| First Author | Liu L | Year | 2021 |
| Journal | J Biol Chem | Volume | 297 |
| Issue | 3 | Pages | 101053 |
| PubMed ID | 34364875 | Mgi Jnum | J:312905 |
| Mgi Id | MGI:6792881 | Doi | 10.1016/j.jbc.2021.101053 |
| Citation | Liu L, et al. (2021) Circulating CD138 enhances disease progression by augmenting autoreactive antibody production in a mouse model of systemic lupus erythematosus. J Biol Chem 297(3):101053 |
| abstractText | Systemic lupus erythematosus (SLE) is a progressive autoimmune disease characterized by high levels of antibodies directed against nuclear antigens. Elevated serum CD138, a heparan sulfate-bearing proteoglycan, correlates with increased disease activity in patients with SLE, but the contribution of CD138 to lupus disease is not known. Corroborating patient data, we detected an increase in serum CD138 in MRL/MpJ-Fas(lpr)/J (MRL/Lpr) mice (a model for SLE disease) parallel to disease activity. Although T-cell receptor beta (TCRbeta)+CD138+ T cells typically expand in MRL/Lpr mice as the disease progresses, surprisingly, TCRbeta+CD138- cells were the primary source of circulating CD138, as the transfer of TCRbeta+CD138- cells, but not TCRbeta+CD138+ cells, to young MRL/Lpr mice resulted in higher serum CD138 in the recipients. We found that trypsin was able to cleave CD138 from TCRbeta+CD138+ cells, and that trypsin was highly expressed in TCRbeta+CD138- cells. Moreover, trypsin inhibitors, the "defined trypsin inhibitor" and leupeptin, increased CD138 expression on TCRbeta+CD138- cells, suggesting a contribution of cleaved CD138 to the increase in blood CD138 levels. Furthermore, soluble CD138 was able to bind "a proliferation-inducing ligand" (APRIL) and enhance APRIL-mediated plasma cell generation and autoreactive antibody production through the phosphorylation of extracellular signal-regulated kinase in B cells. The APRIL receptor "transmembrane activator, calcium modulator, and cyclophilin ligand interactor" was involved in the enhancement of APRIL activity by CD138, as the synergistic effect of APRIL and CD138 was ablated in transmembrane activator, calcium modulator, and cyclophilin ligand interactor-deficient B cells. These findings indicate a regulatory role for soluble CD138 in B-cell differentiation and autoreactive antibody production in SLE disease. |
