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

Kuang-Yueh Chiang,Edmund K Waller,Jacques Galipeau,Shuya Kyu,James Roberson,Frances E Lund,Greg Gibson,Doan C Nguyen,Ronghu Wu,Haopeng Xiao,Troy D Randall,Iñaki Sanz,Swetha Garimalla,Igor Albizua,F Eun-Hyung Lee

doi:10.1038/s41467-018-05853-7

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.

Highlights

Human long-lived plasma cells (LLPC) that persist in the absence of antigen for decades after the original infection are the main source of protective anti-viral long-lived antibodies[1]
Consistent with the pronounced death rate of human antibody-secreting cells (ASC) ex vivo, very few ASC could be detected on day one and were essentially absent by day 3 when cultured in conventional media (Fig. 1a)
We found a total of 2558 genes were differentially expressed between blood ASC and bone marrow (BM) LLPC at a false discovery rate (FDR) of 0.05 (Fig. 4c)

Summary

Introduction

Human long-lived plasma cells (LLPC) that persist in the absence of antigen for decades after the original infection are the main source of protective anti-viral long-lived antibodies[1]. Using IgG Elispots to measure individual plasma cell survival and function, we evaluated cellular cocultures, cell-free secretomes of BM-MSC alone as well as in combination with exogenous cytokines under normoxic and hypoxic conditions This approach allowed us to define a new in vitro system able to sustain human ASC for several months. This analysis identifies new proteins, fibronectin and YWHAZ, in the MSC secretome along with APRIL and specialized conditions (hypoxia) from the BM microniche that play a role in LLPC maturation process of survival

Methods

Results

Conclusion