VLA-4-fibronectin interaction is required for the terminal differentiation of human bone marrow cells capable of spontaneous and high rate immunoglobulin secretion.

Abstract

SummaryHuman bone marrow (BM) is a relevant site for immunoglobulin (Ig) generation in vivo. The occurrence of BM cells capable of spontaneous and high rate Ig secretion for 14 d in vitro has been described previously. Accordingly, these cells provide a suitable model for studying terminal B cell maturation within the BM. We have reported recently that these BM cells are not totally differentiated when isolated from the body, as they require inductive signals from adherent stromal BM cells to complete their maturation. Interleukin (IL)-6 produced by these adherent BM cells was identified as one such signal. The present work shows that II.-6 was necessary, but not suf~cient, for the induction of BM Ig-secreting cells, since the cytokine was unable to restore missing IgG in nonadherent BM cell cultures. Supernatants (SN) obtained from cultures of stromal adherent BM cells, either freshly isolated or derived from long-term BM culture (LTBMC), restored Ig secretion by nonadherent BM cells, suggesting that additional soluble factors from BM stromal cells were required. Fibronectin (FN) was identified as that factor, as can be deduced from the following findings: (a) stromal, but not nonadherent, BM cells constitutively produced FN; (b) anti-FN antibodies markedly reduced the IgG secretion in cultures of BM mononuclear cells (BMMC), and blocked the inductive effect of stromal cell SN on nonadherent BM cells, and such a blockade could be reversed by exogenous FN; and (c) finally, although neither IL-6 nor FN alone exerted any effect, the combination of both factors induced optimal Ig secretion by nonadherent BM cells. Furthermore, VLA-4 molecules seemed to be the FN receptor that was active in this culture system, as indicated by: (a) BM Ig-secreting cells exhibited the phenotype VLA-4 + VLA-5-; (b) mAbs directed to VLA-4 (anti-CD29 and anti-CD49d), but not those directed to other adhesion molecules, inhibited Ig secretion by BMMC cultures, and this effect was reversed by FN; (c) the inductive role of the entire FN molecule could be replaced by a fragment containing the CS-1 region, but not by a fragment containing the RGDS sequence; and (d) only mAbs anti-CD49d capable of blocking VLA-4-FN interaction inhibited induction by either the FN or the CS-l-containing fragment of FN. These results suggest that, in addition to II~6, the interaction of FN produced by stromal BM cells with VLA-4 molecules present on the surface of BM producers is critical for the latter cells to differentiate into the prolonged and high rate Ig-secreting stage characteristic of these cells. Therefore, cells from the marrow microenvironment might contribute to the terminal maturation of Ig-secreting BM cells in vivo.

Extracellular vesicles from bone marrow‐derived mesenchymal stromal cells support ex vivo survival of human antibody secreting cells

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IFN‐β therapy modulates B‐cell and monocyte crosstalk via TLR7 in multiple sclerosis patients

“…IL-6 promotes terminal differentiation of B cells to plasma cells [23,37] and exerts also a pronounced effect on the survival and/or Ig secretion [38]. BAFF regulates, in tandem with APRIL (a proliferation-inducing ligand), B-cell survival, differentiation and class switching, determines the size of the peripheral B-cell pool and is essential for maintenance of the peripheral B-cell repertoire and initiation of T-cell independent B-cell responses [39].…”

A Division-Linked Mechanism for the Rapid Generation of Ig-Secreting Cells from Human Memory B Cells

“…Thus, acquisition of CD38 expression may correlate with selection into a population of T cell stimulation-independent, rapidly proliferating plasma cell precursors, which contribute to an initial expansion of the selected population of ISCs (9,10,47,49,54). The rapidly dividing CD38 ϩ ISCs presumably then acquire altered homing characteristics, resulting in their migration to sites including bone marrow (55,56), where they undergo terminal differentiation to yield long-lived quiescent CD38 ϩ plasma cells (38,45,52,53,57,58). In this way, Ig produced by the selected ISCs will be sustained for long periods even after Ag clearance (2,14).…”