The establishment of the plasma cell survival niche in the bone marrow

Abstract

Antibodies continuously secreted by plasma cells play a central role in humoral immune protection of the organism. These plasma cells are generated during the germinal center reaction, and it is likely that they here acquire the potential to develop into long-lived cells. To achieve longevity, these cells require factors provided by the microenvironment. Indeed, only a few of the plasmablasts arising during an immune response will differentiate into mature plasma cells, which may survive for decades in specialized survival niches in the bone marrow. Here, we discuss how the survival niche in the bone marrow is established and what is known about the cell-cell interactions needed to support the long-term survival of plasma cells. A particular emphasis is put on the role of eosinophils, which have been shown to be key providers of plasma cell survival factors. The data suggest that the reticulum of bone marrow stromal cells supports a dynamic survival niche, in which long-lived plasma cells are provided with essential factors by a continuously turning over population of eosinophils and other cells.

Gene Therapy Delivery of Myelin Oligodendrocyte Glycoprotein (MOG) via Hematopoietic Stem Cell Transfer Induces MOG-Specific B Cell Deletion

“…Mature plasma B cells, however, no longer require Ag stimulation for survival or Ab production and as a result downregulate CD20, which leads to resistance to rituximab treatment (56). Mature plasma B cells are highly dependent on their microenvironment for survival factors, and in the BM, this microenvironment is made up primarily of stromal cells and eosinophils, among other immune cells that themselves are susceptible to chemotherapy (57,58). Therefore, although plasma cells themselves can be difficult to target, the BM lymphopenia associated with chemotherapy preconditioning may itself be enough to ablate the survival niches that plasma cells rely on.…”

STAT-3 Activation by Differential Cytokines Is Critical for Human In Vivo–Generated Plasma Cell Survival and Ig Secretion

“…Among others, these include BAFF, APRIL, IGF-1, VEGF, and SDF-1a, whose signaling mechanisms are not primarily mediated through JAK-STAT pathways (19,24,31,46). Experiments in mice PCs and human mucosal PCs support the view that some of these latter factors cooperate with STAT-3-activating cytokines (namely, IL-6) to induce prolonged PC survival (19,24,31,46,47). Present data reveal that in human PCs, the expression of the receptors for these cytokines is highly heterogeneous.…”

“…These latter are generated in tissue niches, which provide the PCs with appropriate survival factors. The different auxiliary cell types, and the cytokines and other molecules reported as participants in PC survival niches have been recently revised (24,31). In a previous study, we have demonstrated that human SLO, but not BM, PCs express IL-21R and respond to IL-21 by activating STAT-3 and increasing their survival (32).…”

The Adult Hematopoietic Niches — Cellular Composition, Histological Organization and Physiological Regulation

“…CXCL12, some adhesion molecules principally, VCAM1 constitutively expressed by BM stromal cells, and extracellular matrix molecules, such as fibronectin and hyaluronic acid [124] contribute to their retention, but remarkably many arriving plasmablasts fail to establish in the BM. Possible mere competence between arriving plasmablasts, maturing pre-or pro-B cells and/or pre-existing long-lived plasma cells by the space or, more specifically, by the CXCL12-expressing niches could explain these results [125]. Another remarkable finding is that about 50% of the recent immigrant plasmablasts interact with eosinophils (Eos), a smaller number with MØ and some with megakariocytes [126,127].…”

“…At this point it is important to remark that in vitro studies have shown IL5, IL6, TNFα, BAFF (B-cell activating factor), APRIL (a proliferation-inducing ligand) and CXCL12 as well as fibronectin, CD44 and CD28 as plasma cell survival factors [125]. However, in vivo studies have particularly pointed out the importance of APRIL.…”