Sustained dapsone-induced remission of hypocomplementemic urticarial vasculitis--a case report

Hypocomplementemic urticarial vasculitis (HUV) is often misdiagnosed. The response to drug therapy may be unsatisfactory, and immunosuppressive therapy may be associated with significant side effects. A 35-year-old patient whose condition was resistant to cyclophosphamide, corticosteroids, pentoxyphylline, cyproheptadine, sulindac, and colchicine was maintained in remission with dapsone, which may be the drug of choice for HUV. Emphysema has been reported to complicate HUV, but this is the first account of vasculitis-related emphysema with no confounding history of tobacco smoke exposure. The relationship of proteolytic injury to the pulmonary and other manifestations is considered, as is the possible role for dapsone in reducing it.     

Spectroscopic evidence for a conformational transition in horseradish peroxidase at very low pH

Resonance Raman (RR), electronic absorption, and circular dichroism (CD) spectroscopies of the ferric, ferrous, and ferrous-CO forms of horseradish peroxidase (HRP-C) at pH 3.1 are reported. The CD spectra in the UV region show only a small decrease in the alpha-helical content upon pH lowering, whereas dramatic changes are observed in the Soret region. The final form of ferric HRP-C is 5-coordinate high-spin heme whose histidine ligand is replaced by a water ligand with a polar character. The electronic and CD spectra show the presence of an intermediate form with a 6-coordinate heme. Therefore, the cleavage of the proximal Fe-imidazole bond is preceded by the binding of a distal water molecule. For the ferrous form of HRP-C, the pH-dependence of the absorption spectra revealed only the native form in the range pH 5-7 and an unfolded form with a Soret maximum at 383 nm at pH 3.1. An intermediate state, characterized by a Soret maximum at 424 nm, was observed only in a transient way, within a few milliseconds. A metastable and a final species are observed also for the ferrous-CO complex at pH 3.1, as proved by isosbestic points in the electronic absorption spectra. The two forms show different RR nu(Fe-C) and IR nu(CO) modes. The metastable form corresponds to a heme where histidine is replaced by water. The final form is due to the displacement of the water ligand by the proximal histidine. We propose a kinetic model to account for our results at pH 3.1 for the ferric, ferrous, and ferrous-CO forms.     

Cyclosporine-insensitive partial signaling and multiple roles of Ca2+ in Fas ligand-induced lysis

The induction of Fas ligand (FasL) mRNA expression and FasL-mediated cytotoxicity in CD8+ CTL is a rapid and transient response to activation via the TCR. This response can also be initiated by pharmacologic activation of two major TCR signaling pathways using phorbol ester (PMA) and calcium ionophore (ionomycin). In these experiments using CD8+ alloreactive cell lines, we demonstrate that induction of FasL mRNA can occur in response to either PMA or ionomycin independently. However, only the ionomycin pathway is sensitive to inhibition by cyclosporine A. Both pathways are blocked by genistein, a general protein tyrosine kinase inhibitor. The magnitude of induction of FasL mRNA is not proportional to the manifested FasL-dependent cytotoxicity. We also found a calcium requirement for cytotoxicity that is unrelated to FasL mRNA induction. In addition to the positive effects of constitutive and induced calcium levels on FasL-mediated cytotoxicity, calcium may play a role in the rapid down-regulation of the response. We also present data suggesting that CD2 and LFA-1 contribute to FasL-mediated cytotoxicity. Together these results suggest pathways by which partial TCR activation could, among the many activation-induced functions of a T cell, selectively lead to the induction of FasL-mediated cytotoxicity that can be regulated by lineage/ activation-dependent accessory molecules on the target.     

Sphingosine-1-phosphate as a ligand for the G protein-coupled receptor EDG-1

The sphingolipid metabolite sphingosine-1-phosphate (SPP) has been implicated as a second messenger in cell proliferation and survival. However, many of its biological effects are due to binding to unidentified receptors on the cell surface. SPP activated the heterotrimeric guanine nucleotide binding protein (G protein)-coupled orphan receptor EDG-1, originally cloned as Endothelial Differentiation Gene-1. EDG-1 bound SPP with high affinity (dissociation constant = 8.1 nM) and high specificity. Overexpression of EDG-1 induced exaggerated cell-cell aggregation, enhanced expression of cadherins, and formation of well-developed adherens junctions in a manner dependent on SPP and the small guanine nucleotide binding protein Rho.     

Rheumatoid-like joint lesions in rabbits injected intravenously with bovine serum

Rheumatoid-like synovial lesions have been produced experimentally in 21% of rabbits receiving intravenous injections of bovine serum by various regimens. They were characterized by lining cell hyperplasia, accumulations, often follicular, of lymphocytes and plasma cells just under the lining layer, sometimes with extensive fibroplasia and pannus formation with cartilage erosion.