title: C4 Deficiency is a predisposing factor for Streptococcus pneumoniae-induced autoantibody production.
abstract: Reductions in C4 levels may predispose individuals to infection with encapsulated bacteria as well as autoimmunity. In this study, we examined the role C4 has in protection against Streptococcus pneumoniae-induced autoimmunity. Mild respiratory infection with serotype 19F pneumococci selectively induced systemic anti-dsDNA IgA production in naive C4(-/-) mice, but not in C3(-/-) or wild-type mice. Systemic challenge with virulent serotype 3 pneumococci also induced anti-dsDNA IgA production in immune C4(-/-) mice. Remarkably, pneumococcal polysaccharide (PPS) vaccination alone induced C4(-/-) mice to produce increased anti-dsDNA IgA levels that were maintained in some mice for months. These effects were most pronounced in female C4(-/-) mice. Importantly, immunization-induced increases in anti-dsDNA IgA levels were strongly associated with increased IgA deposition in kidneys. Cross-reactivity between pneumococcal Ags and dsDNA played a partial role in the induction of anti-dsDNA IgA, but a major role for PPS-associated TLR2 agonists was also revealed. Administration of the TLR2/4 antagonist, OxPAPC, at the time of PPS immunization completely blocked the production of anti-dsDNA IgA in C4(-/-) mice without suppressing PPS-specific Ab production. The TLR2 agonist, Pam3CSK4, similarly induced anti-dsDNA IgA production in C4(-/-) mice, which OxPAPC also prevented. LPS, a TLR4 agonist, had no effect. Pam3CSK4, but not LPS, also induced dsDNA-specific IgA production by C4(-/-) splenic IgA(+) B cells in vitro, indicating that TLR2 agonists can stimulate autoantibody production via B cell-intrinsic mechanisms. Collectively, our results show an important role for C4 in suppressing autoantibody production elicited by cross-reactive Ags and TLR2 agonists associated with S. pneumoniae.
authors.affiliation: Department of Microbiology and Immunology, Wake Forest School of Medicine, Winston-Salem, NC 27101.
authors.forename: Rama D
authors.initials: RD
authors.lastname: Yammani
authors.affiliation: Department of Microbiology and Immunology, Wake Forest School of Medicine, Winston-Salem, NC 27101.
authors.forename: Marcela A
authors.initials: MA
authors.lastname: Leyva
authors.affiliation: Department of Microbiology and Immunology, Wake Forest School of Medicine, Winston-Salem, NC 27101.
authors.forename: Ryan N
authors.initials: RN
authors.lastname: Jennings
authors.affiliation: Department of Microbiology and Immunology, Wake Forest School of Medicine, Winston-Salem, NC 27101 kmhaas@wakehealth.edu.
authors.forename: Karen M
authors.initials: KM
authors.lastname: Haas
mesh_terms: D000818:Animals; D000917:Antibody Formation / Q000187:drug effects / Q000235:genetics; D001323:Autoantibodies / Q000276:immunology / Q000378:metabolism*; D001402:B-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D002478:Cells, Cultured; D003181:Complement C4 / Q000235:genetics / Q000378:metabolism*; D003429:Cross Reactions; D004247:DNA / Q000276:immunology; D005260:Female; D020022:Genetic Predisposition to Disease; D007070:Immunoglobulin A / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D055666:Lipopeptides / Q000008:administration & dosage / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010713:Phosphatidylcholines / Q000008:administration & dosage / Q000494:pharmacology; D011135:Polysaccharides, Bacterial / Q000276:immunology; D013290:Streptococcal Infections / Q000276:immunology*; D013296:Streptococcus pneumoniae / Q000276:immunology*; D051195:Toll-Like Receptor 2 / Q000819:agonists; D051197:Toll-Like Receptor 4 / Q000819:agonists
chemical_list: D001323:Autoantibodies; D003181:Complement C4; D007070:Immunoglobulin A; D055666:Lipopeptides; C508075:Pam(3)CSK(4) peptide; D010713:Phosphatidylcholines; D011135:Polysaccharides, Bacterial; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; C472349:oxidized-L-alpha-1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine; D004247:DNA