CD18-deficient cells respond to lipopolysaccharide in vitro.

The CD11/CD18 complex of leukocyte adhesion molecules has been shown to bind LPS on the surface of gram negative bacteria and LPS-coated erythrocytes (J. Exp. Med. 164:1876, 1986). LPS elicits several responses in leukocytes including secretion of TNF-alpha and IL-1 beta, and priming for enhanced release of oxygen radicals such as superoxide anion. To determine if expression of CD18 molecules is necessary for these effects of LPS, we have examined the responses of leukocytes from CD18-deficient patients. Three of the patients in this study are characterized for the first time here, and three were described elsewhere. Monocytes and macrophages from CD18-deficient patients synthesized normal amounts of IL-1 beta and TNF-alpha in response to LPS. Further, PMN and monocytes from CD18-deficient patients showed normal priming for enhanced release of superoxide anion in response to LPS. Although a small contribution of CD18 molecules to some responses cannot be ruled out by our data, we may conclude that CD18 molecules are not essential for cellular responses to LPS.

Efficacy and safety of loratadine (10 mg once daily), terfenadine (60 mg twice daily), and placebo in the treatment of seasonal allergic rhinitis.

A total of 317 patients received loratadine, 10 mg once daily, terfenadine 60 mg twice daily, or placebo in a 14-day, double-blind, randomized study in seasonal allergic rhinitis. Four nasal and four nonnasal symptoms were evaluated. At the end point evaluation, mean total scores of combined nasal and nonnasal symptoms decreased from baseline (improved) 46%, 44%, and 35%, respectively, for loratadine, terfenadine, and placebo. The difference between loratadine and placebo treatment was significant (p = 0.03). Loratadine was particularly effective compared with placebo in relieving nasal discharge, sneezing, and itching/burning eyes. Therapeutic response to treatment was good or excellent in 66 (64%) of 103 loratadine-treated patients, 58 (56%) of 104 terfenadine-treated patients, and 48 (47%) of 102 placebo-treated patients. Adverse experiences reported during the study were usually mild or moderate and were not significantly different among the three treatment groups. Sedation (somnolence) was reported by 10 loratadine-treated patients, seven terfenadine-treated patients, and eight placebo-treated patients. Loratadine, 10 mg once daily, was comparable to terfenadine, 60 mg twice daily, and significantly superior to placebo in the symptomatic relief of seasonal allergic rhinitis.

Cytokine-induced respiratory burst of human neutrophils: dependence on extracellular matrix proteins and CD11/CD18 integrins.

Human polymorphonuclear leukocytes (PMN) released large quantities of hydrogen peroxide in response to tumor necrosis factor, but only when the cells were adherent to surfaces coated with extracellular matrix proteins. The PMN did not respond when exposed to cytokines and matrix proteins in suspension, or when exposed to cytokines while adherent to surfaces coated with stearic acid. PMN from children with genetic deficiency of the CD11/CD18 integrins underwent a normal respiratory burst upon adherence to uncoated polystyrene, but not in response to tumor necrosis factor when tested on polystyrene that was coated with serum, fibronectin, vitronectin, fibrinogen, thrombospondin, or laminin. Anti-CD18 antibodies, alone of sixteen antibodies tested, induced a similar defect in PMN from normal donors, when the PMN were tested on surfaces coated with serum, fibrinogen, thrombospondin, or laminin; no defect was induced by the anti-CD18 monoclonal antibody IB4 in normal PMN tested on surfaces coated with fibronectin or vitronectin. Thus, for cytokines to induce a respiratory burst in PMN, the cells must be able to use CD11/CD18 integrins and must interact with matrix proteins in the solid phase. CD11/CD18, which is already known to serve as a receptor for fibrinogen, may also be a receptor for thrombospondin and laminin. Finally, receptor(s) exist on PMN for fibronectin and vitronectin which are not blocked by the anti-CD18 antibody IB4 but which are nonetheless CD11/CD18 dependent.

CR3 (CD11b/CD18) expresses one binding site for Arg-Gly-Asp-containing peptides and a second site for bacterial lipopolysaccharide.

Polymorphonuclear leukocytes (PMN) from three patients deficient in the CD18 family of receptors (LFA-1, CR3, and p150,95) exhibited an inability to bind erythrocytes coated with C3bi or bacterial LPS. These observations confirm that the CD18 family, and CR3 in particular, can bind the structurally dissimilar molecules C3bi and LPS. Further studies showed that LPS and C3bi bind to CR3 at distinct sites. mAb OKM10 against CR3 blocked binding of C3bi to PMN but did not block the binding of LPS. In contrast, mAb 904, directed against a different epitope on CR3, blocked binding of LPS to PMN but not binding of C3bi, thus suggesting that different regions of CR3 were involved in binding these two ligands. In addition, synthetic peptides based on the sequence in C3bi recognized by CR3 competitively blocked the binding of C3bi to CR3 but did not block the binding of LPS. Rather, occupation of the peptide binding site on CR3 by the synthetic peptides enhanced binding of LPS. These results indicate that CR3 has two distinct binding sites, one that recognizes ligands composed of protein and a second that recognizes LPS.

Reticuloendothelial system Fc receptor function in systemic lupus erythematosus: effect of decreased sensitization on clearance of autologous erythrocytes.

Recent reports of reticuloendothelial system Fc receptor function using anti-Rh(D) coated red blood cells (RBC) provide conflicting data regarding the degree of abnormality in systemic lupus erythematosus (SLE). The effect of different sensitizing doses of anti-Rh(D) on Fc receptor function was evaluated in 10 controls and 9 patients with SLE (5 with renal disease, 4 without) using 1 microgram anti-Rh(D) (6,700 molecules anti-Rh(D)/RBC by saturation analysis) and 0.125 microgram anti-Rh(D) (1,100 molecules/RBC). At the lower sensitizing dose the sensitivity of the assay was significantly increased. To correctly interpret the significance of studies of Fc receptor function from different centers, it is necessary to know the exact sensitizing doses used for each study.

Reticuloendothelial system Fc receptor function in systemic lupus erythematosus.

Reticuloendothelial system Fc receptor function was measured in 10 patients with systemic lupus erythematosus (SLE) taking corticosteroids, 10 SLE patients not receiving corticosteroids and in 19 controls, 9 of whom were corticosteroid-dependent asthmatics and 10 of whom were healthy. Clearance studies were performed using autologous 51 Cr-labeled erythrocytes that had been sensitized with human IgG anti-Rh(D) [6,700 molecules/cell]. The clearance curves could be split into a fast (t1/2 fast) and a slow (t1/2 slow for any of the groups of patients. The results were correlated with serum C3, C4, DNA-binding, fluid phase 125I-Clq binding, a disease activity index, corticosteroid dose and duration of therapy with corticosteroids. The only significant correlation was an inverse correlation of C4 with the t1/2 slow in SLE patients not on corticosteroids (r=- 0.71, p less than 0.05). The t1/2 slow of the 3 SLE patients with active nephritis (86 +/- 40 min) was significantly different from the 17 SLE patients with inactive nephritis or normal renal function (37 +/- 5 min) (P less than 0.05). We conclude that there is no overall defect of Fc receptor function in our patients with SLE although there is decreased clearance in patients with active lupus nephritis.