TLR4⁺CXCR4⁺ plasma cells drive nephritis development in systemic lupus erythematosus.

Abstract

In patients with systemic lupus erythematosus (SLE), immune tolerance breakdown leads to autoantibody production and immune-complex glomerulonephritis. This study aimed to identify pathogenic plasma cells (PC) in the development of lupus nephritis. PC subsets in peripheral blood and renal tissue of patients with SLE and lupus mice were examined by flow cytometry and confocal microscopy, respectively. Sorting-purified PCs from lupus mice were adoptively transferred into <i>Rag2</i>-deficient recipients, in which immune-complex deposition and renal pathology were investigated. In culture, PCs from lupus mice and patients with SLE were treated with a TLR4 inhibitor and examined for autoantibody secretion by enzyme-linked immunospot assay (ELISPOT). Moreover, lupus mice were treated with a TLR4 inhibitor, followed by the assessment of serum autoantibody levels and glomerulonephritis activity. The frequencies of TLR4⁺CXCR4⁺ PCs in peripheral blood and renal tissue were found significantly increased with the potent production of anti-dsDNA IgG, which were associated with severe renal damages in patients with SLE and mice with experimental lupus. Adoptive transfer of TLR4⁺CXCR4⁺ PCs from lupus mice led to autoantibody production and glomerulonephritis development in <i>Rag2</i>-deficient recipients. In culture, TLR4⁺CXCR4⁺ PCs from both lupus mice and patients with SLE showed markedly reduced anti-dsDNA IgG secretion on TLR4 blockade. Moreover, in vivo treatment with TLR4 inhibitor significantly attenuated autoantibody production and renal damages in lupus mice. These findings demonstrate a pathogenic role of TLR4⁺CXCR4⁺ PCs in the development of lupus nephritis and may provide new therapeutic strategies for the treatment of SLE.