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Udgivelsesdato: 2003-Aug-15, We report that CCR3 is not expressed on freshly isolated peripheral and germinal B cells, but is up-regulated after stimulation with IL-2 and IL-4 (approximately 98% CCR3(+)). Ligation of CCR3 by eotaxin/chemokine ligand (CCL) 11 induces apoptosis in IL-2- and IL-4-stimulated primary CD19(+) (approximately 40% apoptotic cells) B cell cultures as well as B cell lines, but has no effect on chemotaxis or cell adhesion. Freshly isolated B cells express low levels of CD95 and CD95 ligand (CD95L) (19 and 21%, respectively). Expression is up-regulated on culture in the presence of a combination of IL-2, IL-4, and eotaxin/CCL11 (88% CD95 and 84% CD95L). We therefore propose that ligation of such newly induced CCR3 on peripheral and germinal B cells by eotaxin/CCL11 leads to the enhanced levels of CD95 and CD95L expression. Ligation of CD95 by its CD95L expressed on neigboring B cells triggers relevant death signaling pathways, which include an increase in levels of Bcl-2 expression, its functional activity, and the release of cytochrome c from the mitochondria into the cytosol. These events initiate a cascade of enzymatic processes of the caspase family, culminating in programmed cell death. Interaction between CCR3 and eotaxin/CCL11 may, besides promoting allergic reactions, drive activated B cells to apoptosis, thereby reducing levels of Ig production, including IgE, and consequently limit the development of the humoral immune response. The apoptotic action of eotaxin/CCL11 suggests a therapeutic modality in the treatment of B cell lymphoma.

We report that NF-AT1 and NF-AT4 are expressed cytoplasmically in resting eosinophils, whereas NF-AT2 and NF-AT3 have not been seen. Likewise, NF-AT1 mRNA and NF-AT4 mRNA have been detected in resting eosinophils, and their levels can be significantly up-regulated by the Th2-associated cytokines IL-4 and IL-5. There is no detectable NF-AT protein expression in the nuclei of resting eosinophils. However NFATs appear in the nuclei of IL- 4-, IL-5-, or ionomycin-stimulated eosinophils. Only NF-AT1 and NF-AT4, but not NF-AT2 and NF-AT3, have translocated into the nuclei in IL-4- or IL5- stimulated eosinophils. These findings delineate a novel pathway in the cytokine network in which Th2 lymphocytes 'control' eosinophils via the release of IL-4 and IL-5, and activation of NF-AT in eosinophils. The findings also suggest that a later feedback 'talking' may exist between eosinophils and Th2 lymphocytes.

Background: A growing body of evidence suggests that proinflammatory cytokines play a role in allergic inflammation by attracting and activating inflammatory cells. In this study, we have investigated the relationship between interleukin-8 (IL-8) in nasal lavage fluid and the local activation of eosinophils and neutrophils following nasal allergen challenge of allergic patients. Methods: Nasal challenges were performed with grass pollen extract in 14 allergic patients and 5 nonallergic controls. Nasal lavage fluid was collected repeatedly for 10 h, and the levels of eosinophil cationic protein (ECP) and myeloperoxidase (MPO) were used as markers of eosinophil and neutrophil activation, respectively. The levels of these molecules were compared with that of IL-8 in nasal lavage fluid. Results: Allergen challenge of allergic patients produced a significant late-phase increase in the levels of ECP and MPO. Furthermore, the level of MPO showed a highly significant correlation with the level of IL-8 in lavage fluid (r = 0.8, p < 0.0001), whereas there was no significant relationship between the levels of ECP and IL-8. Conclusion: Interestingly, our findings suggest that both eosinophils and neutrophils are activated following nasal allergen challenge. In addition, our results are consistent with the hypothesis that IL-8 acts as a chemoattractant/activator of neutrophils during the late phase of the allergic inflammation. In contrast, we were not able to demonstrate any significant relationship between the level of IL-8 in lavage fluid and the activation of eosinophils.

Human mast cells can be divided into two subtypes: MC(TC) cells, which contain tryptase and chymase, and MC(T) cells, which contain tryptase only. Herein we have used a combination of histamine, tryptase and chymase immunohistochemistry as a novel approach to the study of mast cells. Using this technique, we have discovered a new type of MC(TC) mast cell in biopsies of the nasal mucosa from healthy subjects and allergic patients. These mast cells have histamine-positive, dendrite-like cellular processes. Some cells have only one slender process, whereas other cells have several long processes extending from different parts of the cell body. Some of the cellular processes divide into two or three terminal branches, and histamine is sometimes found in small swellings along the course of the processes. Our findings contribute new aspects to the concept of mast cell heterogeneity. Thus, human mast cells may vary not only with respect to mediator content, but also with respect to gross morphologic features such as the presence of dendrite-like cellular processes. The recognition of this extreme heterogeneity may be an important step toward a better understanding of mast cell biology.