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Circulating CD138 enhances disease progression by augmenting autoreactive antibody production in a mouse model of systemic lupus erythematosus.

ABSTRACT: 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 β (TCRβ)+CD138+ T cells typically expand in MRL/Lpr mice as the disease progresses, surprisingly, TCRβ+CD138- cells were the primary source of circulating CD138, as the transfer of TCRβ+CD138- cells, but not TCRβ+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 TCRβ+CD138+ cells, and that trypsin was highly expressed in TCRβ+CD138- cells. Moreover, trypsin inhibitors, the "defined trypsin inhibitor" and leupeptin, increased CD138 expression on TCRβ+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.

SUBMITTER: Liu L

PROVIDER: S-EPMC8405997 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ObjectiveTo evaluate the specificity of expression patterns of cell-free circulating microRNAs (miRNAs) in systemic lupus erythematosus (SLE).MethodsTotal RNA was purified from plasma, and 45 different specific, mature miRNAs were determined using quantitative reverse transcription-polymerase chain reaction assays. A total of 409 plasma samples were obtained from 364 different patients with SLE, healthy control subjects, and control subjects with other autoimmune diseases. The results in the primary cohort of 62 patients with SLE and 29 healthy control subjects were validated in 2 independent cohorts: a validation cohort comprising 68 patients with SLE and 68 healthy control subjects, and a disease control cohort comprising 20 patients with SLE (19 of whom were from the other validation cohort), 46 healthy control subjects, 38 patients with vasculitis, 18 patients with rheumatoid arthritis, and 20 immunosuppressed patients.ResultsSeven miRNAs were statistically significantly differentially expressed in plasma from patients with SLE. The expression of miRNA-142-3p (miR-142-3p) and miR-181a was increased, and the expression of miR-106a, miR-17, miR-20a, miR-203, and miR-92a was decreased. In addition, the expression of miR-342-3p, miR-223, and miR-20a was significantly decreased in SLE patients with active nephritis. A predictive model for SLE based on 2 or 4 miRNAs differentiated patients with SLE from control subjects (76% accuracy) when validated independently (P < 2 × 10(-9) ). Use of the 4-miRNA model provided highly significant differentiation between the SLE group and disease controls, except for those with vasculitis.ConclusionCirculating miRNAs are systematically altered in SLE. A 4-miRNA signature was diagnostic of SLE, and a specific subset of miRNA profiles was associated with nephritis. All of the signature miRNAs target genes in the transforming growth factor β signaling pathways. Other targets include regulation of apoptosis, cytokine-cytokine receptors, T cell development, and cytoskeletal organization. These findings highlight possible dysregulated pathways in SLE and suggest that circulating miRNA patterns distinguish SLE from other immunoinflammatory phenotypes.

Project description:The diagnosis of Systemic Lupus Erythematosus (SLE) is challenging due to its heterogeneous clinical presentation and lack of robust biomarkers for laboratory testing to distinguish it from other autoimmune or infectious diseases. Current diagnostic criterion relies on a combination of clinical examination and laboratory tests, and it does not readily distinguish between those with active clinical disease from those that are clinically quiescent. Several groups have attempted to apply emerging high throughput profiling technologies to diagnose SLE. Despite showing promising diagnostic potential, many of them are expensive and technically challenging for routine clinical uses. Here we report a pilot study of applying a technically simple and highly customisable leukocyte capture antibody microarray to profile healthy (n=24) and SLE patients (n=60) of various disease activities. Our analysis reveals a set of surface antigen biomarkers that have significant association with SLE. In addition, we present a computational method to calculate a score from the entire microarray profile to obtain a score that correlate most reliably with SLE disease activity. Although the current version of our microarray alone does not match the discriminatory power of the standard laboratory tests (serum dsDNA, complements C3 and C4), the combination of the two yields a test with significantly increased discriminatory ability than what can be achieved individually. This work paves the way for a customised SLE-specific antibody microarray for accurate diagnosis and monitoring of SLE that can be readily translated to routine clinical use. Blood samples were collected from 60 patients of Systemic Lupus Erythematosus (SLE) of different disease activity (11 active, 16 semi-active, and 33 inactive), and compared it with blood samples from 24 healthy blood donors. For each subject, we extracted PBMCs and apply them to a leukocyte capture antibody microarray. The microarray was then scaned by a DotScan™ slide reader (Medsaic; Eveleigh, NSW, Australia). The number of immobilized cells was proportional to the light scattered at each antibody spot. Binding of PBMCs to each antibody dot was monitored by light scatter and averaged between the duplicate spots on each slide. We then performed statistical analysis to identify CD antigen markers that are associated with SLE, as well as determining the potential diagnostic ability of this microarray for SLE.

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Circulating CD138 enhances disease progression by augmenting autoreactive antibody production in a mouse model of systemic lupus erythematosus.

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