Reduced Ability of Neonatal and Early-Life Bone Marrow Stromal Cells to Support Plasmablast Survival

Abstract

In human infants (<1 year), circulating IgG Abs elicited in response to most T-dependent Ags rapidly decline and return to baseline within a few months after immunization for yet-unknown reasons. In mice immunized between 1 and 4 wk of age, a limited establishment of the bone marrow (BM) pool of long-lived plasma cells is observed. In this study, we show that tetanus toxoid (TT)-specific plasmablasts generated in the spleen are efficiently attracted in vitro and in vivo toward early-life BM stromal cells, which express adult levels of CXCL12. Similarly, adoptively transferred TT plasmablasts efficiently reach the BM compartment of 2-wk-old and adult mice. In contrast, TT plasmablasts fail to persist in the early-life BM compartment, as indicated by the persistence of a significantly lower number of TT plasmablasts in the early-life compartment than in the adult BM compartment 48 h after transfer. This limited persistence is associated with an increased rate of in vivo apoptosis of TT-specific plasmablasts that have reached the early-life BM and with a significantly lower survival rate of TT-specific plasmablasts cocultured on early-life BM stromal cells compared with adult BM stromal cells. Thus, early-life BM stromal cells fail to provide the molecular signals that support plasmablast survival and differentiation into surviving plasma cells.

B Cell Memory to a Serogroup C Meningococcal Conjugate Vaccine in Childhood and Response to Booster: Little Association with Serum IgG Antibody

“…It has been postulated that the poor ability of infants to generate persistent Ab to polysaccharide-protein conjugate vaccines is due to a reduced ability to retain and support long-lived plasma cells in the bone marrow (33,34). Additional factors include immaturity of the follicular dendritic cell network and therefore limited germinal center responses (35), limited costimulatory signals (e.g., CD21), decreased and/or delayed affinity maturation, and limited plasma cell supporting factors.…”

“…It is assumed that the IgG ASC detected are of memory B cell origin [as they have CD27 + memory B cell surface expression (43), and mature plasma cells are unable to survive more than 2-3 d in cell culture (33,44)]; however, there may be different populations of somatically mutated memory B cells originating from the germinal center compartments or preplasma cells (plasmablasts) involved. Further research is required to delineate the subpopulation of B cells stimulated to proliferate in the ELISPOT assay.…”

TACI, unlike BAFF-R, is solely activated by oligomeric BAFF and APRIL to support survival of activated B cells and plasmablasts

“…Survival of CD138 ϩ , tetanus toxoid-specific splenic plasmablasts, obtained at the peak of a booster response, was measured in the presence or absence of various BAFF and APRIL proteins, essentially as described 31,32 (Document S1).…”

Homing and Adhesion Patterns Determine the Cellular Composition of the Bone Marrow Plasma Cell Niche

“…Total cellular RNA of FACS-sorted cells was isolated by RNeasy mini kit (Qiagen, Hilden, Germany) and cDNA synthesized as previously described (24). SYBR Green assays (Invitrogen) and amplicons were designed as previously described (24).…”

“…SYBR Green assays (Invitrogen) and amplicons were designed as previously described (24). The following primers (Invitrogen) were used: IL-6 forward 59-CTATGAAGTTCCTCTCTGCAAGAGACT-39 and IL-6 reverse 59-GGGAAGGCCGTGGTTGTC-39; BAFF forward 59-CCGCGG-CCACAGGAA-39 and BAFF reverse 59-TGAGAGGTCTACATCTTGTT-CTGTTTC-39; APRIL-forward 59-TTTCACAATGGGTCAGGTGGTA-39 and APRIL reverse 59-AGGCATACTTCTGATACATCGGAAT-39; MIF forward 59-GCACAGCATCGGCAAGATC-39 and MIF reverse 59-CAG-CTTACTGTAGTTGCGGTTCTG-39; EEF1A1 forward 59-TCCACTTGG-TCGCTTTGCT-39 and EEF1A1 reverse 59-CTTCTTGTCCACAGCTTT-GATGA-39; and TBP forward 59-TTGACCTAAAGACCATTGCACTTC-39 and TBP reverse 59-TTCTCATGATGACTGCAGCAAA-39.…”