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Infection and Immunity, August 2008, p. 3761-3770, Vol. 76, No. 8
0019-9567/08/$08.00+0     doi:10.1128/IAI.00291-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Impaired Opsonization with C3b and Phagocytosis of Streptococcus pneumoniae in Sera from Subjects with Defects in the Classical Complement Pathway{triangledown}

Jose Yuste,1 Ashwin Sen,1 Lennart Truedsson,2 Göran Jönsson,2,3 Liang-Seah Tay,4 Catherine Hyams,1 Helen E. Baxendale,5 Fiona Goldblatt,6 Marina Botto,7 and Jeremy S. Brown1*

Centre for Respiratory Research, Royal Free and University College Medical School, Rayne Institute, London WC1E 6JJ, United Kingdom,1 Department of Laboratory Medicine, Section of Microbiology, Immunology and Glycobiology, Lund University, Lund, Sweden,2 Department of Infectious Diseases, Lund University Hospital, Lund, Sweden,3 Department of Infectious Diseases, Faculty of Medicine, Imperial College, Hammersmith Campus, London W12 0NN, United Kingdom,4 Infectious Diseases and Microbiology Unit, Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, United Kingdom,5 Centre for Rheumatology Research, Royal Free and University College Medical School, 46 Cleveland Street, London W1T 4JF, United Kingdom,6 Molecular Genetics and Rheumatology Section, Faculty of Medicine, Imperial College, Hammersmith Campus, London W12 0NN, United Kingdom7

Received 4 March 2008/ Returned for modification 17 April 2008/ Accepted 2 June 2008

Results from studies using mice deficient in specific complement factors and clinical data on patients with an inherited deficiency of the classical complement pathway component C2 suggest that the classical pathway is vital for immunity to Streptococcus pneumoniae. However, the consequences of defects in classical pathway activity for opsonization with C3b and the phagocytosis of different S. pneumoniae serotypes in human serum are not known, and there has not been a systematic analysis of the abilities of sera from subjects with a C2 deficiency to opsonize S. pneumoniae. Hence, to investigate the role of the classical pathway in immunity to S. pneumoniae in more detail, flow cytometry assays of opsonization with C3b and the phagocytosis of three capsular serotypes of S. pneumoniae were performed using human sera depleted of the complement factor C1q or B or sera obtained from C2-deficient subjects. The results demonstrate that, in human serum, the classical pathway is vital for C3b-iC3b deposition onto cells of all three serotypes of S. pneumoniae and seems to be more important than the alternative pathway for phagocytosis. Compared to the results for sera from normal subjects, C3b-iC3b deposition and total anti-S. pneumoniae antibody activity levels in sera obtained from C2–/– subjects were reduced and the efficiency of phagocytosis of all three S. pneumoniae strains was impaired. Anticapsular antibody levels did not correlate with phagocytosis or C3b-iC3b deposition. These data confirm that the classical pathway is vital for complement-mediated phagocytosis of S. pneumoniae and demonstrate why subjects with a C2 deficiency have a marked increase in susceptibility to S. pneumoniae infections.

* Corresponding author. Mailing address: Centre for Respiratory Research, Department of Medicine, Royal Free and University College Medical School, Rayne Institute, 5 University St., London WC1E 6JJ, United Kingdom. Phone: 44 20 7679 6008. Fax: 44 20 7679 6973. E-mail: jeremy.brown{at}ucl.ac.uk

{triangledown} Published ahead of print on 9 June 2008.

Editor: J. N. Weiser

Infection and Immunity, August 2008, p. 3761-3770, Vol. 76, No. 8
0019-9567/08/$08.00+0     doi:10.1128/IAI.00291-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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