Soluble syndecan I (CD138) released by MRL/Lpr T cells enhances APRIL-mediated lupus B cell survival and differentiation

Abstract High level of soluble serum syndecan-1 (CD138), a heparan sulfate–bearing proteoglycan, in systemic lupus erythematosus (SLE) patients correlates with disease activity and lupus nephritis. Mechanisms responsible for the increase in serum CD138 and the immunopathological function of serum CD138 in lupus development remain poorly understood. In this study, recapitulating the findings in SLE patients, we found a sharp increase in serum CD138 levels parallel to the progression of disease in MRL/Lpr (lupus prone) mice. Although TCRβ+CD138+ T cells expand with age in MRL/Lpr mice, TCRβ+CD138− cells are the likely source of circulating CD138 as the transfer of TCRβ+CD138− cells, but not TCRβ+CD138+ cells, led to an increase in serum CD138 in the recipient mice. We found that CD138 expressed on lupus T cells was resistant to cleavage by MMP9 and collagenase, but it was very sensitive to trypsin. We also found high levels of trypsin production by TCRβ+CD138− cells. Suggesting a role for trypsin expressed by these cells in the elevated serum CD138 in lupus mice, trypsin produced by TCRβ+CD138− cells effectively cleaved CD138 from T cells. Interestingly, soluble CD138 was able to bind APRIL and enhance APRIL-mediated ERK activation and B cell differentiation. The ability of CD138 to potentiate APRIL-induced B cell differentiation was dependent on TACI expression, as the synergistic effect of APRIL and CD138 on plasma cell formation was strongly ablated on TACI deficient B cells. These findings reveal a role for soluble CD138 in B cell differentiation and autoreactive antibody production in MRL/Lpr mice. Understanding the mechanisms by which soluble CD138 is produced and how it functions may reveal novel druggable targets for lupus disease.