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

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+CD138+ T cells expand in MRL/Lpr mice as the disease progresses, surprisingly, TCR+CD138- cells were the primary source of circulating CD138 as the transfer of TCR+CD138- cells to young MRL/Lpr mice, but not TCR+CD138+ cells, resulted with higher serum CD138 in the recipient mice. We found that elevated trypsin, expressed by TCR+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+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.

Clinically identifiable autoreactivity is common in severe SARS-CoV-2 Infection

Severe SARS-CoV-2 infection is linked to the presence of autoantibodies against multiple targets, including phospholipids and type-I interferons. We recently identified activation of an autoimmune-prone B cell response pathway as correlate of severe COVID-19, raising the possibility of de novo autoreactive antibody production during the antiviral response. Here, we identify autoreactive antibodies as a common feature of severe COVID-19, identifying biomarkers of tolerance breaks that may indicate subsets of patients that may particularly benefit from immunomodulation.

Disease stage-specific pathogenicity of CD138 (syndecan 1)-expressing T cells in systemic lupus erythematosus

ABSTRACTObjectiveTo identify and characterize CD138 (syndecan 1)-expressing T cells in SLE-prone mice.MethodsWe characterized CD138-expressing T cells in MRL/Lpr mice by flow cytometry assay and by gene analysis. Functional properties of TCRβ+CD138+ cells were assessed either by activating through TCR or by co-incubating with purified B cells in the presence of auto-antigens. Purified TCRβ+CD138+ cells were adoptively transferred into MRL/Lpr mice and lupus disease was assessed by measuring serum auto-antibodies, proteinuria and by histopathological evaluation of kidney.ResultsWe found that the frequency of TCRβ+CD138+ cells was significantly higher in MRL/Lpr mice than in wild-type MRL mice (p < 0.01), and the increase in their numbers correlated with disease severity. Majority of the TCRβ+CD138+ cells were CD4 and CD8 double-negative and 20% were CD4. Compared to TCRβ+CD138− cells, TCRβ+CD138+ cells exhibited central memory phenotype with reduced ability to proliferate, and produce the cytokines IFNγ and IL-17. When co-cultured with B cells, the ability of TCRβ+CD138+ cells to promote plasma cell formation and autoreactive antibody production was dependent on the presence of auto-antigens and CD4 co-receptor expression. Surprisingly, adoptively transferred TCRβ+CD138+ cells slowed down the disease progression in young MRL/Lpr mice but had the opposite effect when DNA was co-administered or when TCRβ+CD138+ cells were transferred into older MRL/Lpr mice with established disease.ConclusionHere, we provided evidence for the pathogenic role of CD138-expressing T cells when auto-antigens are exposed to immune system. Thus, monitoring the changes in TCRβ+CD138+ cell-frequency may serve as a tool to assess SLE severity. Moreover, CD138-expressing T cells may be targeted to alleviate lupus progression.