Regulation of human immune responses to allergens

Abstract

The incidence of allergic diseases is increasing in the industrialized countries. Epidemiological studies indicate that there is an association between exposure to high levels of endotoxin or cat allergen during infancy and reduced risk of developing allergic diseases later in childhood. The aim of this study was to investigate if allergen extracts from birch, cat and house dust mite induce proinflammatory cytokine production from human innate immune cells. We also examined the levels of soluble CD14 (sCD14) and soluble CD83 (sCD83) in plasma during infancy and whether the early gastrointestinal bacterial colonization pattern could be related to the plasma levels of these two proteins. Finally, we investigated if bacterial components or the immunoregulatory proteins sCD14 and sCD83, would be able to modulate neonatal adaptive immune responses to birch allergen extract. To enable these studies, we optimized an in vitro model for allergic T cell sensitization using human autologous neonatal immune cells.We found that cat allergen extract induced TNF and IL-6 production from human CD14-positive monocytes and macrophages but not from CD14-negative DCs. The cytokine production from monocytes in response to cat allergen extract was reduced by blocking CD14. Both sCD14 and sCD83 were found to be present in the circulation during infancy. The plasma levels of sCD14 increased during the first 18 months of life, whereas the levels of sCD83 in plasma peaked at 4 months of age. Both proteins were found in higher amounts in plasma during infancy relative to plasma from adult individuals. We observed that children who were colonized with S. aureus at an early age had significantly higher levels of sCD14 in plasma at 4 months of age relative to children who were not colonized with this bacterium. Moreover, both neonatal monocytes and monocyte-derived dendritic cells (DCs) released sCD14 in response to S. aureus stimulation in vitro. Children with food allergy tended to have lower levels of sCD14 in plasma and were significantly less colonized with S. aureus relative to healthy children. In contrast, sCD83 was not found to be related to the intestinal bacterial colonization in vivo. However, DCs, but not monocytes, released sCD83 in response to bacterial stimulation in vitro. Birch allergen extract induced high levels of the Th2 cytokine IL-13 from neonatal T cells. Interestingly, in contrast to the Toll-like receptor 2 agonist Pam3Cys, the Toll-like receptor 4 agonist lipopolysaccharide as well as sCD14 or sCD83 were able to suppress birch allergen-induced Th2 differentiation. In conclusion, our results suggest that strong activation of the developing immune system might be involved in down-regulating immune responses that may lead to allergic diseases in children. This effect may be mediated either directly via stimulation of antigen-presenting cells, or indirectly via induction of soluble immunoregulatory proteins such as sCD14 and sCD83.