Surfactant proteins A and D protect mice against pulmonary hypersensitivity induced by Aspergillus fumigatus antigens and allergens
Taruna Madan, … , Kenneth B.M. Reid, P. Usha Sarma
Taruna Madan, … , Kenneth B.M. Reid, P. Usha Sarma
Published February 15, 2001
Citation Information: J Clin Invest. 2001;107(4):467-475. https://doi.org/10.1172/JCI10124.
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Article

Surfactant proteins A and D protect mice against pulmonary hypersensitivity induced by Aspergillus fumigatus antigens and allergens

Abstract

Allergic bronchopulmonary aspergillosis (ABPA) is an allergic disorder caused by an opportunistic fungal pathogen, Aspergillus fumigatus (Afu). Lung surfactant proteins SP-A and SP-D can interact with the glycosylated antigens and allergens of Afu, inhibit specific IgE binding to these allergens, and block histamine release from sensitized basophils. We have now examined the therapeutic effect of exogenous administration of human SP-A, SP-D, and a recombinant fragment of SP-D (rSP-D), in a murine model of pulmonary hypersensitivity induced by Afu antigens and allergens, which resembles human ABPA immunologically. The ABPA mice exhibited high levels of Afu-specific IgG and IgE, blood eosinophilia, extensive infiltration of lymphocytes and eosinophils in the lung sections, and a Th2 cytokine response. Treatment with SP-A, SP-D, and rSP-D lowered blood eosinophilia, pulmonary infiltration, and specific Ab levels considerably, which persisted up to 4 days in the SP-A–treated ABPA mice, and up to 16 days in the SP-D– or rSP-D–treated ABPA mice. The levels of IL-2, IL-4, and IL-5 were decreased, while the level of IFN-γ was raised in the splenic supernatants of the treated mice, indicating a marked shift from Th2 to Th1 response. These results clearly implicate pulmonary SP-A and SP-D in the modulation of allergic reactions.

Authors

Taruna Madan, Uday Kishore, Mamta Singh, Peter Strong, Howard Clark, Ejaj M. Hussain, Kenneth B.M. Reid, P. Usha Sarma

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(a) SDS-PAGE (15% wt/vol) analysis of purified preparations of rSP-D und...
(a) SDS-PAGE (15% wt/vol) analysis of purified preparations of rSP-D under reducing as well as nonreducing conditions (Coomassie staining). A recombinant, homotrimeric fragment composed of the eight Gly-Xaa-Yaa repeats, α-helical coiled-coil neck region, and CRD of human SP-D was expressed in E. coli as the inclusion bodies and purified. The recombinant protein behaved as a homotrimer of about 60 kDa when examined by gel filtration chromatography and chemical cross-linking (data not shown). Under reducing conditions (lane 2), it ran as a monomer of about 18 kDa. No higher oligomers were seen when rSP-D was run under nonreducing conditions (lane 3), confirming that the trimerization was not a result of aberrant disulfide bridges between CRD regions. The rSP-D was also assessed for correct folding using disulfide mapping, and its crystallographic structure complexed with maltose in the carbohydrate-binding pockets (A.K. Shrive et al., unpublished data). (b) SDS-PAGE (10% wt/vol) analysis of purified preparations of SP-D and SP-A under reducing conditions (Coomassie staining). The majority of SP-D is composed of a 43-kDa polypeptide chain (lane 1) with faint bands corresponding to dimers and trimers of the 43-kDa chain (confirmed by immunoblotting). Two bands are seen, a major band corresponding to the 32-kDa polypeptide chain of SP-A (lane 2), together with a proportion of nonreducible dimers (64 kDa). Traces of higher oligomers and some aggregates (confirmed by immunoblotting) can also been seen. The nonreduced preparations of SP-D and SP-A behaved on SDS-PAGE as described previously (13).