TY - JOUR
T1 - A common polymorphism in the SFTPD gene influences assembly, function, and concentration of surfactant protein D
AU - Leth-Larsen, Rikke
AU - Garred, Peter
AU - Jensenius, Henriette
AU - Meschi, Joseph
AU - Hartshorn, Kevan
AU - Madsen, Jens
AU - Tornoe, Ida
AU - Madsen, Hans O.
AU - Sørensen, Grith
AU - Crouch, Erika
AU - Holmskov, Uffe
PY - 2005/2/1
Y1 - 2005/2/1
N2 - Surfactant protein D (SP-D) plays important roles in the host defense against infectious microorganisms and in regulating the innate immune response to a variety of pathogen-associated molecular pattern. SP-D is mainly expressed by type II cells of the lung, but SP-D is generally found on epithelial surfaces and in serum. Genotyping for three single-nucleotide variations altering amino acids in the mature protein in codon 11 (Met11Thr), 160 (Ala 160Thr), and 270 (Ser270Thr) of the SP-D gene was performed and related to the SP-D levels in serum. Individuals with the Thr/Thr11-encoding genotype had significantly lower SP-D serum levels than individuals with the Met/Met11 genotype. Gel filtration chromatography revealed two distinct m.w. peaks with SP-D immunoreactivity in serum from Met/Met11-encoding genotypes. In contrast, Thr/Thr 11 genotypes lacked the highest m.w. form. A similar SP-D size distribution was found for recombinant Met11 and Thr11 expressed in human embryonic kidney cells. Atomic force microscopy of purified SP-D showed that components eluting in the position of the high m.w. peak consist of multimers, dodecamers, and monomers of subunits, whereas the second peak exclusively contains monomers. SP-D from both peaks bound to mannan-coated ELISA plates. SP-D from the high m.w. peak bound preferentially to intact influenza A virus and Gram-positive and Gram-negative bacteria, whereas the monomeric species preferentially bound to isolated LPS. Our data strongly suggest that polymorphic variation in the N-terminal domain of the SP-D molecule influences oligomerization, function, and the concentration of the molecule in serum.
AB - Surfactant protein D (SP-D) plays important roles in the host defense against infectious microorganisms and in regulating the innate immune response to a variety of pathogen-associated molecular pattern. SP-D is mainly expressed by type II cells of the lung, but SP-D is generally found on epithelial surfaces and in serum. Genotyping for three single-nucleotide variations altering amino acids in the mature protein in codon 11 (Met11Thr), 160 (Ala 160Thr), and 270 (Ser270Thr) of the SP-D gene was performed and related to the SP-D levels in serum. Individuals with the Thr/Thr11-encoding genotype had significantly lower SP-D serum levels than individuals with the Met/Met11 genotype. Gel filtration chromatography revealed two distinct m.w. peaks with SP-D immunoreactivity in serum from Met/Met11-encoding genotypes. In contrast, Thr/Thr 11 genotypes lacked the highest m.w. form. A similar SP-D size distribution was found for recombinant Met11 and Thr11 expressed in human embryonic kidney cells. Atomic force microscopy of purified SP-D showed that components eluting in the position of the high m.w. peak consist of multimers, dodecamers, and monomers of subunits, whereas the second peak exclusively contains monomers. SP-D from both peaks bound to mannan-coated ELISA plates. SP-D from the high m.w. peak bound preferentially to intact influenza A virus and Gram-positive and Gram-negative bacteria, whereas the monomeric species preferentially bound to isolated LPS. Our data strongly suggest that polymorphic variation in the N-terminal domain of the SP-D molecule influences oligomerization, function, and the concentration of the molecule in serum.
UR - http://www.scopus.com/inward/record.url?scp=19944430458&partnerID=8YFLogxK
U2 - 10.4049/jimmunol.174.3.1532
DO - 10.4049/jimmunol.174.3.1532
M3 - Article
C2 - 15661913
AN - SCOPUS:19944430458
VL - 174
SP - 1532
EP - 1538
JO - Journal of Immunology
JF - Journal of Immunology
SN - 0022-1767
IS - 3
ER -