasma membrane-enriched fraction from rat hepatocytes. The results suggest that KCNQ1, probably with KCNE2 or KCNE3 as its accessory unit, provides a significant fraction of IKvol in rat hepatocytes.

[AIDS at Central University Hospital of Brazzaville: experience of the "Grands Enfants" pediatric department]. / Le SIDA au CHU de Brazzaville: expérience du service de pédiatrie "Grands enfants".

The epidemiological factors, clinical aspects and short term evolution of children infected by aids were assessed over a period of five years in "Grands Enfants" paediatric service of Brazzaville CHU. The medical reports of 81 patients have been collected, their average age was 9 years old +/- 3.5. The HIV 1 was the only identified virus. 59% of children's parents were divorced, and 7% were single. The infection transmission was vertical in 70% of cases, transfusional in 28% of cases and indeterminate in 1% of cases. The symptoms were: the impairment of body status in 90% of cases, shown by a weight loss in 89% of cases; a long-term fever was observed in 56% of cases and a chronic diarrhoea was noticed in 54% of cases. The lymphadenopathies and digestive Candida were observed in 26% and 36% of cases. 6% of the patients had a psychomotor retardation. The respiratory infections and the diarrhoea were pathologies the most frequently noticed. The associated infections were essentially pulmonary tuberculosis 40% of cases, the otitis, the pneumococcal and cryptococcal meningia 2% of cases. The Burkitt lymphoma and the Kaposi sarcoma were shown in 1% of cases. The evolution was shown by a high mortality due to a dehydration in 59% of cases, a respiratory pathology in 22% of cases and anaemia in 15% of cases. This high mortality points out the problem of the treatment of patients, a problem increased by family poverty.

Cytokine expression by murine DX5+ cells in response to IL-12, IL-18, or the combination of IL-12 and IL-18.

In this study we analyzed the response of DX5+ NK and NK T cells to in vitro stimulation with IL-12 or IL-18. Production of IFN-gamma in response to either IL-12 or IL-18 was dependent upon costimulation with either IL-2 or IL-15. DX5+ splenocytes showed a rapid (6 h) and sustained (6-72 h) accumulation of IFN-gamma transcripts followed by a delayed (12-24 h) up-regulation of IL-10 or IL-13 expression in response to IL-2 + IL-12 or IL-2 + IL-18, respectively. Incubation of DX5+ splenocytes with the combination of IL-2 + IL-12 + IL-18 resulted in up-regulation of IFN-gamma and IL-13 transcripts but down-regulation of IL-10 expression. Furthermore, two distinct populations of cells producing differing amounts of IFN-gamma were observed by intracellular staining after stimulation with IL-2 + IL-12 + IL-18. Last, we demonstrate that DX5+ cells respond to IL-18 independently of IL-12, as cells from both wild-type and IL-12Rbeta2KO mice produce IFN-gamma and IL-13 in response to IL-2 + IL-18.