Factors of the bone marrow microniche that support human plasma cell survival and immunoglobulin secretion

Abstract

Human antibody-secreting cells (ASC) in peripheral blood are found after vaccination or infection but rapidly apoptose unless they migrate to the bone marrow (BM). Yet, elements of the BM microenvironment required to sustain long-lived plasma cells (LLPC) remain elusive. Here, we identify BM factors that maintain human ASC > 50 days in vitro. The critical components of the cell-free in vitro BM mimic consist of products from primary BM mesenchymal stromal cells (MSC), a proliferation-inducing ligand (APRIL), and hypoxic conditions. Comparative analysis of protein–protein interactions between BM-MSC proteomics with differential RNA transcriptomics of blood ASC and BM LLPC identify two major survival factors, fibronectin and YWHAZ. The MSC secretome proteins and hypoxic conditions play a role in LLPC survival utilizing mechanisms that downregulate mTORC1 signaling and upregulate hypoxia signatures. In summary, we identify elements of the BM survival niche critical for maturation of blood ASC to BM LLPC.

Plasma cells: You are what you eat

“…178,[180][181][182][183][184] The necessity of some of these cell types and secreted cytokines has been disputed, but a common proposed feature of these populations is their ability to secrete pro-survival cytokines and in turn support plasma cell longevity. 190 Culturing these cells under physiological oxygen tension and with MSC supernatants further enhanced survival, suggesting an as yet unexplored role for hypoxia in plasma cell survival. Human plasma cells co-cultured with primary mesenchymal stromal cells (MSCs) survived in in vitro cultures for up to 8 weeks, vs those cultured in media alone, that died within one day.…”

“…133,179 A number of accessory cell types such as eosinophils, basophils, megakaryocytes, regulatory T cells, and mesenchymal cells have all been proposed to enhance plasma cell survival. 190 Functional secretome analyses revealed that fibronectin-1 and the 14-3-3 zeta/delta proteins promote plasma cell survival, suggesting a role for the extracellular matrix proteins. [185][186][187][188][189] The integration of these signals with primary plasma cell metabolism, however, has been understudied with a notable recent exception.…”

“…Human plasma cells co-cultured with primary mesenchymal stromal cells (MSCs) survived in in vitro cultures for up to 8 weeks, vs those cultured in media alone, that died within one day. 190 Functional secretome analyses revealed that fibronectin-1 and the 14-3-3 zeta/delta proteins promote plasma cell survival, suggesting a role for the extracellular matrix proteins. 190 Culturing these cells under physiological oxygen tension and with MSC supernatants further enhanced survival, suggesting an as yet unexplored role for hypoxia in plasma cell survival.…”

“…190 Functional secretome analyses revealed that fibronectin-1 and the 14-3-3 zeta/delta proteins promote plasma cell survival, suggesting a role for the extracellular matrix proteins. 190 Culturing these cells under physiological oxygen tension and with MSC supernatants further enhanced survival, suggesting an as yet unexplored role for hypoxia in plasma cell survival. A deeper understanding of the complex interactions between these cells and systems will undoubtedly provide a more complete basic understanding of the factors that promote plasma cell longevity, as well as malignancies.…”

Understanding and measuring human B‐cell tolerance and its breakdown in autoimmune disease

“…Direct ASC interrogation can be enhanced by recent improvements in the ability to maintain the survival of PB in vitro for several weeks. 59 In turn, in vitro stimulation leading to antibody production can be applied to multiple B-cell populations including transitional, naive, memory, and effector DN B-cells using different activation conditions. 52,60-65 Similar protocols can be applied to ELISPOT detection to obtain a more quantitative measurement at Nevertheless, single-cell cultures afford the ability to test antibodies against multiple antigens (including the use of large antigens arrays) while also providing mRNA for the generation of mAbs derived from the cells of interest for both validation and additional testing and applications.…”