Interleukin-13 and interleukin-13 receptor in Hodgkin's disease: possible autocrine mechanism and involvement in fibrosis.

AIMS: Hodgkin's disease (HD) is characterized by the presence of Hodgkin and Reed-Sternberg (H-RS) cells against a hyperplastic background of reactive cells such as lymphocytes, histiocytes, plasma cells, eosinophils, neutrophils, and stromal cells. There is ample evidence to suggest that proliferation and survival of HD-derived cells is due to cytokine signalling. Recently, high expression of interleukin (IL)-13 was described in HD-derived cell lines. Here we investigated the possible involvement of IL-13 in the pathophysiology, especially autocrine pathways of H-RS cells. METHODS AND RESULTS: The expression of IL-13 and IL-13 receptor (IL-13R) was determined by immunostaining and reverse transcriptase-polymerase chain reaction in 39 cases of HD, including 17 cases with nodular sclerosis (NS) type, 19 cases with mixed cellularity (MC), and three cases with lymphocyte predominance (LP) type. Expression of IL-13 was confined to H-RS cells and a few lymphocytes. IL-13R was expressed in H-RS cells, lymphocytes, histiocytes, fibroblasts, and endothelial cells. H-RS cells of MC and NS types frequently expressed both IL-13 and IL-13R. However, the number of IL-13-positive H-RS cells was statistically higher in NS-type than in MC-type, but the number of IL-13R was similar. IL-13R-positive fibroblasts were frequently encountered in NS-type. H-RS cells of LP type rarely expressed IL-13. CONCLUSIONS: Our results suggest that IL-13 might be involved in autocrine pathways of H-RS cells and fibrosis at least in NS-type. Our results also indicated that in addition to the morphological and phenotypic differences, the neoplastic cells of LP type might be functionally different from H-RS cells of MC- and NS-types.

Genetic variants of IL-13 signalling and human asthma and atopy.

Asthma and atopy show epidemiological association and are biologically linked by T-helper type 2 (T(h)2) cytokine-driven inflammatory mechanisms. IL-4 operates through the IL-4 receptor (IL-4R, a heterodimer of IL-4Ralpha and either gammac or IL-13Ralpha1) and IL-13 operates through IL-13R (a heterodimer of IL-4Ralpha and IL-13Ralpha1) to promote IgE synthesis and IgE-based mucosal inflammation which typify atopy. Recent animal model data suggest that IL-13 is a central cytokine in promoting asthma, through the stimulation of bronchial epithelial mucus secretion and smooth muscle hyper-reactivity. We investigated the role of common genetic variants of IL-13 and IL-13Ralpha1 in human asthma, considering IgE levels. A novel variant of human IL-13, Gln110Arg, on chromosome 5q31, associated with asthma rather than IgE levels in case-control populations from Britain and Japan [peak odds ratio (OR) = 2.31, 95% CI 1.33-4.00]; the variant also predicted asthma and higher serum IL-13 levels in a general, Japanese paediatric population. Immunohistochemistry demonstrated that both subunits of IL-13R are prominently expressed in bronchial epithelium and smooth muscle from asthmatic subjects. Detailed molecular modelling analyses indicate that residue 110 of IL-13, the site of the charge-modifying variants Arg and Gln, is important in the internal constitution of the ligand and crucial in ligand-receptor interaction. A non-coding variant of IL-13Ralpha1, A1398G, on chromosome Xq13, associated primarily with high IgE levels (OR = 3. 38 in males, 1.10 in females) rather than asthma. Thus, certain variants of IL-13 signalling are likely to be important promoters of human asthma; detailed functional analysis of their actions is needed.

Toward the antibody-catalyzed chemiluminescence. Design and synthesis of hapten.

Hapten 4 was synthesized to generate catalytic antibodies triggering chemiluminescence by catalyzing the decomposition of the 1,2-dioxetane 3. The hapten 4 was so designed as to elicit a negatively charged functional group in the antibody combining site to catalyze the beta-elimination of the protecting group in 3 as well as to lock the protecting group into an energetically favorable anti-periplanar conformation.

Characterization of a catalytic antibody for stereoselective ester hydrolysis--a catalytic residue and mode of product inhibition.

A catalytic antibody which catalyzes stereoselective ester hydrolysis was characterized, and the role of a catalytic Arg residue is discussed in terms of product inhibition. A monoclonal antibody 1C7 generated against the phosphonate 1 was highly stereoselective for (R)-isomer in hydrolyzing racemic ester 2. However, the reaction was almost stoichiometric due to strong inhibition by the product acid 3. One Arg residue in the antibody combining site was essential to the catalysis, and the same Arg was expected to play a dominant role in product inhibition by charge interaction with the negatively charged product acid. Indeed, the antibody experienced much less product inhibition with the hydrolysis of a carbonate ester 7, which yields a neutral alcohol 8 devoid of a negative charge, and exhibited at least 100 turnovers without any loss of activity. In addition, high stereoselectivity for (R)-isomer was still retained. The amino acid sequence and computer modeling of the variable domain of 1C7 suggested that Arg97 in the complementarity-determining region (CDR) of heavy chain was the putative catalytic residue.