A dominant complement fixation pathway for pneumococcal polysaccharides initiated by SIGN-R1 interacting with C1q.
The intricate system of serum complement proteins provides resistance to infection. A pivotal step in the complement pathway is the assembly of a C3 convertase, which digests the C3 complement component to form microbial binding C3 fragments recognized by leukocytes. The spleen and C3 provide resistance against blood-borne S. pneumoniae infection. To better understand the mechanisms involved, we studied SIGN-R1, a lectin that captures microbial polysaccharides in spleen. Surprisingly, conditional SIGN-R1 knockout mice developed deficits in C3 catabolism when given S. pneumoniae or its capsular polysaccharide intravenously. There were marked reductions in proteolysis of serum C3, deposition of C3 on organisms within SIGN-R1(+) spleen macrophages, and formation of C3 ligands. We found that SIGN-R1 directly bound the complement C1 subcomponent, C1q, and assembled a C3 convertase, but without the traditional requirement for either antibody or factor B. The transmembrane lectin SIGN-R1 therefore contributes to innate resistance by an unusual C3 activation pathway.
Kang
Young-Sun
YS
Laboratory of Cellular Physiology and Immunology and Chris Browne Center for Immunology and Immune Diseases, The Rockefeller University, 1230 York Avenue, New York, NY 10021, USA.
Do
Yoonkyung
Y
Lee
Hae-Kyung
HK
Park
Sung Ho
SH
Cheong
Cheolho
C
Lynch
Rebecca M
RM
Loeffler
Jutta M
JM
Steinman
Ralph M
RM
Park
Chae Gyu
CG
D000818:Animals; D000937:Antigen-Antibody Reactions / Q000276:immunology; D016466:CHO Cells; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D003167:Complement Activation / Q000276:immunology*; D015922:Complement C1q / Q000276:immunology* / Q000378:metabolism*; D003176:Complement C3 / Q000737:chemistry / Q000378:metabolism; D003171:Complement Pathway, Classical / Q000276:immunology; D006224:Cricetinae; D003412:Cricetulus; D005347:Fibroblasts / Q000166:cytology; D006801:Humans; D037181:Lectins, C-Type / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011135:Polysaccharides, Bacterial / Q000276:immunology*; D011485:Protein Binding; D011956:Receptors, Cell Surface / Q000378:metabolism*; D013154:Spleen / Q000166:cytology; D013296:Streptococcus pneumoniae / Q000276:immunology*; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
D015815:Cell Adhesion Molecules; D015922:Complement C1q; D003176:Complement C3; D037181:Lectins, C-Type; D011135:Polysaccharides, Bacterial; D011956:Receptors, Cell Surface; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin