Circulating CD138 (syndecan-1) enhances APRIL-mediated autoreactive B cell survival and differentiation in MRL/Lpr mice

Abstract

High levels of serum CD138, a heparan sulfate-bearing proteoglycan, correlates with increased disease activity in systemic lupus erythematosus (SLE) patients. Mechanisms responsible for serum CD138 production and its biological function in SLE disease remain poorly understood. In this study, corroborating patient data, we detected an increase in serum CD138 in MRL/Lpr mice parallel to disease activity. Although TCR{beta}+CD138+ T cells expand in MRL/Lpr mice as the disease progresses, surprisingly, TCR{beta}+CD138- cells were the primary source of circulating CD138 as the transfer of TCR{beta}+CD138- cells to young MRL/Lpr mice, but not TCR{beta}+CD138+ cells, resulted with higher serum CD138 in the recipient mice. We found that elevated trypsin, expressed by TCR{beta}+CD138- cells, was able to cleave CD138 from T cells. Moreover, suggesting the contribution of cleaved CD138 to the increase in blood CD138, trypsin inhibitors defined trypsin inhibitor (DTI) or leupeptin increased CD138 expression on TCR{beta}+CD138- cells. Furthermore, soluble CD138 was able to bind a proliferation inducing ligand (APRIL) and enhanced APRIL-mediated plasma cell generation and autoreactive antibody production through the phosphorylation of extracellular-signal-regulated kinase (ERK) in B cells. APRIL receptor, transmembrane activator, calcium modulator, and cyclophilin ligand interactor (TACI) was involved in the enhancement of APRIL activity by CD138, as the synergistic effect of APRIL and CD138 was ablated on TACI deficient B cells. These findings indicate a regulatory role for soluble CD138 in B cell differentiation and autoreactive antibody secretion in SLE disease.