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* Laboratory of Bacterial Polysaccharides, Division of Bacterial, Parasitic, and Allergenic Products, Center for Biologics Evaluation and Research, Rockville, MD 20852;
Division of Emerging and Transfusion Transmitted Diseases, U.S. Food and Drug Administration, Rockville, MD 20852; and
Department of Pediatric and Adolescent Medicine, Mayo Clinic, Mayo Medical School, Rochester, MN 55905
Capsular polysaccharides of encapsulated bacteria do not induce immune response in newborns and the mechanism for this unresponsiveness is not clear. In adults, transmembrane activator and calcium-modulator and cytophilin ligand interactor (TACI) is a TNFR family member molecule with a pivotal role in Ab responses against polysaccharide vaccines. We investigated the expression and the functions of the TNF family cytokines, B cell-activating factor of the TNF family (BAFF) and a proliferation-inducing ligand (APRIL), and their receptors in newborn mice and found that TACI expression on B lymphocytes was dramatically reduced (p < 0.0001) in newborns as compared with adults. More importantly, TACI ligands BAFF or APRIL were unable to induce IgA/IgG/IgM secretion from newborn B lymphocytes. Additionally, TACI expression seems to be important in plasma cell development. Indeed, in contrast to adults, stimulation of newborn B lymphocytes with BAFF or APRIL did not result in up-regulation of CD138 expression. In vitro or in vivo exposure of newborn B lymphocytes to oligodeoxynucleotides (CpG ODN) led to up-regulation of TACI expression on newly formed, follicular, and marginal zone as well as B1 B lymphocyte populations, and rendered them responsive to BAFF- or APRIL-mediated CD138 expression and IgA/IgG secretion. Finally, immunization of newborn BALB/c mice but not TACI knockout mice with CpG ODN containing (4-hydroxy-3-nitrophenyl)acetyl-Ficoll led to development of IgG Abs against (4-hydroxy-3-nitrophenyl)acetyl. These findings demonstrate that low TACI expression may be a critical factor that determines the susceptibility of newborns to infections with encapsulated bacteria and the impaired immunogenicity of polysaccharide vaccines. Finally, CpG ODNs may correct deficient newborn response to polysaccharide vaccines by up-regulating TACI.
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 S.K. was funded by a program at the Center for Biologics Evaluation and Research administered by Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and the U.S. Food and Drug Administration.
2 Address correspondence and reprint requests to Dr. Mustafa Akkoyunlu, Laboratory of Bacterial Polysaccharides, Division of Bacterial, Parasitic and Allergenic Products, Center for Biologics Evaluation and Research, 1410 Rockville Pike (HFM-428), Rockville, MD 20852-1448. E-mail address: mustafa.akkoyunlu{at}fda.hhs.gov
3 Abbreviations used in this paper: TI-II, T-independent type II; CPS, capsular polysaccharide; MZ, marginal zone; DC, dendritic cell; BAFF, B lymphocyte-activating factor belonging to TNF superfamily; TACI, transmembrane activator and calcium-modulator and cytophilin ligand interactor; BCMA, B cell maturation Ag; ODN, oligodeoxynucleotide; KO, knockout; NF, newly formed; FO, follicular; MFI, mean fluorescence intensity; NP-Ficoll, (4-hydroxy-3-nitrophenyl)acetyl-Ficoll.
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