No abstract

The presence of cytokines and the toxic eosinophil granule product major basic protein (MBP) was investigated in nasal aspirates from children with naturally occurring virus-induced asthma exacerbations and compared with levels in nasal aspirates taken from the same children when asymptomatic. Increased levels of MBP accompanied by increased levels of the chemokines RANTES and macrophage-inhibitory protein 1alpha were observed in nasal aspirates from children during the virus-induced exacerbations. Granulocyte-macrophage colony-stimulating factor was mostly undetectable in samples obtained during both symptomatic and asymptomatic periods. Interleukin-5 levels were low, but tended to increase in samples from symptomatic children. These data confirm that the eosinophil product MBP and the eosinophil chemoattractant chemokines RANTES and macrophage-inhibitory protein 1alpha are increased in upper respiratory viral infections associated with asthma exacerbations and suggest an important role for these chemokines in regulating eosinophil influx and activation. These chemokines may represent targets for therapeutic intervention in virus-induced asthma exacerbations.

SUMMARY The immunopathology caused by schistosome helminths varies greatly in humans and among mouse strains. A severe form of parasite egg-induced hepatic granulomatous inflammation, seen in CBA mice, is driven by Th17 cells stimulated by IL-1β and IL-23 produced by dendritic cells that express CD209a (SIGNR5), a C-type lectin receptor (CLR) related to human DC-SIGN. Here, we show that CD209a-deficient CBA mice display decreased Th17 responses and are protected from severe immunopathology. In vitro, CD209a augments the egg-induced IL-1β and IL-23 production initiated by the related CLRs Dectin-2 and Mincle. While Dectin-2 and Mincle trigger an FcRγ-dependent signaling cascade that involves the tyrosine kinase Syk and the trimolecular Card9-Bcl10-Malt1 complex, CD209a promotes the sustained activation of Raf-1. Our findings demonstrate that CD209a drives severe Th17 cell-mediated immunopathology in a helminthic disease based on synergy between DC-SIGN- and Dectin-2-related CLRs.

Interleukin-4 (IL-4

We investigated the effects of signaling molecule inhibitors on the expression and function of ␤ 1 integrins in Jurkat cells. Jurkat cells expressed ␣ 4 ␤ 1 and ␣ 5 ␤ 1 , with significant levels of constitutively activated ␤ 1 integrins as assessed by labeling with mAb 15/7 that distinguishes between activation states. Adhesion to fibronectin (Fn) was mediated equally through ␣ 4 and ␣ 5 subunits, and was potentiated by the ␤ 1 integrin activating mAb 8A2. Fn adhesion was decreased by okadaic acid through effects on both ␣ 4 ␤ 1 and ␣ 5 ␤ 1 . Tyrphostin A23 also decreased adhesion but was less potent. Neither inhibitor had any effect on the surface expression of total or activated ␤ 1 integrins. The effect of tyrphostin was completely reversed by 8A2; the effect of okadaic acid was only partially reversed. Using Calyculin A, we determined that Jurkat adhesion to Fn was regulated via protein phosphatase 1, independent of the levels of integrins or integrin activation epitopes. Activation of Jurkat cells with a CD3-stimulating mAb enhanced adhesion to Fn and was partially blocked by okadaic acid. These data demonstrate different regulatory pathways for constitutive versus activationdependent adhesion via ␤ 1 integrins, and implicate both tyrosine kinases and serine-threonine phosphatases in integrin function. J. Leukoc. Biol. 64: 753-758; 1998.