Journal of Immunology 2014-12-01

C4 Deficiency is a predisposing factor for Streptococcus pneumoniae-induced autoantibody production.

Rama D Yammani, Marcela A Leyva, Ryan N Jennings, Karen M Haas

文献索引：J. Immunol. 193(11) , 5434-43, (2014)

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摘要

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. Copyright © 2014 by The American Association of Immunologists, Inc.