Modulation of immune cell functions by human lung surfactant protein SP-D in allergic asthma

Abstract

Lung surfactant protein D (SP-D) is a soluble pattern recognition and innate immune molecule, which has been shown to be protective against lung infection, allergy, asthma and inflammation. SP-D is composed of an N-terminal collagen region and a homotrimeric, C-terminal carbohydrate binding domain (CRD). A recombinant form of trimeric CRD region (rhSP-D) has been shown to offer protection against asthma and inflammation in murine models by bringing down IgE levels, eosinophilia, and causing T helper cell polarisation from a pathogenic Th2 to a protective Th1 phenotype. Thus, rhSP-D can provide a therapeutic effect by dampening asthmatic symptoms in mice. The therapeutic mechanisms include inhibition of allergen-IgE binding and histamine release by sensitized mast cells, downregulation of allergen/antigen-specific IgG and IgE antibodies, pulmonary and peripheral eosinophilia, a shift from Th2 to Th1 cytokine response, interference with airway remodelling processes, and apoptosis- induction in sensitised eosinophils from allergic patients. The majority of the ex vivo and in vivo studies where a therapeutic effect of rhSP-D has been reported can not be explained by hitherto described candidate receptor involvement, especially CD91-calreticulin complex that requires collagen region for its cellular response. Thus, it is pertinent to examine at the cellular and molecular level how a trimeric lectin domain of human SP-D modulates immune cells. This was achieved by firstly expressing, purifying and characterising the recombinant rhSP-D and examining the interaction of rhSP-D with various immune cells such as macrophages, which are potent antigen presenting cells and play a crucial role in the maintenance of the inflammatory and humoral response to allergens. The highlight of this study is the demonstration that rhSP-D interferes with the co-operative binding of allergen-IgE complexes to B cells, and also downregulates expression of CD23, a low affinity IgE receptor (FcεRII), found on B cells. This suggests that inhibition of IgE-facilitated antigen presentation may represent a mechanism whereby SP-D suppresses Th2-driven allergic inflammation. In addition, this study is also the first to establish the calcium-dependent interactions between rhSP-D, CD23 and CD21. The possibility of formation of a trimolecular complex on the B cell surface may account for the suppression of IgE in therapeutic murine models since rhSP-D may interfere with CD21-CD23 mediated IgE production by primed B cells.