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Salmonella Induces a Switched Antibody Response without Germinal Centers That Impedes the Extracellular Spread of Infection¹

Medical Research Council Centre for Immune Regulation, University of Birmingham, Birmingham, United Kingdom

T-dependent Ab responses are characterized by parallel extrafollicular plasmablast growth and germinal center (GC) formation. This study identifies that, in mice, the Ab response against Salmonella is novel in its kinetics and its regulation. It demonstrates that viable, attenuated Salmonella induce a massive early T-dependent extrafollicular response, whereas GC formation is delayed until 1 mo after infection. The extrafollicular Ab response with switching to IgG2c, the IgG2a equivalent in C57BL/6 mice, is well established by day 3 and persists through 5 wk. Switching is strongly T dependent, and the outer membrane proteins are shown to be major targets of the early switched IgG2c response, whereas flagellin and LPS are not. GC responses are associated with affinity maturation of IgG2c, and their induction is associated with bacterial burden because GC could be induced earlier by treating with antibiotics. Clearance of these bacteria is not a consequence of high-affinity Ab production, for clearance occurs equally in CD154-deficient mice, which do not develop GC, and wild-type mice. Nevertheless, transferred low- and high-affinity IgG2c and less efficiently IgM were shown to impede Salmonella colonization of splenic macrophages. Furthermore, Ab induced during the infection markedly reduces bacteremia. Thus, although Ab does not prevent the progress of established splenic infection, it can prevent primary infection and impedes secondary hemogenous spread of the disease. These results may explain why attenuated Salmonella-induced B cell responses are protective in secondary, but not primary infections.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from the Medical Research Council and the Royal Society.

² Address correspondence and reprint requests to Dr. Adam F. Cunningham, Room 432, Institute Biomedical Research, University of Birmingham, Birmingham B15 2TT, U.K. E-mail address: A.F.Cunningham{at}bham.ac.uk

³ Abbreviations used in this paper: WT, wild type; EF, extrafollicular; AID, activation-induced cytidine deaminase; Bcl6, B cell lymphoma 6; GC, germinal center; OMP, outer membrane protein of S. typhimurium.

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