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* Department of Microbiology, University of Heidelberg, Germany;
Research Center Borstel, Borstel, Germany;
Institute for Immunology, University of Heidelberg, Germany;
Department of Internal Medicine, Division of Clinical Pharmacology, University of Munich, Germany;
¶ Max-von-Pettenkofer Institute of Microbiology, University of Munich, Germany;
|| Department of Internal Medicine, Division of Clinical Pharmacology, University of Bonn, Germany
B cells possess functional characteristics of innate immune cells, as they can present Ag to T cells and can be stimulated with microbial molecules such as TLR ligands. Because crude preparations of Staphylococcus aureus are frequently used as polyclonal B cell activators and contain potent TLR2 activity, the scope of this study was to analyze the impact of S. aureus-derived TLR2-active substances on human B cell activation. Peripheral B cells stimulated with chemically modified S. aureus cell wall preparations proliferated in response to stimulation with crude cell wall preparations but failed to be activated with pure peptidoglycan, indicating that cell wall molecules other than peptidoglycan are responsible for B cell proliferation. Subsequent analysis revealed that surface protein A (SpA), similar to BCR cross-linking with anti-human Ig, sensitizes B cells for the recognition of cell wall-associated TLR2-active lipopeptides (LP). In marked contrast to TLR7- and TLR9-triggered B cell stimulation, stimulation with TLR2-active LP and SpA or with crude cell wall preparations failed to induce IgM secretion, thereby revealing qualitative differences in TLR2 signaling compared with TLR7/9 signaling. Notably, combined stimulation with SpA plus TLR2 ligands induced vigorous proliferation of a defined B cell subset that expressed intracellular IgM in the presence of IL-2. Conclusion: S. aureus triggers B cell activation via SpA-induced sensitization of B cells for TLR2-active LP. Combined SpA and TLR2-mediated B cell activation promotes B cell proliferation but fails to induce polyclonal IgM secretion as seen after TLR7 and TLR9 ligation.
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1 This study was supported by the Deutsche Forschungsgemeinschaft Grant DI898/1-1 (to I.B.-D.), the Deutsche Forschungsgomeinschaft Sonderforschungsbereich Grant 576-B11 (to A.S.), and the Deutsche Forschungsgomeinschaft Priority Program "Innate Immunity" Grant SPP 1110 (to S.I. and U.Z.). G.H. is supported by the Bundesministerium für Bildung und Forschung Biofuture 0311896, Deutsche Forschungsgomeinschaft Grants HA 2780/5-1 and Sonderforschungsbereich 571, and the Mildred-Scheel-Stiftung (Deutsche Krebshilfe) Joint Grant 10-2074-Wo 2.
2 Address correspondence and reprint requests to Dr. Isabelle Bekeredjian-Ding, Department of Microbiology, University of Heidelberg, Im Neuenheimer Feld 324, Heidelberg, Germany. E-mail address: isabelle.bekeredjian-ding{at}med.uni-heidelberg.de
3 Abbreviations used in this paper: SpA, surface protein A; BHK, baby hamster kidney; LP, lipopeptide; LTA, lipoteichoic acid; MALP-2, macrophage-activating lipopeptide-2; Nod, nucleotide oligomerization domain; ODN, oligodeoxynucleotide; OG, N-octyl-
-D-glucopyranoside; SAC, S. aureus Cowan I strain; TA, teichoic acid; WTA, wall teichoic acid; HF, hydrofluoridic acid.
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