Scientific Publications by FDA Staff

J Immunol 2008 Jul 15;181(2):976-90

Deficient TACI Expression on B Lymphocytes of Newborn Mice Leads to Defective Ig Secretion in Response to BAFF or APRIL.

Kanswal S, Katsenelson N, Selvapandiyan A, Bram RJ, Akkoyunlu M

Akkoyunlu, M, Ctr Biol Evaluat & Res, Lab Bacterial Polysaccharides, Div Bacterial Parasit & Allergen Prod, 1410 Rockville Pike HFM-428, Rockville, MD 20852 USA Ctr Biol Evaluat & Res, Lab Bacterial Polysaccharides, Div Bacterial Parasit & Allergen Prod, Rockville, MD 20852 USA US FDA, Div Emerging & Transfus Transmitted Dis, Rockville, MD 20852 USA Mayo Clin & Mayo Fdn, Mayo Med Sch, Dept Pediat & Adolescent Med, Mayo Clin, Rochester, MN 55905 USA

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.